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Placebo effects have been reported in patients with chronic neuropathic pain. Expected pain levels and positive emotions are involved in the observed pain relief, but the underlying neurobiology is largely unknown. Patients with neuropathic pain are highly motivated for pain relief, and as motivational factors such as expectations of reward, as well as pain processing in itself, are related to the dopaminergic system, it can be speculated that dopamine release contributes to placebo effects in neuropathic pain. Nineteen patients with neuropathic pain after thoracic surgery were tested during a placebo intervention consisting of open and hidden applications of the pain-relieving agent lidocaine (2 mL) and no treatment. The dopamine antagonist haloperidol (2 mg) and the agonist levodopa/carbidopa (100/25 mg) were administered to test the involvement of dopamine. Expected pain levels, desire for pain relief, and ongoing and evoked pain were assessed on mechanical visual analog scales (0-10). Significant placebo effects on ongoing (P ≤ 0.003) and evoked (P ≤ 0.002) pain were observed. Expectancy and desire accounted for up to 41.2% and 71.5% of the variance in ongoing and evoked pain, respectively, after the open application of lidocaine. We found no evidence for an effect of haloperidol and levodopa/carbidopa on neuropathic pain levels (P = 0.071-0.963). Dopamine seemed to influence the levels of expectancy and desire, yet there was no evidence for indirect or interaction effects on the placebo effect. This is the first study to suggest that dopamine does not contribute to placebo effects in chronic neuropathic pain.

Temporomandibular joint disorder (TMD) is a complex musculoskeletal disorder that presents with pain, limited jaw opening, and abnormal noises in the temporomandibular joint. Despite the significant impact that TMD has in terms of suffering and financial burden, relatively few new treatments have emerged; therefore, development of novel treatments to treat TMD pain remains a high priority. The rationale of this study was to use a double-blind, vehicle-controlled clinical trial to evaluate the effects of a high-concentration (8%) capsaicin cream on TMD. This is based on the hypothesis that targeting TRP vanilloid subfamily member 1 (TRPV1) for pain control may provide a novel method for pain relief in TMD patients. TRPV1 is primarily expressed on a population of nociceptive-specific neurons and provides a candidate target for the development of pain treatments. Capsaicin is the primary agonist for TRPV1 and has been used previously in relatively low doses (0.025% to 0.075%) as a therapeutic for a variety of pain disorders, including postherpetic neuralgia and osteoarthritis; however, analgesic efficacy remains equivocal. TMD and healthy control subjects were assigned to either an active capsaicin or vehicle control group. The treatments were applied for 2 h and then removed. Quantitative sensory testing (QST) was completed prior to drug application (baseline), 2 h after drug application, and 1 wk later. Perceived pain intensity was measured using a visual analog scale (VAS) following capsaicin or vehicle cream application. Significantly lower pain was reported in the week after application in the capsaicin-treated TMD subjects. For QST measures, there was a decreased thermal pain threshold 2 h after capsaicin application for both the control and TMD groups, but this resolved within a week. Capsaicin had no effect on pressure pain threshold or mechanical sensitivity in both TMD and healthy individuals. This study demonstrates that 8% topical capsaicin therapy is a relatively safe, simple, and effective treatment for patients with TMD. Knowledge Transfer Statement: This study evaluated a novel topical capsaicin therapy for reducing orofacial pain. The results of this study can be used to provide another treatment option for patients with TMD.

A large number of analgesics have failed to prove superiority over placebo in randomized controlled trials (RCTs), and as this has been related to increasing placebo responses, there is currently an interest in specifying predictors of the placebo response. The literature on placebo mechanisms suggests that factors related to patients' expectations of treatment efficacy are pivotal for the placebo response. Also, general characteristics of RCTs have been suggested to influence the placebo response. Yet, only few meta-analyses have directly tested these hypotheses. Placebo data from 9 industrially sponsored, randomized, double-blind, placebo-controlled, multicenter phase III trials in 2017 adult patients suffering from chronic painful osteoarthritis (hip or knee) or low back pain were included. The primary outcome was pain intensity. Based on previous studies, we chose 3 expectancy-related primary predictors: type of active medication, randomization ratio, and number of planned face-to-face visits. In addition, explorative analyses tested whether RCT and patients' characteristics predicted the placebo response. Opioid trials, a high number of planned face-to-face visits, and randomization ratio predicted the magnitude of the placebo response, thereby supporting the expectancy hypothesis. Exploratory models with baseline pain intensity, age, washout length, and discontinuation because of adverse events accounted for approximately 10% of the variability in the placebo response. Based on these results and previous mechanisms studies, we think that patients' perception of treatment allocation and expectations toward treatment efficacy could potently predict outcomes of RCTs.

Milnacipran is a serotonin-norepinephrine reuptake inhibitor that was approved by the U.S. Food and Drug Administration as effective therapy for fibromyalgia (FM) symptoms. However, its analgesic mechanism of action is not well understood. We hypothesized that improvement of mechanical and heat hyperalgesia would be a critical component of overall milnacipran efficacy in FM. We used a novel quantitative sensory testing protocol for assessment of mechanical and heat pain sensitivity that can be used for testing of peripheral and central pain mechanisms and their impact on clinical pain over time. We applied tonic mechanical and heat pain stimuli to 46 patients with FM during a randomized controlled trial with either 50 mg milnacipran (n = 23) or placebo (n = 23) twice daily over 6 weeks. During this trial, mean clinical pain (standard deviation) was evaluated daily, and mechanical and heat pain sensitivity every 2 weeks. At study entry, clinical pain was 5.0 (1.8) and 5.5 (1.8) visual analog scale units for patients with FM randomized to placebo and milnacipran, respectively ( P > .05). Over 6 weeks, clinical pain of patients with FM significantly declined by 15%, but this improvement was not statistically different between milnacipran and placebo. However, repeated measures of mechanical and heat pain sensitivity reliably predicted up to 80% of the variance in clinical FM pain at every time point. Clinical pain and mechanical/heat pain sensitivity of patients with FM steadily declined during this trial, but the effects of milnacipran were not found to be superior to placebo. Repeated measures of mechanical/heat hyperalgesia reliably predicted large amounts of the variance in clinical pain across all participants, indicating their relevance for FM pain. Perspective Although clinical pain and hyperalgesia decreased during this 6-week trial, the efficacy of milnacipran was not superior to placebo. The high correlations between clinical pain and hyperalgesia ratings at every time point seem to emphasize the relevant contributions of mechanical and heat hyperalgesia to clinical FM pain.

Recent studies have posited that machine learning (ML) techniques accurately classify individuals with and without pain solely based on neuroimaging data. These studies claim that self-report is unreliable, making “objective” neuroimaging classification methods imperative. However, the relative performance of ML on neuroimaging and self-report data have not been compared. This study used commonly reported ML algorithms to measure differences between “objective” neuroimaging data and “subjective” self-report (ie, mood and pain intensity) in their ability to discriminate between individuals with and without chronic pain. Structural magnetic resonance imaging data from 26 individuals (14 individuals with fibromyalgia and 12 healthy controls) were processed to derive volumes from 56 brain regions per person. Self-report data included visual analog scale ratings for pain intensity and mood (ie, anger, anxiety, depression, frustration, and fear). Separate models representing brain volumes, mood ratings, and pain intensity ratings were estimated across several ML algorithms. Classification accuracy of brain volumes ranged from 53 to 76%, whereas mood and pain intensity ratings ranged from 79 to 96% and 83 to 96%, respectively. Overall, models derived from self-report data outperformed neuroimaging models by an average of 22%. Although neuroimaging clearly provides useful insights for understanding neural mechanisms underlying pain processing, self-report is reliable and accurate and continues to be clinically vital. Perspective The present study compares neuroimaging, self-reported mood, and self-reported pain intensity data in their ability to classify individuals with and without fibromyalgia using ML algorithms. Overall, models derived from self-reported mood and pain intensity data outperformed structural neuroimaging models.

A better understanding of the neural mechanisms underlying pain processing and analgesia may aid in the development and personalization of effective treatments for chronic pain. Clarification of the neural predictors of individual variability in placebo analgesia (PA) could aid in this process. The present study examined whether the strength of effective connectivity (EC) among pain-related brain regions could predict future placebo analgesic response in healthy individuals. In Visit 1, fMRI data were collected from 24 healthy subjects (13 female, mean age=22.56, SD=2.94) while experiencing painful thermal stimuli. During Visit 2, subjects were conditioned to expect less pain via a surreptitiously lowered temperature applied at two of the four sites on their feet. They were subsequently scanned again using the Visit 1 (painful) temperature. Subjects used an electronic VAS to rate their pain following each stimulus. Differences in ratings at conditioned and unconditioned sites were used to measure placebo response (PA scores). Dynamic causal modeling was used to estimate the EC among a set of brain regions related to pain processing at Visit 1 (periaqueductal gray, thalamus, rostral anterior cingulate cortex, dorsolateral prefrontal cortex). Individual PA scores from Visit 2 were regressed on salient EC parameters estimates from Visit 1. Results indicate that both greater left hemisphere modulatory DLPFC→PAG connectivity and right hemisphere, endogenous thalamus→DLPFC connectivity were significantly predictive of future placebo response (R2 = 0.82). To our knowledge, this is the first study to identify the value of EC in understanding individual differences in PA, and may suggest the potential modifiability of endogenous pain modulation.

Although functional magnetic resonance imaging (fMRI) has been proposed as a method to elucidate pain-related biomarkers, little information exists related to psychometric properties of fMRI findings. This knowledge is essential for potential translation of this technology to clinical settings. The purpose of this study was to assess the test-retest reliability of pain-related brain activity and how it compares to the reliability of self-report. Twenty-two healthy controls (mean age = 22.6 years, standard deviation = 2.9) underwent 3 runs of an fMRI paradigm that used thermal stimuli to elicit experimental pain. Functional MRI summary statistics related to brain activity during thermal stimulation periods were extracted from bilateral anterior cingulate cortices and anterior insula. Intraclass correlations (ICCs) were conducted on these summary statistics and generally showed “good” test-retest reliability in all regions of interest (ICC range = .32–.88; mean = .71); however, these results did not surpass ICC values from pain ratings, which fell within the “excellent” range (ICC range = .93–.96; mean = .94). Findings suggest that fMRI is a valuable tool for measuring pain mechanisms but did not show an adequate level of test-retest reliability for fMRI to potentially act as a surrogate for individuals' self-report of pain. Perspective This study is one of the first reports to demonstrate the test-retest reliability of fMRI findings related to pain processing and provides a comparison to the reliability of subjective reports of pain. This information is essential for determining whether fMRI technology should be potentially translated for clinical use.

Placebo, as well as nocebo, effects have been primarily investigated in studies with healthy volunteers exposed to acute experimental pain. Yet with regard to chronic pain patients, there is emerging evidence for significant placebo effects but not for nocebo effects. Expectations of pain relief are known to contribute to placebo effects, and lately the influence of emotional feelings has also been investigated. In this line of research, an experiential method has been applied to capture the emotional feelings that chronic pain patients experience during placebo and nocebo interventions. The findings indicate that the patients’ expectations of treatment effects are highly embedded in their emotional feelings. Hence, in order to optimize placebo factors in the clinical treatment of patients, it may be pivotal to investigate and enhance both expectancies and emotional feelings about treatments.

Background Patients with musculoskeletal pain syndrome including fibromyalgia (FM) complain of chronic pain from deep tissues including muscles. Previous research suggests the relevance of impulse input from deep tissues for clinical FM pain. We hypothesized that blocking abnormal impulse input with intramuscular lidocaine would decrease primary and secondary hyperalgesia and FM patients’ clinical pain.

Arguments made for the advantages of replacing pain ratings with brain-imaging data include assumptions that pain ratings are less reliable and objective and that brain image data would greatly benefit the measurement of treatment efficacy. None of these assumptions are supported by available evidence. Self-report of pain is predictable and does not necessarily reflect unreliability or error. Because pain is defined as an experience, magnitudes of its dimensions can be estimated by well-established methods, including those used to validate brain imaging of pain. Brain imaging helps to study pain mechanisms and might be used as proxy measures of pain in persons unable to provide verbal reports. Yet eliminating pain ratings or replacing them with neuroimaging data is misguided because brain images only help explain pain if they are used in conjunction with self-report. There is no objective readout mechanism of pain (pain thermometer) that is unaffected by psychological factors. Benefits from including neuroimaging data might include increased understanding of underlying neural mechanisms of treatment efficacy, discovery of new treatment vectors, and support of conclusions derived from self-report. However, neither brain imaging nor self-report data are privileged over the other. The assumption that treatment efficacy is hampered by self-report has not been shown; there is a plethora of treatment studies showing that self-report is sensitive to treatment. Dismissal of patients’ self-reports (pain ratings) by brain-imaging data is potentially harmful. The aim of replacing self-report with brain-imaging data is misguided and has no scientific or philosophical foundation. Perspective Although brain imaging may offer considerable insight into the neural mechanisms of pain, including relevant causes and correlations, brain images cannot and should not replace self-report. Only the latter assesses the experience of pain, which is not identical to neural activity. Brain imaging may help to explain pain, but replacing self-report with brain-imaging data would be philosophically and scientifically misguided and potentially harmful to pain patients.

Analgesia is particularly susceptible to placebo responses. Recent studies in humans have provided important insights into the neurobiology underlying placebo-induced analgesia. However, human studies provide incomplete mechanistic explanations of placebo analgesia because of limited capacity to use cellular, molecular, and genetic manipulations. To address this shortcoming, this article describes the development of a rat model of conditioned analgesia in an operant pain assay. Specifically, rats were conditioned to associate a placebo manipulation with the analgesic effect of 1mg/kg morphine (subcutaneously) on facial thermal pain. We found that conditioned (placebo) responding bore 3 of the hallmarks of placebo-induced analgesia: (1) strong interanimal variability in the response, (2) suppression by the opiate antagonist naloxone (5mg/kg subcutaneously), and (3) a positive predictive relationship between the unconditioned analgesic effect and the conditioned (placebo) effect. Because of the operant nature of the assay and the use of only a mild noxious thermal stimulus, we suggest that these results provide evidence of placebo-induced analgesia in a preclinical model that utilizes an affective behavioral end point. This finding may provide opportunities for invasive preclinical studies allowing greater understanding of placebo-induced analgesia, thus paving the way for avenues to harness its benefits.

Adding a verbal suggestion to a treatment can add significant increases in linguistic and semantic processing associated with the suggestion, increases that are probably linked to placebo/nocebo effects. Brain regions associated with this processing include those that process the memory and meaning of verbal placebo suggestions. This processing also adds significant decrease in activity of brain areas that process pain. The test stimulus seems to cue the effects and is consistent with somatic focus and sensory feedback reinforcing expectations and other factors that mediate placebo analgesic effects. Nocebo modulation may work similarly. Placebo and nocebo responses are not static or passive but reflect enactive cognitive processes that change dynamically over time and with somatic feedback. These processes can be learned and enhanced, suggesting a potential wealth of opportunity to use placebo factors to enhance efficacy of treatments and medications and to diminish nocebo factors.

Temporal summation of “second pain” (TSSP) or “windup” results from the summation of C-fiber-evoked responses of dorsal-horn neurons. This phenomenon is dependent on stimulus frequency (≥.33 Hz) and relevant to central sensitization and chronic pain. Our previous neuroimaging studies characterized brain regions associated with TSSP in normal control (NC) and fibromyalgia (FM) groups. During an fMRI scan, subjects received sensitivity-adjusted repetitive heat pulses at .33 on the right foot. FM subjects required significantly lower stimulus intensities than NC to achieve similar TSSP and no significant group differences in the pain-related brain activity were detected. In our current study, we asked whether the effective connectivity among a set of TSSP-related brain regions identified in our previous work differs amongst FM and NC groups. Structural equation modeling was used to characterize the effective connectivity amongst a priori selected brain areas, including the thalamus, S1, S2, posterior insula, and the anterior midcingulate cortex (aMCC) within the left and right hemispheres. This analysis confirmed our a priori models of effective connectivity among these regions mainly confirmed those hypothesized, yet some unpredicted connections were additionally identified (thalamus to aMCC and aMCC to S1). While the models of effective connectivity were not identical in the FM and NC groups, they were very similar. Additionally, the TSSP related effective connectivity of right and left hemisphere regions was very similar. These results provide evidence for significant overlap of the fundamental brain mechanisms that process sensory and affective information related to TSSP in NC and FM groups. Perspective Models of effective connectivity involving pain-related processes were estimated with fMRI data from chronic pain and healthy populations. Models were estimated in both hemispheres, and although similar, fibromyalgia was associated with unique models of pain-related processes. Group differences involved the left hemisphere and S1, S2, and posterior insula.

Although altered resting-state functional connectivity (FC) is a characteristic of many chronic pain conditions, it has not yet been evaluated in patients with chronic fatigue. Our objective was to investigate the association between fatigue and altered resting-state FC in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Thirty-six female subjects, 19 ME/CFS and 17 healthy controls, completed a fatigue inventory before undergoing functional magnetic resonance imaging. Two methods, (1) data driven and (2) model based, were used to estimate and compare the intraregional FC between both groups during the resting state (RS). The first approach using independent component analysis was applied to investigate five RS networks: the default mode network, salience network (SN), left frontoparietal networks (LFPN) and right frontoparietal networks, and the sensory motor network (SMN). The second approach used a priori selected seed regions demonstrating abnormal regional cerebral blood flow (rCBF) in ME/CFS patients at rest. In ME/CFS patients, Method-1 identified decreased intrinsic connectivity among regions within the LFPN. Furthermore, the FC of the left anterior midcingulate with the SMN and the connectivity of the left posterior cingulate cortex with the SN were significantly decreased. For Method-2, five distinct clusters within the right parahippocampus and occipital lobes, demonstrating significant rCBF reductions in ME/CFS patients, were used as seeds. The parahippocampal seed and three occipital lobe seeds showed altered FC with other brain regions. The degree of abnormal connectivity correlated with the level of self-reported fatigue. Our results confirm altered RS FC in patients with ME/CFS, which was significantly correlated with the severity of their chronic fatigue.

Neurophysiological responses related to lessening of pain sensitivity are a suggested mechanism of manual therapy. Prior studies have observed generalized lower pain thresholds associated with carpal tunnel syndrome (CTS) in comparison to healthy controls. The present study sought to determine whether similar findings were present in suprathreshold measures and measures specific to central integration of pain (temporal summation and after sensations). Additionally, we wished to determine whether measures of pain sensitivity were related to clinical outcomes in participants with signs and symptoms of CTS receiving a manual therapy intervention. Individuals with signs and symptoms of CTS reported greater pain sensitivity to suprathreshold measures of mechanical pain, temporal summation, and after sensation in comparison to healthy controls. Immediate lessening of mechanical pain sensitivity and after sensations in response to a manual therapy intervention and 3- week attenuation of temporal summation following a 3- week course of manual therapy were associated with 3- week changes in clinical pain intensity in participants with signs and symptoms of CTS. These findings suggest heightened pain sensitivity across several parameters may be associated with CTS. Furthermore, changes in mechanical pain, after sensation, and temporal summation may be related to improvements in clinical outcomes.

Placebo analgesic effects appear to be related to patients' perception of the therapeutic intervention. In this paper, we review quantitative findings of how the relationship with the physician and the verbal suggestions given for relief may influence patients' perception of a treatment and how patients' expectations and emotional feelings may affect treatment outcome. We also present qualitative data from interviews with patients who have experienced pain relief following a placebo or an active treatment. A special focus is given to the temporal development of placebo analgesia at psychological and neurophysiological levels. Finally, we discuss the extent to which the quantitative and qualitative findings supplement or contrast with each other, and we touch upon possible implications of patients' direct experience as central for placebo analgesia.

Fibromyalgia (FM) is a chronic, widespread musculoskeletal pain disorder that is very prevalent in the general population (approximately 5%). Accumulating evidence suggests that FM is associated with central pain processing abnormalities, ie, central sensitization. Several previous studies of chronic pain patients, including FM, have shown gray matter atrophy of brain areas associated with sensory and affective pain processing. These findings, however, have not been confirmed in all FM studies. In this study, we investigated gray matter volumes of brain areas associated with pain-related areas of FM patients identified by functional brain imaging. Using voxel-based morphometric (VBM) analysis of magnetic resonance brain images, we compared 19 pain-related brain areas of 14 female FM patients and 11 healthy controls (NC). We found that FM patients had significantly less gray matter volumes than NC in 3 of these brain regions, including the anterior and mid-cingulate, as well as mid-insular cortices. Importantly, FM patients demonstrated neither global gray matter atrophy nor gray matter changes associated with depression, as shown in some studies. Using a more stringent analysis than other VBM studies, we provide evidence for decreased gray matter volumes in a number of pain-related brain areas in FM. Although the mechanisms for these gray matter changes are presently unclear, they may contribute to some of the core features of this chronic disorder including affective disturbances and chronic widespread pain. Perspective Increasing evidence supports the association of chronic pain with accelerated gray matter atrophy in pain disorders like low back pain, IBS, and FM syndrome. However, cause-effect relationships between chronic pain and decreased gray matter volumes have not been established yet and will require future prospective studies.

We examined the relationship between catastrophizing and a 3-stage model of pain processing, consisting of pain sensation intensity (stage 1), pain unpleasantness (stage 2), and suffering (stage 3). We studied 310 patients with chronic and severe osteoarthritic knee pain (68.7% female) using 4 competing structural equation models. A strong relationship was found between the suffering construct and its indicators. Of the 4 theoretically plausible models, we found a model with 3 specific pathways of pain sensation leading to the final stage of pain-related suffering. A unique contribution of this study is the integration of catastrophizing into the 3 pain stages. In this model, catastrophizing mediates the relationship between pain-related unpleasantness and suffering, as well as the relationship between sensation and suffering through unpleasantness. Psychological intervention targeting catastrophizing could provide reduction of pain-related suffering that adds to the benefits of therapies directed toward the primary sensory and immediate unpleasant dimensions of pain. These results emphasize the benefit of integrating knowledge of the psychological and neural mechanisms of pain. Catastrophizing makes a unique contribution to suffering apart from the contribution of immediate unpleasantness. The study results emphasize the benefit of integrating knowledge of the psychological and neural mechanisms of pain, and the importance of psychological intervention targeting catastrophizing to reduce pain-related suffering.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder in which the pathophysiological mechanisms of the pain and hypersensitivity are not well understood. IBS patients frequently complain of pain in body regions somatotopically distinct from the gut, suggesting that central hyperalgesic mechanisms may be involved. In the current study, during the wind-up testing session, a series of 6 heat pulses were presented with an interstimulus interval (ISI) of 3 seconds. Following the 1st, 3rd, and 6th thermal stimuli, subjects were asked to rate the late thermal sensation or second pain. IBS patients who demonstrated temporal summation of pain (TSSP) then received dextromethorphan and placebo in a randomized, double-blind, fashion to block wind-up. The results showed: 1) a subset of IBS patients, but not controls, showed TSSP in response to a series of noxious heat pulses; and 2) TSSP was blocked by administration of dextromethorphan, an NMDA receptor antagonist. In summary, these findings further elucidate mechanisms of somatic hypersensitivity in a subset of IBS patients. Our results also support an etiologic basis for abnormal NMDA receptor mechanisms in some IBS patients. Future studies are needed to determine if NMDA receptor antagonists may be used to treat IBS patients. Perspective This study evaluates temporal summation of second pain in a subset of IBS patients that is blocked by Dextromethorphan, an NMDA receptor antagonist. Theses results could lead to the use of an NMDA receptor antagonist in the treatment of pain in a subset of IBS patients.

Because fibromyalgia (FM) patients frequently report activity-dependent deep tissue pains, impulse input from painful body regions may be relevant for their musculoskeletal complaints. In addition, peripheral impulse input may induce and maintain thermal and mechanical hyperalgesia of FM patients. If so, activity and rest may alternately enhance and diminish intensity of FM pain. However, the effects of exercise on pain are ambiguous in studies of FM. Whereas exercise-only studies demonstrated increased pain and hyperalgesia during and after physical activity, some exercise studies that included rest periods resulted in decreased FM pain and increased function. To further clarify these effects, we examined the effects of alternating exercise with rest on clinical pain and thermal/mechanical hyperalgesia of 34 FM patients and 36 age-matched healthy controls (NC). Using an ergometer, all subjects performed arm exercise to exhaustion twice alternating with 15-minute rest periods. Although strenuous muscle activity was reported as painful by most FM subjects, overall clinical pain consistently decreased during the rest periods. Additionally, FM subjects' pain sensitivity to mechanical pressure decreased after each exercise and rest session. Conclusion: Alternating strenuous exercise with brief rest periods not only decreased overall clinical pain of FM subjects but also their mechanical hyperalgesia. No prolonged worsening of overall FM pain and hyperalgesia occurred despite vigorous muscle activity. Our findings contribute further evidence that FM pain and hyperalgesia are at least partially maintained by muscle impulse input, and that some types of exercises may be beneficial for FM. Perspective FM is a pain-amplification syndrome that depends at least in part on peripheral tissue impulse input. Whereas muscle activity increased overall pain, short rest periods produced analgesic effects.

We previously reported that 3 different electronic visual analogue and numerical pain scales are useful in providing refined capacity to discriminate discrete levels of pain intensity. Using the same subjects and scales, we now investigated whether pain scaling is influenced by past pain events and by recalled memories of these events in the rating of pain. Normal control subjects (NC: 19 male, 30 female) and female fibromyalgia (FM) (n = 17) patients received 5-second suprathreshold heat stimuli (45–49°C) to both forearms. The participants rated these experimental heat stimuli using the previously described electronic pain scales. Subsequently, they were asked to report whether they used any prior pain experiences during the process of rating their pain. Out of 49 NC, only 6 females (12.2%) and 7 males (14.3%), and out of 17 FM patients, only 3 females (17.6%) stated that they had used past pain experiences during scaling. Notably, pain ratings of experimental heat stimuli did not statistically differ between subjects who used past pain experiences during scaling as compared to those who did not. Furthermore, ratings of their most severe past pains were not significantly correlated with ratings of experimental pain stimuli. These results do not provide support for the strong assertion that pain rating scales are elastic, ie, being used differently depending on the severity of past pain events such as childbirth. Perspective Less than 25% of subjects used memories of past pain events during pain scaling. In addition, if they were used, these pain memories did not influence pain scaling with electronic eVAS and eNUM scales. Thus, use of these scales allows reliable comparisons of experimental and clinical pain ratings within and between subjects .

Irritable bowel syndrome (IBS) is a highly prevalent gastrointestinal disorder that is often accompanied by both visceral and somatic hyperalgesia (enhanced pain from colorectal and somatic stimuli). Neural mechanisms of both types of hyperalgesia have been analyzed by neuroimaging studies of IBS patients and animal analog studies of "IBS-like" rats with delayed rectal and somatic hypersensitivity. Results from these studies suggest that pains associated with both visceral and widespread secondary cutaneous hyperalgesia are dynamically maintained by tonic impulse input from the non-inflamed colon and/or rectum and by brain-to-spinal cord facilitation. Enhanced visceral and somatic pains are accompanied by enhanced pain-related brain activity in IBS patients as compared to normal control subjects; placebos can normalize both their hyperalgesia and enhanced brain activity. That pain in IBS which is likely to be at least partly maintained by peripheral impulse input from the colon/rectum is supported by results showing that local rectal-colonic anesthesia normalizes visceral and somatic hyperalgesia in IBS patients and visceral and somatic hypersensitivity in "IBS-like" rats. Yet these forms of hyperalgesia are also highly modifiable by placebo and nocebo factors (e.g., expectations of relief or distress, respectively). Our working hypothesis is that synergistic interactions occur between placebo/nocebo factors and enhanced afferent processing so as to enhance, maintain, or reduce hyperalgesia in IBS. This explanatory model may be relevant to other persistent pain conditions.

Fibromyalgia (FM) syndrome is characterized by pain and widespread hyperalgesia to mechanical, thermal, and electrical stimuli. Despite convincing evidence for central sensitization of nociceptive pain pathways, the role of peripheral tissue impulse input in the initiation and maintenance of FM is unclear. Therefore this randomized, double-blind, placebo-controlled trial of 22 female normal controls (NCs) and 28 female FM subjects tested the effects of trapezius muscle (TrapM) tender point injections with 1% lidocaine on local pain thresholds as well as on remote heat hyperalgesia at the forearm. Prior to muscle injections shoulder pain was standardized by tonic mechanical muscle stimulation, resulting in local pain ratings of 4.0 ± 0.5 VAS units. Tonic muscle stimulation was interrupted for the TrapM injections but was continued afterwards at the same level. NC as well as FM subjects experienced significant increases of TrapM pressure pain thresholds from lidocaine injections but not from placebo injections (p < 0.001). Additionally, heat hyperalgesia of FM participants was significantly reduced at areas remote from the injection site (forearm) by lidocaine but not by placebo (p = 0.02). Neither lidocaine nor saline injections significantly affected clinical FM pain ratings, a result most likely due to the very low dose of lidocaine (50 mg) used in this trial. Conclusion: Lidocaine injections increased local pain thresholds and decreased remote secondary heat hyperalgesia in FM patients, emphasizing the important role of peripheral impulse input in maintaining central sensitization in this chronic pain syndrome; similar to other persistent pain conditions such as irritable bowel syndrome and complex regional pain syndrome.

Background: N-methyl- d -aspartic acid (NMDA) receptors play an important role in the development of hypersensitivity to visceral and somatic stimuli following inflammation or tissue injury. Our objective was to investigate the role of NMDA NR1 receptors in the spinal cord (T10-L1; L4-S1) of a subset of rats that remain hypersensitive following the histological resolution of TNBS-induced colitis compared to saline treated rats and rats that had recovered both behaviorally and histologically. We hypothesized that NMDA NR1 subunit expression mediates hypersensitivity following transient TNBS colitis. Methods: Male Sprague–Dawley rats (150g–250 g) received 20 mg/rat intracolonic trinitrobenzene sulfonic acid (TNBS) in 50% ethanol or saline. Animals underwent nociceptive visceral/somatic pain testing 16 weeks after resolution of TNBS colitis. Animals were sacrificed and their spinal cords (T10-L1; L4-S1) were retrieved and 2-dimensional polyacrylamide gel electrophoresis and immunohistocytochemistry techniques were used to investigate spinal-NMDA receptor expression. Results: NR1 001 was the only NMDA NR1 receptor subunit that was expressed in recovered and control rats, whereas hypersensitive animals expressed NR1 011 and NR1 111 as well as NR1 001 subunits. Immunohistochemistry analysis demonstrated increased expression of NMDA NR1-N1, C1, and C2-plus expression in laminae I and II of the spinal cord (T10-L1; L4-S1) in hypersensitive rats but not in recovered/control rats. Conclusions: Selective increases in the expression of the NMDA NR1 splice variants occur in hypersensitive rats following resolution of TNBS colitis. This suggests that the NMDA NR1 receptor plays an important role in the development of neuronal plasticity and central sensitization. The recombination of NR1 splice variants may serve as a key functional protein that maintains hypersensitivity following resolution of TNBS colitis.

Not only are some clinical conditions experienced as more painful than others, but the variability in pain ratings of patients with the same disease or trauma is enormous. Available evidence indicates that to a large extent these differences reflect individual differences in pain sensitivity. Pain sensitivity can be estimated only through the use of well-controlled experimental pain stimuli. Such estimates show substantial heritability but equally important environmental effects. The genetic and environmental factors that influence pain sensitivity differ across pain modalities. For example, genetic factors that influence cold pressor pain have little impact on phasic heat pain and visa versa. Individual differences in pain sensitivity can complicate diagnosis, among other reasons because low sensitivity to pain may delay self-referral. Inclusion of patients with reduced pain sensitivity can attenuate treatment effects in clinical trials, unless controlled for. Measures of pain sensitivity are predictive of acute postoperative pain, and there is preliminary evidence that heightened pain sensitivity increases risk for future chronic pain conditions. At this time, however, it is unclear which experimental pain modalities should be used as predictors for future pain conditions. Careful assessment of each individual's pain sensitivity may become invaluable for the prevention, evaluation, and treatment of pain. Perspective Large individual differences in pain sensitivity can complicate diagnosis and pain treatment and can confound clinical trials. Pain sensitivity may also be of great importance for the development of clinical pain. Thus, assessment of pain sensitivity may be relevant for the prevention, evaluation, and treatment of acute and chronic pain.

Temporal summation of "second pain" (TSSP) is considered to be the result of C-fiber-evoked responses of dorsal horn neurons, termed 'windup'. TSSP is dependent on stimulus frequency (or=0.33Hz) and is relevant for central sensitization and chronic pain. We have previously shown that compared to normal controls (NC), fibromyalgia (FM) subjects show abnormal TSSP, requiring lower stimulus intensities/frequencies to achieve similar TSSP. However, it is unknown whether abnormal TSSP in FM is influenced by peripheral sensitization of C-fiber nociceptors and/or bias in pain ratings. Thus, we evaluated 14 FM subjects and 19 NC with pain threshold tests to selective C-fiber stimulation, 30s heat stimuli, and repetitive brief (1.5s) heat pulses at 0.33Hz using a contact heat stimulator (CHEPS). The intensity of heat pulses was varied to achieve maximal TSSP ratings of 45+/-10 (numerical pain scale 0-100) in both FM and NC groups. We found that NC and FM subjects had similar pain thresholds to C-fiber stimulation and yet FM subjects required lower heat pulse temperatures to generate the same magnitudes of TSSP (p.05). This combination of findings does not support peripheral sensitization and suggests central TSSP abnormalities in FM subjects. In a second experiment, all aspects of individually adjusted TSSP heat pulses were kept the same except that the baseline temperature (BT) between heat pulses was surreptitiously alternated between 35 degrees C and 40 degrees C. These changes of BT resulted in significantly greater TSSP ratings of FM subjects compared to NC subjects, both at 35 degrees C and at 40 degrees C, but did not change their response to the first heat pulse of a stimulus train. These findings provide strong support for alterations of central pain sensitivity and not peripheral sensitization or rating bias as responsible for TSSP differences between NC and FM subjects.

Our understanding and conceptualization of the placebo effect has shifted in emphasis from a focus on the inert content of a physical placebo agent to the overall simulation of a therapeutic intervention. Research has identified many types of placebo responses driven by different mechanisms depending on the particular context wherein the placebo is given. Some placebo responses, such as analgesia, are initiated and maintained by expectations of symptom change and changes in motivation/emotions. Placebo factors have neurobiological underpinnings and actual effects on the brain and body. They are not just response biases. Other placebo responses result from less conscious processes, such as classical conditioning in the case of immune, hormonal, and respiratory functions. The demonstration of the involvement of placebo mechanisms in clinical trials and routine clinical practice has highlighted interesting considerations for clinical trial design and opened up opportunities for ethical enhancement of these mechanisms in clinical practice.

Temporal summation of second pain (TSSP) results from repetitive stimulation of peripheral C-fibers (>0.33 Hz) and is thought to reflect summation mechanisms of dorsal horn neurons (ie, windup). Both TSSP and windup result in short term enhancement of C fiber-evoked responses that decay rapidly after the end of stimulation. However, very low stimulus frequencies (0.17 to 0.08 Hz) can maintain this enhancement after TSSP and windup have occurred. This maintained enhancement is termed TSSP-maintenance (TSSP-M) and is indicative of central sensitization. TSSP-M may be especially relevant for chronic pain conditions such as fibromyalgia (FM) and may play an important role in its pathogenesis. Whereas TSSP-M of heat induced pain is well-characterized in human subjects at spinal cord levels related to the upper body, TSSP-M at spinal levels related to the lower body has not been previously studied. The present study was designed to evoke TSSP-M at the upper and lower extremities of normal controls (NC) and FM patients and thus characterize their spatial distribution of central sensitization. Twenty-three NC and 26 FM patients were enrolled in this study. TSSP-M testing consisted of repetitive heat pain stimulation at the thenar eminences of the hands or feet. The subjects rated the pain intensity of repetitive heat stimuli as well as 15- and 30-second pain aftersensations. The experiments demonstrated significant TSSP-M for both NC and FM patients. In contrast to NC, TSSP-M ratings of heat stimuli were increased in FM patients and their TSSP-aftersensations (TSSP-AS) were prolonged. There was, however, no statistical difference between TSSP-M ratings or TSSP-AS at the hands or feet in either NC or FM patients. These findings demonstrate that central sensitization of FM patients is widespread and similar along the spinal neuroaxis. Perspective The pain of FM seems to be accompanied by generalized central sensitization, involving the length of the spinal neuroaxis. Thus, widespread central sensitization appears to be a hallmark of FM and may be useful for the clinical case definition of this prevalent pain syndrome. In addition, measures of widespread central sensitization, like TSSP-M could also be used to assess treatment responses of FM patients.

Inflammation of visceral structures in rats has been shown to produce visceral/somatic hyperalgesia. Our objectives were to determine if trinitrobenzene sulfonic acid (TNBS) induced colitis in rats leads to visceral/somatic hypersensitivity. Male Sprague-Dawley rats (200-250 g) were treated with 20 mg of TNBS in 50% ethanol (n = 40) or an equivalent volume of ethanol (n = 40) or saline (n = 25) via the colon. Colonic distension, Von Frey, Hargreaves, and tail reflex tests were used to evaluate for visceral, mechanical, and thermal sensitivity. The rats demonstrated visceral hypersensitivity at 2-28 days following TNBS administration (P < 0.0001). The ethanol-treated rats also demonstrated visceral hypersensitivity that resolved after day 14. TNBS-treated rats demonstrated somatic hypersensitivity at days 14-28 (P < 0.0001) in response to somatic stimuli of the hind paw. TNBS colitis is associated with visceral and somatic hypersensitivity in areas of somatotopic overlap. This model of colitis should allow further investigation into the mechanisms of visceral and somatic hypersensitivity.

Background: Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by both visceral and somatic hyperalgesia, producing a similar effect seen with the central hypersensitivity mechanism in fibromyalgia (FM). Objectives: The aim of the current study was to compare magnitudes of visceral and thermal hypersensitivity in IBS patients and FM patients with IBS (FM + IBS) compared with healthy controls. Methods: Female patients with IBS (n = 12), FM+IBS (n = 12), and control participants (n = 13) rated pain intensity to hot water immersion (45 and 47°C) of the hand/foot and to phasic distension of the rectum (35, 55mm Hg) on a Mechanical Visual Analog Scale. The data were analyzed with 3 separate 1-way analyses of variance with post hoc Tukey tests. Results: For both thermal and visceral stimuli, the control group had lower pain ratings than either the IBS or FM + IBS groups (P < 0.001). IBS patients rated rectal distension as more painful than the FM+IBS group (P = 0.005). During hot water immersion of the foot, the FM + IBS group had higher pain ratings than the IBS group (P < 0.001). During hand immersion, FM + IBS and IBS patients did not significantly differ in their pain intensity ratings (P = 0.4). Conclusions: FM + IBS patients show greater thermal hypersensitivity compared with IBS patients. However, IBS patients exhibit higher pain ratings to rectal distension compared with FM + IBS patients. This data suggests that regions of primary and secondary hyperalgesia are dependent on the primary pain complaint.

Patients with chronic fatigue syndrome (CFS) frequently demonstrate intolerance to physical exertion that is often reported as increased and long-lasting fatigue. Because no specific metabolic alterations have been identified in CFS patients, we hypothesized that sensitized fatigue pathways become activated during exercise corresponding with increased fatigue. After exhausting handgrip exercise, muscle metabolites were trapped in the forearm tissues of 39 CFS patients and 29 normal control (NC) by sudden occlusion for up to 5 minutes. A nonocclusive condition of similar duration was used as control. Repeated fatigue and pain ratings were obtained before and after exercise. Mechanical and heat hyperalgesia were assessed by quantitative sensory testing. All subjects fulfilled the 1994 Fukuda Criteria for CFS. Normal control and CFS subjects exercised for 6.6 (2.4) and 7.0 (2.7) minutes (P > 0.05). Forearm occlusion lasted for 4.7 (1.3) and 4.9 (1.8) minutes in NC and CFS subjects, respectively (P > 0.05). Although fatigue ratings of CFS subjects increased from 4.8 (2.0) to 5.6 (2.1) visual analogue scale (VAS) units during forearm occlusion, they decreased from 5.0 (1.8) to 4.8 (2.0) VAS units during the control condition without occlusion (P = 0.04). A similar time course of fatigue ratings was observed in NC (P > 0.05), although their ratings were significantly lower than those of CFS subjects (P < 0.001). Quantitative sensory testing demonstrated heat and mechanical hyperalgesia in CFS subjects. Our findings provide indirect evidence for significant contributions of peripheral tissues to the increased exercise-related fatigue in CFS patients consistent with sensitization of fatigue pathways. Future interventions that reduce sensitization of fatigue pathways in CFS patients may be of therapeutic benefit.

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. Perspective 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.

The magnitude of placebo analgesia is influenced by environmental and perceptual factors. Environmental factors include past exposure to effective analgesic agents and verbal suggestions and cues that foster a perception of being given an effective treatment. Environmental factors, in turn, influence the proximate psychologic mediators of placebo analgesia, which include decreased desire for and increased expectations of pain relief. Strategies to maximize placebo analgesic effects in clinical practice could focus on using verbal suggestions and external cues to increase expectations of pain relief and/or decrease the perceived need for pain reduction. Placebo analgesic effects could be minimized in clinical trials by avoiding these same suggestions and cues.

Background N-methyl-D-aspartic acid (NMDA) spinal cord receptors play an important role in the development of hyperalgesia following inflammation. It is unclear, however, if changes in NMDA subunit receptor gene expression in the colonic myenteric plexus are associated with colonic inflammation. We investigated regulation of NMDA-NR1 receptor gene expression in TNBS induced colitis in rats. Male Sprague-Dawley rats (150 g–250 g) were treated with 20 mg trinitrobenzene sulfonic acid (TNBS) diluted in 50% ethanol. The agents were delivered with a 24 gauge catheter inserted into the lumen of the colon. The animals were sacrificed at 2, 7, 14, 21, and 28 days after induction of the colitis, their descending colon was retrieved for reverse transcription-polymerase chain reaction; a subset of animals' distal colon was used for two-dimensional (2-D) western analysis and immunocytochemistry. Results NR1-exon 5 (N1) and NR1-exon 21 (C1) appeared 14, 21 and 28 days after TNBS treatment. NR1 pan mRNA was up-regulated at 14, 21, and 28 days. The NR1-exon 22 (C2) mRNA did not show significant changes. Using 2-D western analysis, untreated control rats were found to express only NR1001 whereas TNBS treated rats expressed NR1001, NR1011, and NR1111. Immunocytochemistry demonstrated NR1-N1 and NR1-C1 to be present in the myenteric plexus of TNBS treated rats. Conclusion These results suggest a role for colonic myenteric plexus NMDA receptors in the development of neuronal plasticity and visceral hypersensitivity in the colon. Up-regulation of NMDA receptor subunits may reflect part of the basis for chronic visceral hypersensitivity in conditions such as post-infectious irritable bowel syndrome.

Irritable bowel syndrome (IBS) is one of the most common disorders seen by gastroenterologists. Visceral hypersensitivity is now well recognized as a clinical marker for the disease. Intrarectal lidocaine has been previously shown to decrease pain report from rectal distension in patients with IBS without any significant serum lidocaine levels. We conducted a prospective, double-blind, crossover trial on 10 patients with IBS to evaluate the effects of 300 mg intrarectal lidocaine jelly on abdominal pain. Ten Caucasian premenopausal women who met the Rome II criteria for diarrhea-predominant IBS were recruited into the study. All of the patients that participated had intermittent left lower quadrant pain and diarrhea. Each patient participated in 2 sessions in which saline jelly (placebo) and lidocaine jelly was administered on a double-blind, crossover basis. Patients participated in these sessions at a time when their ongoing pain was at least 3 on a 0 to 10 visual analogue scale. In comparison to placebo saline jelly, lidocaine jelly significantly decreased abdominal pain (P.02) for at least 4 hours. None of the patients experienced any side effects. Intrarectal lidocaine may be a potentially useful treatment for chronic abdominal pain in IBS.The possible presence of abnormal sodium channels in the rectal and or colonic visceral afferents of patients with IBS might serve as a clue as to the effectiveness of rectal lidocaine. The dose of lidocaine used in this study may be of sufficient strength to normalize aberrant sodium channels that may be present in the colon of patients with IBS without affecting normal sodium channels of either IBS or control subjects.

A study was conducted to determine whether changes in expected pain levels, desire for pain relief, or anxiety contribute to an increase in placebo analgesia over time as well as to determine whether placebo analgesic effects of IBS patients are related to endogenous opioid mechanisms. Twenty-six women with IBS were exposed to rectal stimulation (35 or 55 mmHg for 30 s) and tested under natural history (NH), rectal placebo (RP) and rectal lidocaine (RL) conditions. During all conditions, 16 patients were given saline intravenously (to test for a placebo effect) and 10 patients were given naloxone intravenously (to test naloxone antagonism of the placebo effect) on a double blind basis. Patients rated expected pain level, desire for pain relief and anxiety at 2 and 22 min after the onset of NH, RP, and RL conditions and they rated actual pain intensity at 5-min intervals for 40 min. There was a large and significant placebo effect (P

The factors that contribute to the magnitude of placebo analgesia have, until recently, been elusive. This review explores the roles of external factors, such as conditioning, and experienced factors, such as expectation and desire for pain reduction, in placebo analgesia. Placebo analgesia effects have been found to reflect decreases in pain beyond that accounted for by the natural history of a pain condition. These effects clearly are influenced by the effectiveness of previous active treatments (ie, conditioning) as well as by environmental factors that provide cues/suggestions for analgesia. However, external factors are effective insofar as they provide expectations for pain reduction and a lowering of desire for relief. Experienced factors, such as expectation and desire for relief, also are integral dimensions of some human emotional states, such as anxiety. We present an explanation of placebo analgesia that suggests that it is the result of mechanisms that also regulate emotional states.

We studied the effect of propofol, a widely used sedative-hypnotic drug, on pain perception. Eighteen subjects received propofol in two sedative concentrations that were balanced and randomized in order. Painful (45 degrees C, 47 degrees C, and 49 degrees C) stimulation temperatures were presented in random order, and nonpainful 31 degrees C stimuli were presented on alternate trials. We used a target-controlled infusion and chose effect site concentrations of 0.5 mug/mL for mild sedation and 1.0 mug/mL for moderate sedation. Using a visual analog scale, subjects rated both pain intensity and unpleasantness higher when sedated with propofol. The average pain intensity was 28/100 for placebo, 35/100 for mild, and 40/100 for moderate sedation. Pain unpleasantness was 23/100 for placebo, 29/100 for mild, and 33/100 for moderate sedation. This effect was unexpected and may be explained by a difference of subjective pain experience by a patient and the perceived level of analgesia by a health care provider in sedated patients. This finding calls further attention to the need for adequate analgesia in patients sedated with propofol.

The mechanisms of spatial summation of pain (SSP) include pain coding dependent on impulse frequency and the number of recruited central neurons. However, SSP may also be influenced by pain inhibitory mechanisms, such as diffuse noxious inhibitory controls. Abnormal interactions between pain inhibitory mechanisms and SSP may be relevant for chronic pain conditions such as fibromyalgia (FM) and may help explain why widespread pain is characteristic for this chronic pain syndrome. The present study was designed to determine the difference of thermal SSP in the upper extremities between FM and normal control (NC) subjects, particularly within and across dermatomes of the hand. Fourteen NC and 19 FM subjects were enrolled in this study. SSP testing sessions involved immersion of each individual fingertip as well as stepwise immersion of the fingers, hands, and forearms in a hot water bath (46 degrees Celsius) for 5s and 20s. In addition, immersion of several fingertips across dermatome C(7)-C(8) was compared to progressive immersion of the index finger (dermatome C(7)). These experiments demonstrated significant spatial summation of heat-induced pain in both FM and NC subjects. SSP was most extensive within the fingers, and became negligible as the stimulus area increased above the hand. Furthermore, SSP was more pronounced within one dermatome such as that of the index finger than across several dermatomes of the hand. These results were similar for both FM and NC subjects. Thus, mechanisms of SSP, including possible inhibitory factors that limit this relevant pain mechanism, appear to be similar for both FM and NC subjects.

Many chronic pain syndromes, including fibromyalgia (FM), show evidence of central nervous system hyperexcitability related to central sensitization. Windup (WU) of second pain reflects increased excitability of spinal cord neurons that is related to central sensitization. Psychophysical testing can help characterize this important central nervous system phenomenon because of the parallels between electrophysiological WU and WU of second pain. Animal experiments have shown that once WU has been established, only low frequency tonic nociceptive input is required to maintain the sensitized state of dorsal horn neurons (WU-maintenance or WU-M). The stimulus frequency necessary to maintain the hyperexcitability of spinal cord neurons can provide a measure of central sensitization. Because central sensitization plays an important role in many chronic pain syndromes including FM, we compared WU-M in 72 normal controls (NC) and 104 FM subjects. WU of second pain was produced by a train of 0.7 s duration thermal pulses applied to the glabrous surface of the hands at a frequency of 0.3 Hz. Enhanced second pain associated with WU could, thereafter, be maintained in FM but not NC subjects for up to 120 s by stimuli delivered at 0.16 and 0.08 Hz (WU-M stimuli). These two frequencies of stimulation do not produce WU when delivered alone. Thus, unlike NC subjects, FM subjects showed enhanced second pain during WU-M stimuli at very low stimulus frequencies, indicating central sensitization. Increased WU sensitivity, enhanced WU-M, and increased WU-related aftersensations help account for persistent pain conditions in FM subjects. In addition to WU, WU-M appears to be a useful tool to study mechanisms of pain in patients with characteristics of central sensitization.

Patients with fibromyalgia (FM) report widespread chronic musculoskeletal pain. Palpation of 9 paired tender points (TPs) is commonly used for the diagnosis of FM according to criteria specified by the American College of Rheumatology. Although TP palpation can be used to assess deep tissue hypersensitivity, it has failed as a reliable indicator of clinical pain intensity in FM. The sum of local areas of pain (SLAP) obtained from a body pain diagram represents a relevant measure of the spatial extent of clinical pain, a feature most likely important for FM pain. Because spatial summation of pain can be an important determinant of clinical pain intensity, we hypothesized that this measure would predict clinical pain intensity in FM patients. Because pain is strongly associated with negative emotions, we evaluated the relationship of pain-related negative affect (PRNA) with clinical pain intensity in FM. The independent contributions of SLAP, PRNA, and TP count to the variance of clinical pain intensity were assessed in 280 FM patients. Clinical pain intensity of 280 FM patients was measured by using a visual analogue scale. FM patients shaded all painful body areas on body pain diagrams. Dolorimetry was used for TP evaluations. PRNA was assessed with the Medical College of Virginia Pain Questionnaire. Hierarchical linear regression was used to test the association of SLAP, TPs, and PRNA with clinical pain intensity. FM patients' mean visual analogue scale rating (0 to 100) of usual clinical pain was 50.1. Mean SLAP, TP count, and PRNA were 11.4, 16.0, and 44.3, respectively. Hierarchical linear regression analysis identified SLAP, TP count, and PRNA as independent predictors of clinical pain that accounted for 45% of the variance in clinical pain intensity ratings in FM patients. Consistent with the literature, TP count predicted only a small part (4%) of this variance. Our statistical model of body pain areas and negative affect predicts a large portion of the variance of pain intensity in FM. This result suggests that the extent of pain areas and negative emotions are uniquely associated with clinical pain intensity in FM. Perspective The number of painful body areas obtained by body pain diagrams is a better predictor of clinical pain intensity than TPs in FM patients. The combination of painful body areas, TP counts, and PRNA predicts 45% of the clinical pain intensity of FM patients. This finding might be useful for clinical evaluations of FM patients.

In this paper, the relationships between neural mechanisms of persistent pain and the neural representations of these conditions in the human and animal brain will be reviewed. Animal models of chronic pain, such as the sciatic nerve constrictive injuries, are accompanied by somatotopically organized increases in several pain-related areas of the brain. Recent human brain imaging studies utilizing functional magnetic resonance imaging and positron emission tomography have elucidated the cerebral representations of visceral and somatic hypersensitivity. Both forms of hypersensitivity are represented in similar brain regions that are activated during acute pain, yet have a more extensive or intense cerebral representation. This suggests that these somatic and visceral hyperalgesic states may be represented by increased activity in the same cerebral pathways and centers that are involved in nociceptive stimuli in normal individuals. Hyperalgesic states during clinically relevant pain are especially reflected in brain areas such as the anterior cingulate and prefrontal cortical regions.

Whether elevated β-secretase (BACE) activity is related to plaque formation or amyloid β peptide (Aβ) production in Alzheimer's disease (AD) brains remains inconclusive. Here, we report that we used sandwich enzyme-linked immunoabsorbent assay to quantitate various Aβ species in the frontal cortex of AD brains homogenized in 70% formic acid. We found that most of the Aβ species detected in rapidly autopsied brains (1-x and Aβ 1-42 , as well as Aβ x-42 . To establish a linkage between Aβ levels and BACE, we examined BACE protein, mRNA expression and enzymatic activity in the same brain region of AD brains. We found that both BACE mRNA and protein expression is elevated in vivo in the frontal cortex. The elevation of BACE enzymatic activity in AD is correlated with brain Aβ 1-x and Aβ 1-42 production. To examine whether BACE elevation was due to mutations in the BACE-coding region, we sequenced the entire ORF region of the BACE gene in these same AD and nondemented patients and performed allelic association analysis. We found no mutations in the ORF of the BACE gene. Moreover, we found few changes of BACE protein and mRNA levels in Swedish mutated amyloid precursor protein-transfected cells. These findings demonstrate correlation between Aβ loads and BACE elevation and also suggest that as a consequence, BACE elevation may lead to increased Aβ production and enhanced deposition of amyloid plaques in sporadic AD patients.