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Mechanisms of hypnotic analgesia were investigated by examining changes in the R-III, a nociceptive spinal reflex, during hypnotic reduction of pain sensation and unpleasantness. The R-III was measured in 15 healthy volunteers who gave VAS-sensory and VAS-affective ratings of an electrical stimulus during conditions of resting wakefulness, suggestions for hypnotic analgesia, and attempted suppression of the reflex during non-hypnotic conditions. The H-reflex was also measured to monitor and control for general changes in alpha-motoneuron excitability. Hypnotic sensory analgesia was related to reduction in the R-III after controlling for changes in the H-reflex (R2 = 0.51, P0.003), suggesting that hypnotic sensory analgesia is at least in part mediated by descending antinociceptive mechanisms that exert control at spinal levels in response to hypnotic suggestion. The relationship between hypnotic affective analgesia and reduction in R-III approached significance (R2 = 0.26; P = 0.053). Reduction in R-III was 67% as great and accounted for 51% of the variance in reduction of pain sensation. In turn, reduction in pain sensation was 75% as great and accounted for 77% of the variance in reduction of unpleasantness. The results suggest that 3 general mechanisms may be involved in hypnotic analgesia. The first, implicated by reductions in R-III, is related to spinal cord antinociceptive mechanisms. The second, implicated by reductions in pain sensation over and beyond reductions in R-III, may be related to brain mechanisms that serve to prevent awareness of pain once nociception has reached higher centers, as suggested by Hilgard.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple abnormalities in pain processing have been reported in patients with chronic musculoskeletal pain syndromes. These changes include mechanical and thermal hyperalgesia, decreased thresholds to mechanical and thermal stimuli (allodynia), and central sensitization, all of which are fundamental to the generation of clinical pain. Therefore, we hypothesized that quantitative sensory tests may provide useful predictors of clinical pain intensity of such patients. Our previous studies of fibromyalgia (FM) patients have shown statistically significant correlations of quantitative sensory test results with clinical pain intensity, including mechanical spatial summation, number of pain areas, wind-up, and wind-up aftersensations. Although these tests predicted up to 59% of the variance in FM clinical pain intensity, their expense and technical complexities limited widespread use in clinical practice and trials. Thus, we developed practical tests of primary (mechanical) and secondary (heat) hyperalgesia that also strongly predict clinical pain intensity in patients with chronic musculoskeletal pain disorders. Thirty-six individuals with FM, 24 with local musculoskeletal pain, and 23 normal controls underwent testing of mechanical and heat hyperalgesia at the shoulders and hands. All subjects rated experimental pains using an electronic visual analog scale. Using either heat or pressure pain ratings as well as tender point counts and negative affect as predictors, up to 49.4% of the patients' variance of clinical pain intensity could be estimated. Results of this study emphasize the important contributions of peripheral and central factors to both local and widespread chronic pain. Overall, measures of mechanical and heat hyperalgesia in combination with tender point and negative affect provided powerful predictors of clinical pain intensity in chronic musculoskeletal pain patients that can be readily used in clinical practice and trials. Perspective Simple tests of mechanical and heat hyperalgesia can predict large proportions of the variance in clinical pain intensity of chronic musculoskeletal pain patients and thus are feasible to be included in clinical practice and clinical trials.

Several studies have shown that placebo analgesia effects can be obtained in healthy volunteers, as well as patients suffering from acute postoperative pain and chronic pain conditions such as irritable bowel syndrome. However, it is unknown whether placebo analgesia effects can be elicited in chronic pain conditions with a known pathophysiology such as a nerve injury. Nineteen patients who had developed neuropathic pain after thoracotomy were exposed to a placebo manipulation in which they received either open or hidden administrations of lidocaine. Before the treatment, the patients rated their levels of spontaneous pain and expected pain and completed a questionnaire on their emotional feelings (Positive Affect Negative Affect Schedule) and went through quantitative sensory testing of evoked pain (brush and cold allodynia, heat pain tolerance, area of pinprick hyperalgesia, wind-up-like pain after pinprick stimulation). The placebo manipulation significantly reduced the area of pinprick hyperalgesia (P=.027), and this placebo effect was significantly related to low levels of negative affect (P=.008; R(2)=0.362) but not to positive affect or expected pain levels. No placebo effect was observed in relation to spontaneous pain or evoked pain, which is most likely due to low pain levels resulting in floor effects. This is the first study to demonstrate a placebo effect in neuropathic pain. The possible mechanisms underlying the placebo effects in hyperalgesia are discussed, and implications for treatment are outlined.

Oral doses of dextromethorphan (DM), a common cough suppressant and N-methyl-D-aspartate (NMDA) receptor antagonist, and their vehicle control were given on a double-blind basis to normal volunteer human subjects who rated intensities of first and second pain in response to repeated painful electric shocks and repeated 52 degrees C heat pulses. Doses of 30 and 45 mg, but not 15 mg, were effective in attenuating temporal summation of second pain, a psychophysical correlate of temporal summation of C afferent-mediated responses of dorsal horn nociceptive neurons, termed 'wind-up'. By contrast, neither first nor second pain evoked by the first stimulus in a train of stimuli were affected by any of these doses of DM. These results further confirm temporal summation of second pain as a psychophysical correlate of wind-up by providing evidence that DM selectively reduces temporal summation of second pain, as has been shown for wind-up.

Numerical rating scales and mechanical visual analogue scales (M-VAS) were compared for their capacity to provide ratio scale measures of experimental pain. Separate estimates of experimental pain sensation intensity and pain unpleasantness were obtained by each method, as were estimates of clinical pain. Orofacial pain patients made numerical scale and VAS ratings in response to noxious thermal stimuli (45-51 degrees C) applied for 5 sec to the forearm by a contact thermode. The derived stimulus-response function was well fit as a power function only in the case of sensory M-VAS. The power function derived from sensory M-VAS ratings predicted temperatures chosen as twice as intense as standard temperatures of 47 degrees C and 48 degrees C, thereby providing evidence for ratio scale characteristics of M-VAS. The stimulus-response function derived from sensory numerical ratings differed from that obtained with M-VAS and did not provide accurate predictions of temperatures perceived as twice intense at 47 degrees C or 48 degrees C. Both M-VAS and numerical rating scales produced reliably different stimulus response functions for pain sensation intensity as compared to pain unpleasantness and both provided consistent measures of experimental and clinical pain intensity. Finally, both mechanical and pencil-and-paper VAS produced very similar stimulus-response functions. The ratio scale properties of M-VAS combined with its ease of administration and scoring in clinical settings offer the possibility of a simple yet powerful pain measurement technology in both research and health care settings.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder in which the pathophysiological mechanisms of the pain and hypersensitivity are incompletely understood. IBS patients frequently complain of pain in body regions somatotopically distinct from the gut, suggesting involvement of central hyperalgesic mechanisms. We tested the role of tonic peripheral impulse input by using both repetitive thermal stimuli to the leg and repetitive stimuli to the rectum. Changes in thermal/visceral pain sensitivity after nociceptive thermal/visceral repetitive stimulation were determined. A subset of IBS patients showed enhanced rectal/thermal pain sensitivity after repetitive thermal/rectal stimulation, respectively. IBS patients then received 60 mg dextromethorphan and placebo (diphenhydramine) in a randomized, double-blind, crossover trial. The results showed that 1) a subset of IBS patients had increased visceral/cutaneous hypersensitivity following a series of repetitive nociceptive stimuli and that 2) this increased pain sensitivity was blocked by administration of dextromethorphan. This is the first human study indicating that repetitive stimulation enhances a bidirectional mechanism of secondary hyperalgesia due to viscerosomatic facilitation in IBS patients. These unique findings elucidate mechanisms of somatic hypersensitivity in IBS patients and support an etiologic basis for abnormal N-methyl-D-aspartate receptor mechanisms that may be the target of future therapies for IBS.Repetitive stimulation enhances a bidirectional mechanism of secondary hyperalgesia due to viscerosomatic convergence in IBS patients. The findings elucidate unique mechanisms of somatic/visceral hypersensitivity in a subset of IBS patients and further support an etiologic basis for abnormal N-methyl-D-aspartate receptor mechanisms that may be future targets of therapies for IBS.

Many patients suffer from chronic gastrointestinal diseases characterized by chronic inflammation, increased intestinal permeability and visceral pain in which there is no definitive treatment. Adult stem cells have recently been used in various disease states to contribute wound-healing processes. In the current study we investigated the ability of intra-colonic adult stem cells application to heal colonic inflammation in IL-10−/− mice with active colitis. The aims of this study were to determine whether intra-colonic infusion of adult colonic stem cells (CSCs) (local stem cell transplantation): (i) restores intestinal permeability; (ii) attenuates visceral hypersensitivity; (iii) heals murine colitis. IL-10−/− mice with active colitis were transplanted with adult stem cells. Mice received either a single intracolonic infusion of CSCs or colonic epithelial cells. Two weeks after transplantation, we measured visceral hypersensitivity and intestinal permeability and correlated these with histological improvement of colitis. IL-10−/− mice that received stem cell transplantation showed histopathologic evidence of recovery from colitis. Improvement in colitis as graded by pathology scores correlated with restoration of intestinal permeability and decreased visceral hypersensitivity. Intra-colonic administration of CSCs is a potential therapeutic method for treating refractory symptoms in patients with chronic gastrointestinal diseases associated with chronic inflammation and visceral hypersensitivity. This method may be safer and should have far fewer side effects than systemic stem cell administration.

1. Three-dimensional spatial patterns of changes in membrane-bound protein kinase C (PKC) were examined in the lumbar spinal cords (L1-L5) of rats with an experimental painful peripheral mononeuropathy. Painful peripheral mononeuropathy was produced by loosely ligating the rat's common sciatic nerve, resulting in chronic constrictive nerve injury (CCI). Changes in spinal cord membrane-bound PKC distribution were assayed by employing an established quantitative [3H]-phorbol-12,13-dibutyrate ([3H]PDBu) autoradiographic assay, which includes spinal cord sectioning, incubation of spinal cord sections with [3H]PDBu, production of autoradiographs, and computer-assisted image processing. 2. Sciatic nerve ligation induced demonstrable thermal hyperalgesia in response to radiant heat stimulation and spontaneous pain-related behaviors (such as lifting of the nerve-ligated hind paw) in CCI rats 3, 7, and 10 days after unilateral sciatic nerve ligation. 3. Consistent with behavioral changes, CCI rats examined 3 or 10 days after sciatic nerve ligation displayed a three-dimensional pattern of increased membrane-bound PKC in the lumbar spinal cord (L1-L5) strikingly different from that of sham-operated rats: in the dorsoventral dimension, reliable increases in membrane-bound PKC occurred mainly within spinal cord laminae I-IV and V-VI in CCI rats; in the ipsilateral-contralateral dimension, changes in membrane-bound PKC were seen on both sides of the spinal cord in CCI rats with reliably higher levels of membrane-bound PKC on the side ipsilateral than on the side contralateral to sciatic nerve ligation; in the rostrocaudal dimension, increases in membrane-bound PKC in the spinal cord dorsal horns of CCI rats extended from spinal segments L2-L5. 4. Both three-dimensional increases in spinal cord membrane-bound PKC and nociceptive behaviors (thermal hyperalgesia and spontaneous pain behaviors) in CCI rats were reliably reduced after three daily intrathecal treatments with 80 nmol GM1 ganglioside (a glycosphingolipid shown to prevent PKC translocation/activation), the first of which was given 1 h after sciatic nerve ligation. This reduction was seen 24 h but not 7 days after the last GM1 ganglioside treatment. 5. This three-dimensional increase in membrane-bound PKC in the spinal cord dorsal horn of CCI rats displayed high correlations with thermal hyperalgesia and with spontaneous pain-related behaviors in CCI rats observed both 3 and 10 days after sciatic nerve ligation. Similar correlations were observed between decreases in levels of membrane-bound PKC in the spinal cord dorsal horn and the attenuation of nociceptive behaviors in CCI rats after three daily intrathecal treatments with GM1 ganglioside.(ABSTRACT TRUNCATED AT 400 WORDS)

1. To better characterize temporal and spatial mechanisms involved in the coding of prolonged nociceptive stimuli in the spinal cord, the responses of dorsal horn wide dynamic range (WDR) and nociceptive-specific (NS) neurons to prolonged, repetitive noxious heat stimuli (45–49 degrees C) were examined in unanesthetized, spinal cord transected rats. To relate these neuronal responses to conscious dimensions of pain, human subjects were presented with identical types of prolonged, repetitive stimuli, so that psychophysical ratings of pain intensity and pain unpleasantness could be compared with the magnitudes and temporal features of the responses of NS and WDR neurons. 2. WDR neurons exhibited high rates of impulse discharge throughout 45 min of repetitive nociceptive stimulation, with only partial reduction (31% decrease from peak rates) occurring after 2 min of stimulation. In sharp contrast, NS neurons stimulated under the same conditions displayed substantial reduction of firing (73% decrease from peak rates) after a brief, initial period of activity that occurred within 2 min after onset of stimulation. Psychophysical ratings of pain intensity and pain unpleasantness, like the responses of WDR neurons, did not decrease substantially from initial levels during 7 min of painful stimulation. Furthermore, these ratings remained at high levels during time periods where the impulse frequencies of NS neurons were only at 27% of maximal levels. 3. Graded nociceptive stimuli were employed to characterize the ability of WDR neurons to encode nociceptive intensity over long durations of repetitive stimulation and to delineate further the relationship between WDR and psychophysical responses. Both WDR discharge frequencies and psychophysical ratings of pain intensity and unpleasantness increased in a monotonic manner to graded increases in stimulus temperatures. 4. These results indicate that pain does not decrease substantially during the course of prolonged, repetitive nociceptive stimulation. The fact that the responses of NS neurons decline significantly, whereas both WDR and psychophysical responses do not, suggests that WDR neurons alone are sufficient to evoke both sensory intensity and affective responses to prolonged pain. Furthermore, because subjects could localize and qualitatively describe pain at times when responses of NS neurons were minimal, WDR neurons alone can encode some spatial and qualitative aspects of pain.

The therapeutic effects of dextrorphan and ketamine, two non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, on neuropathic pain-related behaviors were examined in rats with peripheral mononeuropathy induced by loose ligation of the common sciatic nerve (chronic constrictive injury, CCI). Four daily intrathecal treatments (beginning 1 h after nerve ligation) with dextrorphan or ketamine (12.5-100 nmol) reliably attenuated hyperalgesia to radiant heat and spontaneous pain-related behaviors in CCI rats. Thermal hyperalgesia also was reduced in CCI rats receiving a single intrathecal treatment with either dextrorphan or ketamine (50 and 100 nmol for each compound) on day 3 after nerve ligation when thermal hyperalgesia was well developed. Since both dextrorphan and ketamine are currently utilized in other clinical applications, the results suggest a new therapeutic utility of these 'old' compounds in treatment of neuropathic pain syndromes resulting from peripheral nerve injury.

Patients with chronic pain syndromes, like fibromyalgia (FM) complain of widespread pain and tenderness, as well as non-refreshing sleep, cognitive dysfunction, and negative mood. Several lines of evidence implicate abnormalities of central pain processing as contributors for chronic pain, including dysfunctional descending pain inhibition. One form of endogenous pain inhibition, diffuse noxious inhibitory controls (DNIC), has been found to be abnormal in some chronic pain patients and evidence exists for deficient spatial summation of pain, specifically in FM. Similar findings have been reported in patients with localized musculoskeletal pain (LMP) disorders, like neck and back pain. Whereas DNIC reduces pain through activation of nociceptive afferents, vibro-tactile pain inhibition involves innocuous A-beta fiber. To assess whether patients with localized or widespread chronic pain disorders have dysfunctional A-beta related pain inhibition we enrolled 28 normal pain-free controls (NC), 29 FM patients, and 19 subjects with neck or back pain. All received 10 s sensitivity-adjusted noxious heat stimuli to the forearms as test stimuli. To assess endogenous analgesic mechanisms of study subjects, vibro-tactile conditioning stimuli were simultaneously applied with test stimuli either homotopically or heterotopically. Additionally, the effect of distraction on experimental pain was assessed. Homotopic vibro-tactile stimulation resulted in 40% heat pain reductions in all subject groups. Distraction did not seem to affect experimental pain ratings. Conclusions: Vibro-tactile stimulation effectively recruited analgesic mechanisms not only in NC but also in patients with chronic musculoskeletal pain, including FM. Distraction did not seem to contribute to this analgesic effect.

Insensitivity to pain is a rare disorder that is commonly associated with Hereditary Sensory and Autonomic Neuropathies (HSAN I–V) resulting often in autonomic dysfunction and premature death. Very few individuals have been reported with pain insensitivity lacking such autonomic neuropathies. We performed genetic, neurologic, psychological, and psychophysical evaluations in such an individual (OMIM 243000 ) and her first degree relatives. Sequence analysis of genomic DNA revealed two novel SCN9A mutations in this index case (IC). One was a non-conservative missense mutation (C1719R) in exon 26 present only in the IC and one parent. Further sequence analysis of the child’s DNA revealed a 1-bp splice donor deletion in intron 17 which was also present in the other parent and one sibling. Detailed psychophysical testing was used to phenotypically characterize the IC, her family members, and 10 matched normal controls. Similar to family members and controls the IC showed normal somatosensory functioning for non-nociceptive mechanoreception and warmth. However, she demonstrated diminished ability to detect cool temperatures combined with profound deficits in heat and mechanical nociception. Congenital insensitivity to pain in our IC was associated with two novel SCN9A mutations which most likely resulted in a Nav1.7 channelopathy. However, in contrast to individuals with other SCN9A mutations, the observed pain insensitivity was relative and not absolute, which may be consistent with hypomorphic effects of one or both mutations. The ability to sense at least some danger signals may be advantageous and ameliorate the otherwise increased morbidity and mortality of some individuals with congenital insensitivity to pain.

Central activation of excitatory amino acid receptors has been implicated in neuropathic pain following nerve injury. In a rat model of painful peripheral mononeuropathy, we compared the effects of non-competitive NMDA reeptor antagonists (MK 801 and HA966) and a non-NMDA receptor antagonist (CNQX) on induction and maintenance of thermal hyperalgesia induced by chronic constrictive injury (CCI) of the rat common sciatic nerve. Thermal hyperalgesia to radiant heat was assessed by using a foot-withdrawal test and NMDA/non-NMDA receptor antagonists were administered intrathecally onto the lumbar spinal cord before and after nerve injury. Four daily single treatments with 20 nmol HA966 or CNQX beginning 15 min prior to nerve ligation (pre-injury treatment), reliably reduced thermal hyperalgesia in CCI rats on days 3, 5, 7 and 10 after nerve ligation. Thermal hyperalgesia was also reduced in CCI rats receiving a single post-injury treatment with HA966 (20 or 80 nmol) or MK 801 (5 or 20 nmol) on day 3 after nerve ligation when thermal hyperalgesia was well developed. In contrast, a single post-injury CNQX (20 or 80 nmol) treatment failed to reduce thermal hyperalgesia or to potentiate effects of HA966 or MK 801 (5 or 20 nmol) on thermal hyperalgesia in CCI rats. Moreover, multiple post-injury CNQX treatments utilizing the same dose regime as employed for the pre-injury treatment attenuated thermal hyperalgesia but only when the treatment began 1 or 24 h (but not 72 h) after nerve ligation. The results suggest that NMDA and non-NMDA receptor activation may have differential roles in induction and maintenance of thermal hyperalgesia following constrictive nerve injury, and that mechanisms underlying post-injury neuropathic pain may be associated with excitatory amino acid mediated central abnormalities.

A model of the affective-motivational dimension of pain is proposed that is based on phenomenological and psychophysical observations indicating that it is comprised of two stages. The immediate unpleasantness is based on several contributing processes, the most salient of which is the painful sensation itself. It represents an integration of nociceptive and non-painful sensory inputs, such as sight and sound, and is based on the perception of immediate threat to the body and consciousness. The secondary stage of pain affect is based on more complex meanings related to the longer term implications of pain. These two stages are distinct and separately measurable since they have different relationships to nociception and the sensory-discriminative dimension of pain and because there exist pharmacological and psychological factors that can selectively influence each of these stages. The functional relationships of these two stages to specific neural structures may be a promising area of future investigation.

Neuropathic pain following nerve injury is thought to involve central nervous system Ca(2+)-mediated neuronal plastic changes. This study provides evidence that induction and/or maintenance of post-injury neuropathic pain behaviors in the rat is associated with increases in membrane-bound protein kinase C (PKC), a Ca(2+)-dependent process known to mediate central nervous system neuronal plasticity. In addition, spinal cord administration of GM1 ganglioside, an intracellular inhibitor of PKC translocation/activation, reverses both increased levels of membrane-bound PKC and pain-related behaviors. Thus, persistent post-injury neuropathic pain may be mediated by the initiation of excitatory neuropathological processes resulting from an increase in membrane-bound PKC.

Our previous experiments demonstrated that systemic treatment with GM1 ganglioside reduces nociceptive behaviors and spinal cord metabolic activity in a rat model of painful peripheral mononeuropathy produced by experimental sciatic nerve ligation (chronic constrictive injury, CCI). In the present study, we examined the effects of intrathecal (i.t.) GM1 treatment on thermal hyperalgesia and spontaneous pain behaviors resulting from nerve ligation in order to determine the locus of GM1 action. In addition, a local anesthetic agent, bupivacaine, given alone or combined with i.t. GM1, was applied to the injured sciatic nerve to determine if peripheral nerve anesthesia would influence post-injury nociceptive behaviors. Thermal hyperalgesia to radiant heat decreased in a dose-dependent manner when GM1 (10-80 nmol, i.t.) was administered once daily onto the lumbar segments of the spinal cord beginning 1 h after experimental nerve injury and continued for the first 9 days after nerve ligation. Moreover, this GM1 (80 nmol) treatment regimen reliably lowered spontaneous pain behavior rating scores in CCI rats suggesting the possible attenuation of spontaneous pain. The central site of i.t. GM1 action is located at the caudal (probably lumbar) spinal cord, since i.t. injection of 20 nmol GM1 onto the cervical spinal cord did not produce any protective effect. A single perinerve injection of a local anesthetic agent, bupivacaine (0.5%, 0.6 ml), on the 3rd day after nerve ligation reduced thermal hyperalgesia for at least 24 h following injection, a duration longer than that of the local anesthetic action of bupivacaine. Neither a single bupivacaine injection nor four daily i.t.(ABSTRACT TRUNCATED AT 250 WORDS)

During the last two decades there has been a proliferation of studies evaluating the psychophysical and neural attributes of heat-induced pain. Experiments using radiant and contact heat-induced pain have produced different observations thereby broadening our appreciation of the importance of acknowledging how a noxious heat stimulus is delivered; moreover manipulations of stimulus parameters have now provided a foundation for understanding the underlying neural mechanisms of heat-induced pain and their biological significance. The psychophysical attributes of heat-induced pain include highly reliable thresholds for most body regions, minimal adaptation to maintained noxious stimuli, an exquisite sensitivity to small changes in stimulus intensity, slow temporal summation for some types of heat-induced pain (i.e., second pain) but not for others (i.e., first pain), spatial summation---especially for suprathreshold noxious temperatures---and the perceived spread of pain well beyond the actual body area stimulated (i.e., radiation). The present body of information indicates that the pain system is optimally adapted for conveying precise information about intensity, and is less concerned with other stimulus features, such as spatial patterns or boundaries.

Manual therapy is a complementary and alternative medicine encompassing numerous techniques in which a force is directed towards a given structure of the body. Neurodynamic techniques (NDT) are a form of manual therapy in which forces are intended to be directed to the neural structures through positioning and movement of multiple joints.13 Physical therapists may include NDT in the treatment of musculoskeletal pain and, specific to the present study, these techniques have shown promise in the treatment of carpal tunnel syndrome (CTS).66,72,81,92 However, a limitation of the current literature is the lack of a validated sham comparison in randomized controlled trials of the effectiveness of NDT. An appropriate sham could provide further evidence as to the efficacy of NDT and insight into the underlying mechanisms of NDT in the treatment of musculoskeletal pain. A prerequisite of a valid sham for NDT is to provide adequate blinding of participants to the type of intervention they are receiving.48,49,98 To our knowledge, a sham-controlled trial of NDT has not previously been performed; however, prior studies of manual therapy have included sham interventions such as light touch,52 light massage,49 subtherapeutic ultrasound,24 and detuned laser.73 A limitation of these studies is the failure to assess whether participants were adequately blinded to which intervention they received24,73 or whether participant expectation of benefit for the comparison groups were similar.24,49,52,73 The results of sham-controlled studies could be confounded by a significant number of participants receiving the sham intervention, believing they were not receiving an active intervention. Additionally, participants receiving a sham intervention may believe they received an active intervention. However, the sham may provoke lower expectations for treatment effectiveness than the studied intervention. For example, while detuned ultrasound or light touch may be believable as active interventions, they may produce lower expectations among participants for their ability to lessen musculoskeletal pain than a comparative manual therapy intervention. Consequently, both the sham intervention and the studied manual therapy technique may be believable as active interventions, but produce different expectations for their ability to help the individual. These points are reinforced by the observations of placebo-controlled studies unrelated to manual therapy, in which outcomes were not dependent on the intervention received but, rather, on the intervention the participant thought he or she received.2,65 Furthermore, studies have observed expectation as influential in the outcomes associated with manual therapy.7,57 Consequently, a valid sham intervention should blind participants to the intervention group to which they are assigned and should provide similar expectations for treatment success as the studied intervention. In addition to believability, a negligible treatment effect is suggested as a prerequisite for a sham intervention for manual therapy.48,49,98 As the literature suggests a powerful effect of placebo on pain,75,96,97 sham interventions with negligible treatment effects may be inappropriate for manual therapy studies. The current placebo literature suggests, “The focus has shifted from the ‘inert’ content of the placebo agent (eg, starch capsules) to the concept of a simulation of an active therapy within a psychosocial context.”76 Consequently, a believable sham intervention for manual therapy is likely to produce some positive treatment effect. A valid sham for NDT could provide important clues to the mechanisms through which these techniques produce clinical outcomes. Both biomechanical22,36 and neurophysiological effects20,69,71 are associated with manual therapy and are potentially pertinent to NDT. A biomechanical mechanism of NDT is plausible, as adhesions and edema accompany CTS27,28,33,70 and may be responsible for the subsequent signs and symptoms. Furthermore, individuals with CTS may present with limited mobility of the median nerve.26,53 Both in vivo and in vitro studies have demonstrated movement and stress localized to the median nerve with the performance of specific NDT.21,22 Consequently, NDT may be of benefit to individuals experiencing CTS due to biomechanical mechanism such as restoration of mobility to the median nerve13 or the mobilization of edema.12 A neurophysiological mechanism of NDT is also possible, as manual therapy has been theorized to directly mediate neuroplastic changes associated with pain.10 Neuroplastic changes are changes in neurons within the central nervous system in response to stimulation and are suggestive of an adaptive rather than fixed nervous system. Specific to CTS, prior studies have observed altered central processing of pain31,94,95,104 associated with CTS suggestive of neuroplastic changes resulting from prolonged irritation of the median nerve. For example, Fernandez-de-las-Penas et al31 observed generalized decreased threshold to pressure pain in individuals with CTS as compared to healthy controls, suggesting a centrally mediated response to pain. Consequently, NDT may be effective in the treatment of CTS by inducing neuroplastic changes. Support for this theory is provided by immediate hypoalgesia associated with other forms of manual therapy.34,38,91,102 A validated sham control for NDT would allow insight into whether treatment effects are dependent upon a specific stress across the median nerve for individuals with CTS or more general effects of treatment. Additionally, a validated sham could provide a means to test the magnitude of the placebo effect of NDT through a comparison of the outcomes associated with the sham to those associated with NDT and natural history. This randomized trial of NDT in the treatment of participants with CTS had 3 primary purposes. First, we tested the believability of a novel sham for NDT in study participants. We have reported on a potential sham technique in healthy participants exposed to experimental pain5 and wished to study the same technique in a clinical sample. We hypothesized that participants in our study would have similar beliefs for which intervention they received and similar expectations for treatment success, regardless of treatment group assignment. Second, we studied immediate changes in clinical pain intensity and experimental pain sensitivity as an indirect measurement of a potential mechanism of NDT. Immediate hypoalgesia to clinical pain and increases in mechanical pain threshold have been associated with other forms of manual therapy18,91,99,100 and suggests a neurophysiological mechanism of action. Additionally, we have previously observed hypoalgesia of temporal summation associated with spinal manipulation in healthy participant,38 in those experiencing low back pain,8 and associated with NDT5 in healthy participants. Temporal summation is a behavioral measure of central sensitization, characterized by the perception of increasing pain intensity to repetitive heat pulses of unchanging temperature provided at a frequency of less than 3 seconds. Temporal summation has not previously been assessed in individuals with CTS to our knowledge; however, individuals with musculoskeletal pain conditions such as fibromyalgia77,88 and temporomandibular joint dysfunction78,84 demonstrate greater magnitude of temporal summation than healthy controls. Additionally, temporal summation has been observed to significantly contribute to pain-related disability in individuals with chronic low back pain.39 Consequently, temporal summation appears to be a valid measure of pain sensitivity in other musculoskeletal pain conditions worthy of assessment in individuals with CTS. Temporal summation is a proximal measure of dorsal horn excitability,23,42,45,67 and inhibition of temporal summation from NDT could represent a mechanism of action for pain relief. We hypothesized that participants receiving NDT would experience greater immediate within-session inhibition of clinical pain, temporal summation, thermal pain threshold, and pressure pain threshold in comparison to those receiving a sham technique. Confirmation of this hypothesis would suggest that NDT elicits a neurophysiological response beyond that of a sham related to hypoalgesia and, in the case of temporal summation, specific to inhibition of dorsal horn excitability. Our third purpose was to compare outcomes related to pain intensity, upper extremity disability, and neurological status in participants with CTS randomly assigned to receive an NDT specific to the median nerve14,21,22,103 and a sham technique intended to lessen the biomechanical stresses to the median nerve. We hypothesized that participants receiving the NDT would demonstrate greater improvements in measures of clinical pain and disability than those receiving the sham intervention. Additionally, concern has been raised that a direct stretch across a nerve, as implied by some methods of NDT, has the potential for detrimental effects.21,22,40,87 Consequently, we monitored neurological status in participants and hypothesized that worsening of neurological status would not be observed in either treatment group.

Objective. To define patient-determined success criteria for fibromyalgia and back pain treatment across four outcome domains: pain, fatigue, emotional distress, interference with daily activities. Design. Retrospective correlational clinical sample design. Setting. Tertiary care clinics at health science center. Patients. 248 fibromyalgia patients and 52 back pain patients. Interventions. N/A. Outcome Measures. Patient Centered Outcomes Questionnaire, measures of usual pain intensity and pain unpleasantness. Results. Overall, for treatment to be considered successful, fibromyalgia patients required pain levels of 3.30 (54% reduction), fatigue levels of 3.08 (60% reduction), distress levels of 2.49 (60% reduction), and interference levels of 2.67 (63% reduction). Comparatively, back pain patients required pain levels of 2.23 (58% reduction), fatigue levels of 2.29 (57% reduction), distress levels of 1.65 (67% reduction), and interference levels of 1.81 (68% reduction). Overall, both fibromyalgia and back pain patients did not expect to meet their criteria for success. Conclusions. Results highlight the importance of assessing the patient's view of successful outcome. Both fibromyalgia and back pain patients appear to have stringent criteria for success that existing treatments are often unlikely to meet. Comparison across groups indicated fibromyalgia patients have higher usual levels of pain, fatigue, distress, and interference. Interestingly, fibromyalgia patients also require greater changes across domains in order to consider treatment successful, despite rating higher levels of pain, fatigue, distress, and interference as successful. Recognizing patients' success criteria and treatment expectations encourages discussion and development of individualized treatment goals, and wider implementation of individualized treatment for chronic-pain populations is encouraged.

Recent meta-analyses find various magnitudes of placebo analgesia effects in placebo mechanism trials versus placebo control trials, which have led to debate. To further investigate the magnitude of placebo analgesia in placebo mechanism trials the databases "PubMed", "PsycINFO" and "Web of Science" (2002-2007) were searched with the term "placebo analgesia". Twenty-one articles including 24 studies fulfilled the selection criteria (concerning: mechanisms, control, placebo treatment, randomization and pain measures). The validity of studies was assessed by the authors and effect sizes were calculated via difference scores. The magnitude of placebo analgesia in placebo mechanism studies was large (d=1.00) and about five times larger than placebo analgesia effects in placebo control studies (d=0.15-0.27). Differences in magnitude between the two types of studies appear to result from different types of suggestions given for pain relief. The magnitude of placebo effects was larger in studies that used long-term pain stimuli >20s (d=0.96) as opposed to short-term stimuli (d=0.81) and the largest placebo effects were found in studies wherein hyperalgesia was present (d=1.88). These results replicate our previous finding that placebo analgesic effects are higher in mechanism studies than in placebo control studies. However, since magnitudes of placebo analgesic effects are highly variable it may be valuable to investigate the factors and mechanisms that contribute to this variability as well as differences in magnitudes across types of studies.

Long-duration pain and encoding of the distinction between non-nociceptive and nociceptive stimulation is subserved by neurons of the deep layers of the dorsal horn and in the ventrolateral ascending spinal pathways. Long-duration states of hyperexcitability are maintained in these spinal regions by

The study of pain could benefit from approaches that study mechanisms whereby sensory input is shaped by principles of self-organization. Multisensory integration represents a set of self-organizing principles wherein various dimensions of pain experience, such as perceived degree of threat presented by an object, may be partly related to spatiotemporal convergence of multisensory information. Similar self-organizing principles might explain the integration of sensory aspects of pain with other functions, such as memory and learning.

Previously, we demonstrated that placebo analgesia (PA) accompanies reductions in neural activity during painful stimulation. This study investigated areas of the brain where the neural activity was increased during PA. The literature has associated PA with two potential mechanisms of action; one sustained (e.g., engaged for the duration of PA), the other, transitory (e.g., a feedback mechanism). We propose that PA results from the engagement of two complementary pain-modulation mechanisms that are identified with f MRI data as a main effect for condition or a time ∗ condition interaction. The mechanism with sustained activity should activate the emotional regulation circuitry needed for memory formation of the event. The mechanism with transient activity should process cognitive and evaluative information of the stimuli in the context of the placebo suggestion to confirm the expectations set by it. To identify regions involved with these mechanisms, we re-analyzed f MRI data from two conditions: baseline (B) and PA. Results support the presence of both mechanisms, identified as two neural-networks with different temporal characteristics. Regions with sustained activity primarily involved the temporal and parahippocampal cortices. Conversely, brain regions with transient activity included linguistic centers in the left hemisphere and frontal regions of the right hemisphere generally associated with executive functioning. Together, these mechanisms likely engage analgesic processes and then simply monitor the system for unexpected stimuli, effectively liberating resources for other processes. Identifying brain regions associated with pain-modulation with different temporal profiles is consistent with the multidimensionality of PA and highlights the need for continued investigation of this construct.

We regret the typo and acknowledge that the open label run-in phase of the FREEDOM trial lasted 6 weeks [1]. However, we continue to have concerns regarding the validity of data obtained by FREEDOM using an Enriched Enrollment with Randomized Withdrawal (EERW) study design as described in our previous editorial [4]. While this approach may be efficacious clinically, we do not think that sensitivity analyses as suggested by Dr. Crofford, will overcome the problem that prior exposure to an experimental treatment in an open label qualification phase may invalidate drug-placebo comparisons made during a later randomized, double-blinded phase. Because in enrichment designs, the same patients are exposed to several drug and non-drug conditions, the probability of detecting the drug condition becomes enhanced, particularly through drug withdrawal effects that may be very different from the drug’s side effects. These concerns are particularly relevant because of the relatively rapid pregabalin taper used in the placebo group. Most importantly, placebo effects may have inflated the responder analysis. Any cues, no matter how subtle, may increase the somatic focus of study participants, a factor that has been shown to play an important role for placebo effects [2; 3]. Thus true drug effects may have been magnified by placebo related factors, including expectations and conditioning. We think that sensitivity analyses as done in the FREEDOM trial are unlikely to resolve these concerns because no single effect, side effect, or withdrawal symptom may account for problems related to EERW trials. All that is required is that the overall profile of symptoms and side-effect changes provide sufficient cues for patients to notice that they are still receiving or no longer receiving the study medication. Although our comments are not meant to imply that pregabalin does not have any long term efficacy for FM pain, we would like to emphasize that only direct measurement of placebo factors, including patients’ expectations and verification of allocation concealment will allow precise estimates of true treatment effects.

Comparisons of measurement characteristics were made for three types of electronic pain scales: (a) visual analogue scale (VAS), (b) VAS combined with an electronic number box (VAS-N; 0-100), and (c) electronic number box scale (NUM). The three scales were capable of discriminating pain sensations from very small (0.5 degrees C) temperature steps in 13 healthy males, 26 healthy females, and 16 female fibromyalgia (FM) patients. All scales provided monotonic functions when used by subjects to rate pain from 5s nociceptive temperatures (45-49 degrees C), thereby demonstrating the generality of these results across different demographic groups. As expected, FM patients rated heat pain sensations higher on all scales in comparison to healthy females, demonstrating the capacity of these scales to detect well-established group differences in pain sensitivity that exist across these two groups. However, in comparison to male subjects, healthy females gave higher NUM but not VAS or VAS-N ratings to the range of nociceptive presented temperatures. We interpret this difference as a selective scaling bias of female subjects for NUM. Finally, all three groups (total of 55 subjects) found the scales easy to use after brief instructions, though subjects strongly preferred the use of VAS-N or VAS in comparison to NUM scale.

Chronic abdominal pain is a common gastrointestinal symptom experienced by patients. We have previously shown that IBS patients with visceral hypersensitivity also have evidence of thermal hypersensitivity of the hand and foot that is reversed by rectal lidocaine jelly. We have also recently developed an animal model of chronic visceral and somatic hypersensitivity in rats treated with intracolonic trinitrobenzene sulfonic acid (TNBS). The objective of the current study was to determine the effects of intracolonic lidocaine on visceral/somatic hypersensitivity in TNBS-treated rats. A total of 20 hypersensitive rats received either 20 mg intracolonic lidocaine (n = 10) or saline jelly (n = 10). In comparison to saline jelly, intracolonic lidocaine jelly reduced responses to nociceptive visceral/somatic stimuli in hypersensitive rats. The effects were present within 5–30 min after administration of lidocaine and lasted for 6 h. Lidocaine had no effects on recovered rats or control rats that had originally been treated with intracolonic saline instead of TNBS. Local anesthetic blockade of peripheral impulse input from the colon reduces both visceral and somatic hypersensitivity in TNBS-treated rats, similar to results in IBS patients. The results provide further evidence that visceral and secondary somatic hypersensitivity in a subset of TNBS-treated rats reflect central sensitization mechanisms maintained by tonic impulse input from the colon. This study evaluates the reversal of visceral/somatic hypersensitivity in a subset of TNBS-treated rats with intracolonic lidocaine. This animal model may be used in the future to study the mechanisms of local anesthetic agents applied to the gut to reduce visceral pain.

The National Alzheimer's Coordinating Center (NACC) is responsible for developing and maintaining a database of participant information collected from the 29 Alzheimer's Disease Centers (ADCs) funded by the National Institute on Aging (NIA). The NIA appointed the ADC Clinical Task Force to determine and define an expanded, standardized clinical data set, called the Uniform Data Set (UDS). The goal of the UDS is to provide ADC researchers a standard set of assessment procedures, collected longitudinally, to better characterize ADC participants with mild Alzheimer disease and mild cognitive impairment in comparison with nondemented controls. NACC implemented the UDS (September 2005) by developing data collection forms for initial and follow-up visits based on Clinical Task Force definitions, a relational database, and a data submission system accessible by all ADCs. The NIA requires ADCs to submit UDS data to NACC for all their Clinical Core participants. Thus, the NACC web site (https://www.alz.washington.edu) was enhanced to provide efficient and secure access data submission and retrieval systems.

Background Breast cancer surgery is associated with side effects, including postsurgical pain, nausea, and fatigue. We carried out a randomized clinical trial to test the hypotheses that a brief presurgery hypnosis intervention would decrease intraoperative anesthesia and analgesic use and side effects associated with breast cancer surgery and that it would be cost effective. Methods We randomly assigned 200 patients who were scheduled to undergo excisional breast biopsy or lumpectomy (mean age 48.5 years) to a 15-minute presurgery hypnosis session conducted by a psychologist or nondirective empathic listening (attention control). Patients were not blinded to group assignment. Intraoperative anesthesia use (i.e., of the analgesics lidocaine and fentanyl and the sedatives propofol and midazolam) was assessed. Patient-reported pain and other side effects as measured on a visual analog scale (0 – 100) were assessed at discharge, as was use of analgesics in the recovery room. Institutional costs and time in the operating room were assessed via chart review. Results Patients in the hypnosis group required less propofol (means = 64.01 versus 96.64 µ g; difference = 32.63; 95% confidence interval [CI] = 3.95 to 61.30) and lidocaine (means = 24.23 versus 31.09 mL; difference = 6.86; 95% CI = 3.05 to 10.68) than patients in the control group. Patients in the hypnosis group also reported less pain intensity (means = 22.43 versus 47.83; difference = 25.40; 95% CI = 17.56 to 33.25), pain unpleasantness (means = 21.19 versus 39.05; difference = 17.86; 95% CI = 9.92 to 25.80), nausea (means = 6.57 versus 25.49; difference = 18.92; 95% CI = 12.98 to 24.87), fatigue (means = 29.47 versus 54.20; difference = 24.73; 95% CI = 16.64 to 32.83), discomfort (means = 23.01 versus 43.20; difference = 20.19; 95% CI = 12.36 to 28.02), and emotional upset (means = 8.67 versus 33.46; difference = 24.79; 95% CI = 18.56 to 31.03). No statistically significant differences were seen in the use of fentanyl, midazolam, or recovery room analgesics. Institutional costs for surgical breast cancer procedures were $8561 per patient at Mount Sinai School of Medicine. Patients in the hypnosis group cost the institution $772.71 less per patient than those in the control group (95% CI = 75.10 to 1469.89), mainly due to reduced surgical time. Conclusions Hypnosis was superior to attention control regarding propofol and lidocaine use; pain, nausea, fatigue, discomfort, and emotional upset at discharge; and institutional cost. Overall, the present data support the use of hypnosis with breast cancer surgery patients.

OBJECTIVE Sensory testing has been advocated for the diagnosis, prognosis, and outcome evaluation of pain patients, but responses to controlled stimuli have not been well correlated to clinical pain. As an initial step for improving the clinical relevance of sensory testing, this investigation compared appraisals of and responses to controlled pain stimuli. DESIGN A prospective within subjects design was used. METHODS Heat, ischaemic, and delayed-onset muscle pain were induced in the upper extremity of 44 participants (47.7% women) during four experimental sessions. RESULTS The threat of heat and ischaemic pain was higher than delayed-onset muscle pain (F(2,86) = 5.30, p

Temporal summation of “second pain” (TSSP) is the result of C-fiber-evoked responses of dorsal-horn neurons, termed “windup”. This phenomenon is dependent on stimulus frequency (⩾0.33 Hz) and relevant for central sensitization as well as chronic pain. Whereas, our previous functional magnetic resonance imaging (fMRI) study characterized neural correlates of TSSP in 11 healthy volunteers, the present study was designed to compare brain responses associated with TSSP across these healthy participants and 13 fibromyalgia (FM) patients. Volume-of-interest analysis was used to assess TSSP-related brain activation. All participants underwent fMRI-scanning during repetitive heat pulses at 0.33 Hz and 0.17 Hz to the right foot. Stimulus intensities were adjusted to each individual’s heat sensitivity to achieve comparable TSSP-ratings of moderate pain in all subjects. Experimental pain ratings showed robust TSSP during 0.33 Hz but not 0.17 Hz stimuli. When stimulus strength was adjusted to induce equivalent levels of TSSP, no differences in activation of pain-related brain regions occurred across NC and FM groups. Subsequently, the fMRI-data of both groups were combined to increase the power of our statistical comparisons. fMRI-statistical maps identified several brain regions with stimulus and frequency dependent activation consistent with TSSP, including ipsilateral and contralateral thalamus, medial thalamus, S1, bilateral S2, mid- and posterior insula, rostral and mid-anterior cingulate cortex. However, the stimulus temperatures necessary to evoke equivalent levels of TSSP and corresponding brain activity were less in FM patients. These results suggest that enhanced neural mechanisms of TSSP in FM are reflected at all pain related brain areas, including posterior thalamus, and are not the result of selective enhancement at cortical levels.

Background. Chronic abdominal pain is one of the most common gastrointestinal symptoms experienced by patients. Visceral hypersensitivity has been shown to be a biological marker in many patients with chronic visceral pain. We have previously shown that IBS patients with visceral hypersensitivity also have evidence of thermal hyperalgesia of the hand/foot. Objective. The objective of the current study was to develop an animal model of chronic visceral and somatic hypersensitivity in rats treated with intracolonic trinitrobenzene sulfonic acid. Design. Male Sprague–Dawley rats (200–250 g) were treated with either 20 mg/rat trinitrobenzene sulfonic acid (TNBS, Sigma Chemical Co.) in 50% ethanol (n = 75), an equivalent volume of 50% ethanol (n = 20) or an equivalent volume of saline (n = 20). The agents were delivered with a 24-gauge catheter inserted into the lumen of the colon. Mechanical and thermal behavioral tests were performed using an automated von Frey and Hargreaves device to evaluate somatic hyperalgesia. Colonic distension was performed using an automated distension device to evaluate visceral pain thresholds. All animals were tested 16 weeks after TNBS treatment following complete resolution of the colitis. Results. At 16 weeks, 24% of the treated rats (18/75 rats) still exhibited evidence of visceral as well as somatic hypersensitivity compared to saline- and ethanol-treated rats. Conclusion. Transient colonic inflammation leads to chronic visceral and somatic hypersensitivity in a subset of rats. These findings are similar to the subset of patients who develop chronic gastrointestinal symptoms following enteric infection.

We are at a critical juncture in our knowledge of the etiology and pathogenesis of Parkinson disease (PD). It is clear that PD is not a single entity simply resulting from a dopaminergic deficit; rather it is most likely caused by a combination of genetic and environmental factors and, although there is extensive new information on the etiology and pathogenesis of PD that may advance its treatment, new syntheses of this information are needed. The first part of this two-part, state-of-the-art review by leaders in Parkinson research critically examines the field to identify where new knowledge and ideas might be helpful for treatment purposes. Topics reviewed in Part I include the definition of the disease, neuropathologic contributions, and epidemiologic, environmental, and demographic issues. ### Current Knowledge The definition of idiopathic Parkinson disease (PD) remains controversial. Classically, it includes a characteristic motor phenotype (1) and a distinctive neuropathology and substantial loss of dopaminergic neurons from the substantia nigra associated with the presence of α-synuclein-positive inclusions in the cell body (Lewy bodies) and processes (Lewy neurites) of specific neurons of the brainstem. ### Parkinson Syndrome Without Synucleinopathy Some genetically determined Parkinson syndromes resemble, sometimes closely, idiopathic PD, but differ from it neuropathologically, sometimes substantially. In particular, a number of juvenile-onset autosomal recessive cases of familial Parkinson syndrome do not have α-synuclein lesions (2), contrasting with the autosomal dominant forms of the disease which often have unusual types of lesions (3-5). The recently identified leucine-rich repeat kinase 2 ( LRRK2, Park-8 ) mutations produce variable pathologic phenotypes. Although the most common is Lewy body disease, nigral degeneration with ubiquitin inclusions or, in a few cases, even pathologic changes more typical of frontotemporal lobar degeneration or progressive supranuclear palsy have been described in patients with LRRK2 mutations (6). Two recent reports insist on the high prevalence of Lewy bodies in the LRRK2 mutations (7 …

While ethics of placebo use has been debated since discovery of the phenomena, there has yet to be a study that examines the aftereffect of individuals learning of a personal placebo response on their future ability to experience a placebo response. In the first study, eleven participants diagnosed with irritable bowel syndrome in a placebo study were interviewed individually about their personal placebo response. We found no changes in attitudes about the likelihood of using medical and non-medical treatments for pain, likelihood of participating in future studies, or likeability and trust of experimenters. In addition, we found no changes in mood except for a slight improvement in frustration. In the second study, 77 undergraduate students from the University of Florida were divided into three conditions: placebo, control and repeated baseline. We used a double placebo design with verbal placebo suggestion and conditioning to induce a placebo response and to examine the effect of providing information about a participant’s personal placebo response on their future placebo response. Using a heat thermode, we discovered that there were no differences in future pain responding between participants who were told that they experienced a placebo response versus those who were not. In addition, similar to the first study, we found no detrimental effects of the placebo information variables measured. These studies suggest the placebo response persists even after revelation of a personal placebo response and placebo use does not appear to cause adverse effects on mood and other attitude variables assessed.

Pain requires the integration of sensory, cognitive, and affective information. The use of placebo is a common methodological ploy in many fields, including pain. Neuroimaging studies of pain and placebo analgesia (PA) have yet to identify a mechanism of action. Because PA must result from higher order processes, it is likely influenced by cognitive and affective dimensions of the pain experience. A network of brain regions involved in these processes includes the anterior and posterior insula (A-Ins, P-Ins), dorsal anterior cingulate cortex (DACC), dorsolateral prefrontal cortex (DLPFC), and the supplementary motor area (SMA). We used connectivity analyses to investigate the underlying mechanisms associated with Placebo analgesia in a group of chronic pain patients. Structural equation models (SEM) of fMRI data evaluated the inter-regional connectivity of these regions across three conditions: (1) initial Baseline (B1), (2) placebo (PA), and (3) Placebo Match (PM). SEM results of B1 data in the left hemisphere confirmed hypothesized regional relationships. However, inter-regional relationships were dynamic and the network models varied across hemispheres and conditions. Deviations from the B1 model in the PA and PM conditions correspond to our manipulation of expectation for pain. The dynamic changes in inter-regional influence across conditions are interpreted in the context of a self-reinforcing feedback loop involved in the induction and maintenance of PA. Although it is likely that placebo analgesia results partly from afferent inhibition of a nociceptive signal, the mechanisms likely involve the interaction of a cognitive-affective network with input from both hemispheres.

La reduccion del dolor mediante hipnosis se basa en los cambios inducidos por la sugestion en la experiencia del dolor. Estos cambios se ven facilitados por las alteraciones que se producen en la conciencia, alteraciones que van acompanadas de cambios en la actividad cerebral implicada en la regulacion de la conciencia. La reduccion hipnotica del dolor puede consistir en cambios selectivos en la dimension afectiva de la experiencia dolorosa o en la reduccion que tiene lugar tanto en la dimension sensitiva como en la afectiva, dependiendo de la naturaleza de la sugestion (ordenes hipnoticas). Los cambios en los components afectivo y sensitivo del dolor estan asociados con los correspondientes cambios en la actividad de la circunvolucion del cuerpo calloso y en la corteza somatosensitiva, respectivamente. Existen diferentes formas de reduccion hipnotica del dolor que son de utilidad en la practica clinica.

La expectativa de que el dolor va a disminuir ejerce un efecto analgesico poderoso. Este efecto puede producirse incluso en situaciones clinicas en las que existe un dolor intenso. Dependiendo del condicionamiento y de las instrucciones verbales, el efecto analgesico placebo puede conseguirse de forma inmediata en un porcentaje importante de pacientes, y, seguramente, en la mayoria de los pacientes que padecen un dolor intenso. Actualmente, se esta empezando a conocer la neurobiologia de la analgesia mediante placebo. La evidencia demuestra que la comunicacion verbal o las senales verbales predictivas de analgesia provocan una expectativa de analgesia que, a su vez, esta asociada con la activacion de un circuito cerebral que incluye la zona anterior de la circunvolucion del cuerpo calloso y un mecanismo troncoencefalico mediado por los opioides endogenos que controla el funcionamiento de las neuronas transmisoras del dolor del asta dorsal. Un conocimiento mas completo de la respuesta analgesica placebo podria dar lugar a la aparicion de nuevos procedimientos terapeuticos basados en metodos psicologicos ideados para activar el circuito cerebral de modulacion del dolor. Serviria, ademas, para mejorar los aspectos eticos del componente placebo de los tratamientos activos.

Large individual differences in pain sensitivity present a challenge for medical diagnosis and may be of importance for the development of chronic pain. Variance in pain sensitivity is partially mediated by genetic factors, but the extent of this contribution is uncertain. We examined cold-pressor pain and contact heat pain in 53 identical (MZ) and 39 fraternal (DZ) twin pairs, and 4 single twins to determine the heritability of the two phenotypes, and the extent to which the same genetic and environmental factors affect both pain modalities. An estimated 60% of the variance in cold-pressor pain and 26% of the variance in heat pain was genetically mediated. Genetic and environmental factors were only moderately correlated across pain modalities. Genetic factors common to both modalities explained 7% of the variance in cold-pressor and 3% of the variance in heat pain. Environmental factors common to both modalities explained 5% of variance in cold-pressor and 8% of the variance in heat pain. The remaining variance was due to factors that were specific to each pain modality. These findings demonstrate that cold-pressor pain and contact heat pain are mainly distinct phenomena from both a genetic and an environmental standpoint. This may partly explain disparate results in genetic association studies and argues for caution in generalizing genetic findings from one pain modality to another. It also indicates that differences in pain scale usage account for a minor portion of the variance, providing strong support for the validity of subjective pain ratings as measures of experienced pain.

Brain processing of pain in humans is based on multiple ascending pathways and brain regions that are involved in several pain components, such as sensory, immediate affective, and secondary affective dimensions. These dimensions are processed both serially and in parallel. They include spinal ascending pathways that directly target limbic and brainstem structures involved in pain-related emotions as well as a pathway proceeding from the somatosensory cortices to limbic cortical areas. Superimposed on this neural organization is the capacity to process the dimensions of pain in multiple ways, as in patients who lack one cerebral hemisphere but can nevertheless locate and rate pain intensity and pain unpleasantness on both sides of the body. The dimensions of pain also can be psychologically modulated in multiple ways and these changes are accompanied by corresponding changes in relevant brain structures. Finally, understanding psychological modulation of pain and pain-related brain activity is optimized by a scientific framework that integrates principles of contemporary physics, neuroscience, and human experiential science.

Impulse frequency and number of recruited central neurons are relevant for pain encoding and temporal as well as spatial summation of pain (SSP). Whereas SSP of heat-induced pain is well characterized, mechanical SSP (MSSP) has been less studied. MSSP may be relevant for chronic pain conditions like fibromyalgia (FM) and play an important role in the pathogenesis of this chronic pain syndrome. Our study was designed to determine MSSP in twelve normal controls (NC) and eleven FM subjects. MSSP testing consisted of 5sec supratheshold pressure-pain stimulations of forearm muscles by up to three identical probes (separated by 4cm or 8cm). The stimulated areas ranged between 0.79cm2 and 2.37cm2. The subjects rated the pain intensity of mechanical stimuli as well as pain aftersensations. Although MSSP increased monotonically in NC and FM subjects, pressure pain and pressure pain aftersensations were greater in FM subjects and highly associated with clinical pain intensity (r2= .44 to .64), suggesting that spatial and temporal summation factors may contribute to overall clinical pain. However, despite higher experimental pain ratings, the magnitude of MSSP was not statistically different between NC and FM subjects. Furthermore, muscle stimuli elicited more MSSP when separated by 8cm than 4cm and this finding was not different between NC and FM subjects. Thus, mechanisms of MSSP were similar for both FM and NC subjects. The important role of MSSP for pain encoding suggests that decreasing pain in some muscle areas by local anesthetics or other means, may improve overall clinical pain of FM patients.

The concepts of visceral hyperalgesia and visceral hypersensitivity have been examined in a variety of functional gastrointestinal disorders (FGIDs). Although the pathophysiological mechanisms of pain and hypersensitivity in these disorders are still not well understood, exciting new developments in research have been made in the study of the brain-gut interactions involved in the FGIDs.

N-Methyl- d -aspartic acid (NMDA) receptors are known to function in the mediation of pain and have a significant role in the development of hyperalgesia following inflammation. Serine phosphorylation regulation of NMDA receptor function occurs in a variety of conditions. No studies have demonstrated a change in phosphorylation of enteric NMDA receptors following colonic inflammation. We examined the levels of NMDA NR1 phosphorylation in trinitrobenzene sulfonic acid (TNBS) induced colitis in rats and compared it to protein translation and the development of visceral hypersensitivity. We have previously, demonstrated an increase in the C1 cassette of NR1 mRNA expression at 14, 21, and 28 days following TNBS administration. In this study, we examined the NR1 serine phosphorylation at 14 days following TNBS injection. Male Sprague–Dawley rats (200–250 g) were treated with TNBS (20 mg per rat) diluted in 50% ethanol (n = 3) and vehicle controls of 50% ethanol (n = 3). TNBS and vehicle controls were administered with a 24 gauge catheter inserted into the lumen of the rat colon. The animals were sacrificed at 14 days after induction of the colitis and their distal colon was retrieved for two-dimensional (2D) western blot analysis. Serine phosphorylation of the NR1 subunit with C1 cassette appears at 14 days after TNBS injection. In contrast, there was no NR1–C1 expression in the vehicle controls and untreated normal controls. These results suggest a role for colonic-NMDA receptor phosphorylation in the development of neuronal plasticity following colonic inflammation. Phosphorylation of NR1 may partially explain visceral hypersensitivity present during colonic inflammation.

There is convincing evidence that acupuncture (AP) is effective for the treatment of postoperative and chemotherapy-induced nausea/vomiting, as well as postoperative dental pain. Less convincing data support AP's efficacy for chronic pain conditions, including headache, fibromyalgia and low back pain. There is no evidence that AP is effective in treating addiction, insomnia, obesity, asthma or stroke deficits. AP seems to be efficacious for alleviating experimental pain by increasing pain thresholds in human subjects and it appears to activate analgesic brain mechanisms through the release of neurohumoral factors, some of which can be inhibited by the opioid antagonist naloxone. In contrast to placebo analgesia, AP-related pain relief takes some time to develop and to resolve. Furthermore, repetitive use of AP analgesia can result in tolerance that demonstrates cross-tolerance with morphine. However, it appears that not all forms of AP are equally effective for providing analgesia. In particular, electro-AP seems to best deliver stimuli that activate powerful opioid and nonopioid analgesic mechanisms. Thus, future carefully controlled clinical trials using adequate electro-AP may be able to provide the necessary evidence for relevant analgesia in chronic pain conditions, such as headache, fibromyalgia, irritable bowel syndrome and low back pain.