Lack of endogenous opioid release during sustained visceral pain: A [C]carfentanil PET study

Opioidergic neurotransmission in the central nervous system is involved in somatic pain, but its role in visceral pain remains unknown. We aimed to quantify endogenous opioid release in the brain during sustained painful gastric distension. Therefore, 2 dynamic [¹¹C]carfentanil positron emission tomography scans were performed in 20 healthy subjects during 2 conditions: sustained (20 minutes) painful proximal gastric balloon distension at predetermined individual discomfort threshold (PAIN) and no distension (NO PAIN), in counterbalanced order. Pain levels were assessed during scanning using visual analogue scales and after scanning using the McGill Pain Questionnaire. Emotional state was rated after scanning using the Positive and Negative Affect Schedule. Distribution volume ratios in 21 volumes of interest in the pain matrix were used to quantify endogenous opioid release. During the PAIN compared to the NO PAIN condition, volunteers reported a significantly higher increase in negative affect (5.50 ± 1.29 versus 0.10 ± 1.08, P = .0147) as well as higher pain ratings (sensory: 74.05 ± 9.23 versus 1.50 ± 0.95, P < .0001; affective: 91.42 ± 8.13 versus 4.33 ± 6.56, P < .0001). No difference in endogenous opioid release was demonstrated in any of the volumes of interest. Thus, contrary to its somatic counterpart, no opioid release is detected in the brain during sustained visceral pain, despite similar pain intensities. Endogenous opioids may play a less important role in visceral compared to somatic pain.     

Neural correlates of painful genital touch in women with vulvar vestibulitis syndrome

Vulvar vestibulitis syndrome (VVS) is a common cause of dyspareunia in pre-menopausal women. Recent evidence points to the importance of the sensory component in VVS, particularly the heightened processing of tactile and pain sensation in the vulvar vestibule. The goal of the present study was to examine the neural basis of heightened sensitivity to touch (i.e. allodynia) in women with VVS. Using functional magnetic resonance imaging, we compared regions of neural activity in 14 women with VVS and 14 age- and contraceptive-matched control women in response to the application of mild and moderate pressure to the posterior portion of the vulvar vestibule. Intensity and unpleasantness ratings were recorded after each scan; these ratings were significantly higher for women with VVS than controls. All women with VVS described moderate pressure as painful and unpleasant, and 6 of the 14 women with VVS described mild pressure as painful and unpleasant. In contrast, none of the stimuli was painful for control women. Correspondingly, women with VVS showed more significant activations during pressure levels that they found to be either painful or non-painful than did controls during comparable pressure levels. During pressure described as painful by women with VVS, they had significantly higher activation levels in the insular and frontal cortical regions than did control women. These results suggest that women with VVS exhibit an augmentation of genital sensory processing, which is similar to that observed for a variety of syndromes causing hypersensitivity, including fibromyalgia, idiopathic back pain, irritable bowel syndrome, and neuropathic pain.     

Was That Painful or Nonpainful? The Sensation and Pain Rating Scale Performs Well in the Experimental Context

In experiments on pain, participants are frequently exposed to nonpainful and painful stimuli; however, the conventional pain-rating scales lack a nonpainful range and a clear point of transition from nonpainful to painful events. The Sensation and Pain Rating Scale (SPARS) assesses the full stimulus intensity range, extending from no sensation (rating: –50) to worst pain imaginable (rating: +50), and it explicitly identifies pain threshold (rating: 0). Here, we tested the SPARS in 2 experiments by using laser heat stimuli to establish its stimulus–response characteristics (Experiment 1, N = 19, 13 stimulus intensities applied 26 times each across a 1–4 J range), and compared it to 0 to 100 scales that assess nonpainful (0: no sensation, 100: pain) and painful (0: no pain, 100: worst pain imaginable) events (Experiment 2, N?=?7, 9 stimulus intensities applied 36 times each across a 1.5–4.5 J range). Despite high inter- and intraindividual variations, we found a reasonably consistent curvilinear stimulus–response relationship (the curve flattens around pain threshold), with stable response characteristics across the range of the scale. The SPARS ratings transformed to a 0 to 100 range tended to be lower than the 0 to 100 pain rating scale in the noxious stimulus intensity range and greater than the 0 to 100 nonpainful sensation scale in the non-noxious stimulus range, likely reflecting differences in scale dimensionality. The SPARS overcomes limitations in scale range inherent to conventional pain rating scales. As such, it is well suited to experimental studies that must quantify a wider range of perceptual intensity or distinguish between painful and nonpainful events.

Multi-modal induction and assessment of allodynia and hyperalgesia in the human oesophagus

BACKGROUND AND AIMS: Experimental pain models based on single stimuli have to some degree limited visceral pain studies in humans. Hence, the aim of this study was to investigate the effect of multi-modal visceral pain stimuli of the oesophagus in healthy subjects before and after induction of visceral hyperalgesia. We used a multi-modal psychophysical assessment regime and a neurophysiological method (nociceptive reflex) for the characterisation of the experimentally induced hyperalgesia. METHODS: A probe for multi-modal (cold, warm, electrical, and mechanical) visceral stimulation was positioned in the lower part of the oesophagus in eleven healthy subjects. Mechanical stimuli were applied as distensions with a bag, which also had electrodes mounted for electrical stimulation. Thermal stimulation with temperatures from 0 to 60 degrees C was applied with re-circulating water in the bag. To assess the interaction between visceral and somatic pathways, the nociceptive withdrawal reflex to electrical stimuli at the ankle was measured with and without simultaneous mechanical oesophageal distension to painful levels. Finally, the oesophageal sensitisation was induced by perfusion with hydrochloric acid. Multimodal responses (pain threshold, stimulus response function, size of nociceptive reflex, and referred pain areas) were assessed before and after the induced hyperalgesia. RESULTS: The multi-modal psychophysical responses and reflex sizes were assessed twice before sensitisation, and the parameters were reproducible. Sensitisation of the oesophagus resulted in hyperalgesia to electrical and mechanical stimuli (29 and 35% decrease in pain threshold) and allodynia to cold and warmth stimuli (11% increase in sensory rating). After sensitisation, the referred pain area to mechanical stimuli increased more than 300% with a change in the localisation of the referred pain to all stimuli, and the amplitude of nociceptive reflex increased 100%, all indicating the presence of central hyperexcitability. CONCLUSIONS: Visceral hyperalgesia/allodynia can be induced experimentally and assessed quantitatively by the newly introduced multi-modal psychophysical assessment approach. The significant changes of the experimentally evoked referred pain patterns and of the nociceptive reflex evoked from a distant somatic structure indicate that even short-lasting visceral hyperalgesia can generate generalised sensitisation.     

TNF-alpha expression in painful and nonpainful neuropathies. (University Hospital, Basel, Switzerland) Neurology. 2001;56:1371–1377.

The objective of this study was to determine whether the cytokine tumor necrosis factor α (TNF-α) acts as a pain mediator in neuropathic pain in humans. Patients with painful neuropathies showed a stronger TNF-α immunoreactivity in myelinating Schwann cells relative to the epineurial background staining compared with patients with nonpainful neuropathy. Although there was no difference in sTNF-RI levels between painful and nonpainful neuropathies, patients with a mechanical allodynia had elevated serums sTNF-RI as compared to patients without allodynia. Conclude that TNF-α expression of human Schwann cells may be up-regulated in painful neuropathies. The elevation of sTNF-RI in patients with centrally mediated mechanical allodynia suggests that systemic sTNF-RI levels may influence central pain processing mechanisms.     

Visceral sensitivity correlates with decreased regional gray matter volume in healthy volunteers: A voxel-based morphometry study

Regional changes in brain structure have been reported in patients with altered visceral sensitivity and chronic abdominal pain, such as in irritable bowel syndrome. It remains unknown whether structural brain changes are associated with visceral sensitivity. Therefore, we present the first study in healthy individuals to address whether interindividual variations in gray matter volume (GMV) in pain-relevant regions correlate with visceral sensitivity. In 92 healthy young adults (52 female), we assessed rectal sensory and pain thresholds and performed voxel-based morphometry (VBM) to compute linear regression models with visceral sensory and pain thresholds, respectively, as independent variable and GMV in a priori-defined regions of interest (ROIs) as dependent variable. All results were familywise error (FWE) corrected at a level of P_FWE < .05 and covaried for age. The mean (±SEM) rectal thresholds were 14.78 ± 0.46 mm Hg for first sensation and 33.97 ± 1.13 mm Hg for pain, without evidence of sex differences. Lower rectal sensory threshold (ie, increased sensitivity) correlated significantly with reduced GMV in the thalamus, insula, posterior cingulate cortex, ventrolateral and orbitofrontal prefrontal cortices, amygdala, and basal ganglia (all P_FWE < .05). Lower rectal pain threshold was associated with reduced GMV in the right thalamus (P_FWE = .051). These are the first data supporting that increased visceral sensitivity correlates with decreased gray matter volume in pain-relevant brain regions. These findings support that alterations in brain morphology not only occur in clinical pain conditions but also occur according to normal interindividual variations in visceral sensitivity.     

Hypoalgesia related to elevated resting blood pressure is absent in adolescents and young adults with a history of functional abdominal pain

Elevated resting blood pressure (BP) is hypoalgesic in healthy individuals, but this effect is absent in adults with chronic somatic pain. This study tested whether BP-related hypoalgesia is similarly altered in individuals with a history of chronic visceral pain in childhood. Resting BP was assessed in 94 adolescents and young adults with a known history of childhood functional abdominal pain (FAP) and 55 comparable healthy controls. Responses to an acute heat pain stimulus were then evaluated following exposure to two laboratory stressors. A significant participant type × systolic BP (SBP) interaction (p < .005) revealed that elevated resting SBP was associated with significantly higher heat pain threshold (p < .001) in healthy controls, but was unrelated to pain threshold in the FAP group. A similar pattern was observed for heat pain tolerance, with elevated SBP linked to significantly higher pain tolerance (p < .05) in healthy controls, but unrelated to tolerance in the FAP group. Dysfunction in BP-related hypoalgesia associated with FAP was evident regardless of whether childhood FAP had resolved or still persisted at the time of laboratory testing. Subgroup analyses indicated that BP-related hypoalgesia (in healthy controls) and FAP-linked absence of this hypoalgesia was observed only among females. Result suggest that childhood visceral chronic pain may be associated with relatively long-lasting dysfunction in overlapping systems modulating pain and BP that persists even after FAP resolves. Potential implications for later hypertension risk are discussed.     

Psychophysiological responses to pain identify reproducible human clusters

Pain is a ubiquitous yet highly variable experience. The psychophysiological and genetic factors responsible for this variability remain unresolved. We hypothesised the existence of distinct human pain clusters (PCs) composed of distinct psychophysiological and genetic profiles coupled with differences in the perception and the brain processing of pain. We studied 120 healthy subjects in whom the baseline personality and anxiety traits and the serotonin transporter-linked polymorphic region (5-HTTLPR) genotype were measured. Real-time autonomic nervous system parameters and serum cortisol were measured at baseline and after standardised visceral and somatic pain stimuli. Brain processing reactions to visceral pain were studied in 29 subjects using functional magnetic resonance imaging (fMRI). The reproducibility of the psychophysiological responses to pain was assessed at 1 year. In group analysis, visceral and somatic pain caused an expected increase in sympathetic and cortisol responses and activated the pain matrix according to fMRI studies. However, using cluster analysis, we found 2 reproducible PCs: at baseline, PC1 had higher neuroticism/anxiety scores (P ? 0.01); greater sympathetic tone (P < 0.05); and higher cortisol levels (P ? 0.001). During pain, less stimulus was tolerated (P ? 0.01), and there was an increase in parasympathetic tone (P ? 0.05). The 5-HTTLPR short allele was over-represented (P ? 0.005). PC2 had the converse profile at baseline and during pain. Brain activity differed (P ? 0.001); greater activity occurred in the left frontal cortex in PC1, whereas PC2 showed greater activity in the right medial/frontal cortex and right anterior insula. In health, 2 distinct reproducible PCs exist in humans. In the future, PC characterization may help to identify subjects at risk for developing chronic pain and may reduce variability in brain imaging studies.     

Widespread hypersensitivity is related to altered pain inhibition processes in irritable bowel syndrome

The mechanisms of chronic pain in irritable bowel syndrome (IBS) have been widely investigated but remain unclear. The present study investigated the relation between visceral hypersensitivity, cutaneous thermal sensitivity, and central pain mechanisms. Rectal sensitivity was assessed with a barostat, and forearm and calf sensitivity with a contact thermode. Central mechanisms were assessed by counterirritation using sustained cold-pain to the hand and painful electric shocks to the ankle. Psychological symptoms were also assessed, using questionnaires. Female volunteers with diarrhea-predominant IBS (n = 27) and healthy controls (n = 25) participated in the study. IBS patients had lower rectal and calf pain thresholds compared to controls (p’s < 0.05). IBS patients also reported more pain than controls for rectal distensions, and heat pain on the calf and forearm (all p’s < 0.001). Cold-pain inhibited shock-pain in controls but not IBS patients (controls: −13.5 ± 5.3 vs IBS: +1.9 ± 10.5; p < 0.01). In addition, visceral hypersensitivity was significantly correlated to cutaneous thermal hypersensitivity and pain inhibition deficits, although effects were only weak and moderate, respectively. Furthermore, covariance analyses indicated that psychological factors accounted for group differences in visceral hypersensitivity and pain inhibition deficits. In conclusion, this study confirms the relation between altered pain inhibition processes and widespread hypersensitivity in IBS. The present results also suggests that psychological symptoms and altered pain processing in IBS patients may reflect at least in part, common underlying mechanisms.     

Hypersensitivity to visceral and cutaneous pain in the irritable bowel syndrome

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal illnesses and is characterized by altered visceral perception. Previous studies in IBS have failed to demonstrate altered somatic or cutaneous perception. The aims of the study were to determine whether IBS patients have visceral hypersensitivity and cutaneous heat-induced hyperalgesia restricted to lumbosacral dermatomes, consistent with a localized segmental mechanism. Twelve patients (ten women, two men) with IBS and 17 control subjects (13 women, four men) rated pain intensity and unpleasantness to distension of the rectum (35, 55 mmHg) and thermal stimulation (45, 47 degrees C) of the hand and foot. Patients with IBS demonstrated cutaneous allodynia/hyperalgesia to thermal pain applied to the hand and foot. The cutaneous hyperalgesia was pronounced in the lower extremity yet present in the upper extremity to a lesser extent. Psychological testing revealed the IBS patients report more state anxiety and a greater number of somatic symptoms that significantly correlated with most of the pain measures. However, they did not differ from controls on several personality trait measures. These results suggest that patients with IBS have visceral hyperalgesia and cutaneous hyperalgesia that is distributed over a considerable rostral-caudal distance yet optimally expressed in lumbosacral dermatomes. This distribution is consistent with patterns of spinal hyperexcitability observed in experimentally induced persistent pain conditions.     

Disease-Related Microstructural Differences in the Brain in Women With Provoked Vestibulodynia

Provoked vestibulodynia (PVD) is a chronic pelvic pain disorder affecting 16% of the female population. Neuroimaging studies have highlighted central abnormalities in PVD, similar to other chronic pelvic pain disorders, including brain regions involved in sensory processing and modulation of pain. The aim of the study was to determine alterations in the subvoxel, microstructural organization within tissues in PVD compared with healthy control participants (HCs) and a disease control group (irritable bowel syndrome [IBS]). Diffusion tensor imaging magnetic resonance imaging was conducted in 87 age-matched premenopausal women (29 PVD, 29 HCs, 29 IBS). Statistical parameter mapping of fractional anisotropy (FA) and mean diffusivity (MD) maps were used to identify microstructural difference in the brain specific to PVD or shared with IBS. PVD alterations in microstructural organization of the brain were predominantly observed in fibers associated with sensorimotor integration and pain processing that relay information between the thalamus, basal ganglia, sensorimotor, and insular cortex. PVD, compared with HCs, showed extensive increases in the FA of somatosensory and basal ganglia regions. In contrast, PVD and IBS subjects did not show any FA-related group differences. PVD subjects showed greater MD in the basal ganglia compared with HCs (higher MD in the internal capsule and pallidum) and IBS (higher MD in the putamen and pallidum). Increases in MD were associated with increased vaginal muscle tenderness and vulvar pain. The current findings highlight possible shared mechanisms between 2 different pelvic pain disorders, but also highlight the widespread alterations observed specifically in PVD compared with HCs.

Specialized Pro-resolving Mediators Reduce Pro-nociceptive Inflammatory Mediator Production in Models of Localized Provoked Vulvodynia

Localized provoked vulvodynia (LPV) is the most common cause of chronic dyspareunia in premenopausal women, characterized by pain with light touch to the vulvar vestibule surrounding the vaginal opening. The devastating impact of LPV includes sexual dysfunction, infertility, depression, and even suicide. Yet, its etiology is unclear. No effective medical therapy exists; surgical removal of the painful vestibule is the last resort. In LPV, the vestibule expresses a unique inflammatory profile with elevated levels of pro-nociceptive proinflammatory mediators prostaglandin E₂ (PGE₂) and interleukin-6 (IL-6), which are linked to lower mechanical sensitivity thresholds. Specialized pro-resolving mediators (SPMs), lipids produced endogenously within the body, hold promise as an LPV treatment by resolving inflammation without impairing host defense. Ten of 13 commercially available SPMs reduced IL-6 and PGE₂ production by vulvar fibroblasts, administered either before or after inflammatory stimulation. Using a murine vulvar pain model, coupling proinflammatory mediator quantification with mechanical sensitivity threshold determination, topical treatment with the SPM, maresin 1, decreased sensitivity and suppressed PGE₂ levels. Docosahexaenoic acid, a precursor of maresin 1, was also effective in reducing PGE₂ in vulvar fibroblasts and rapidly restored mouse sensitivity thresholds. Overall, SPMs and their precursors may be a safe and efficacious for LPV.Perspective: Vulvodynia, like many pain conditions, is difficult to treat because disease origins are incompletely understood. Here, we applied our knowledge of more recently discovered vulvodynia disease mechanisms to screen novel therapeutics. We identified several specialized pro-resolving mediators as likely potent and safe for treating LPV with potential for broader application.     

Thermal and visceral hypersensitivity in irritable bowel syndrome patients with and without fibromyalgia

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 degrees C) of the hand/foot and to phasic distension of the rectum (35, 55 mm 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.     

Hemiplegic shoulder pain: Evidence of a neuropathic origin

Hemiplegic shoulder pain (HSP) is common after stroke. Whereas most studies have concentrated on the possible musculoskeletal factors underlying HSP, neuropathic aspects have hardly been studied. Our aim was to explore the possible neuropathic components in HSP, and if identified, whether they are specific to the shoulder or characteristic of the entire affected side. Participants included 30 poststroke patients, 16 with and 14 without HSP, and 15 healthy controls. The thresholds of warmth, cold, heat-pain, touch, and graphesthesia were measured in the intact and affected shoulder and in the affected lower leg. They were also assessed for the presence of allodynia and hyperpathia, and computed tomography/magnetic resonance imaging scans of the brain were reviewed. In addition, chronic pain was characterized. Participants with HSP exhibited higher rates of parietal lobe damage (P < 0.05) compared to those without HSP. Both poststroke groups exhibited higher sensory thresholds than healthy controls. Those with HSP had higher heat-pain thresholds in both the affected shoulder (P < 0.001) and leg (P < 0.01), exhibited higher rates of hyperpathia in both these regions (each P < 0.001), and more often reported chronic pain throughout the affected side (P < 0.001) than those without HSP. The more prominent sensory alterations in the shoulder region suggest that neuropathic factors play a role in HSP. The clinical evidence of damage to the spinothalamic-thalamocortical system in the affected shoulder and leg, the presence of chronic pain throughout the affected side, and the more frequent involvement of the parietal cortex all suggest that the neuropathic component is of central origin.     

Gut pain and hyperalgesia induced by capsaicin: a human experimental model

Human experimental visceral pain models using chemical stimulation are needed for the study of visceral hyperexcitability. Our aim was to stimulate the human gut with chemical activators (capsaicin, glycerol) and measure quantitatively the induced hyperexcitability to painful mechanical gut distension. Ten otherwise healthy subjects with an ileostoma participated. Increasing volumes of capsaicin 50 microg/ml (0.25, 0.5, 0.75, 1.0, 1.5, 2.0, and 3 ml), glycerol (2.5, 5, and 10 ml) or saline (2.5, 5, and 10 ml) intermingled with sham stimuli were randomly applied to the ileum via the stomal opening at three occasions separated by a week. After each application, pain intensity, qualities, and referred pain area were assessed together with the pain threshold to distension of the proximal gut. 'Boring' and 'hot' pain were evoked in all subjects by low doses (median 0.5 ml) of capsaicin. The median pain onset, peak pain, and pain duration were 55, 85, and 420 s, respectively. Referred somatic pain developed around the stomal opening with a correlation between the pain area and pain intensity. After application of capsaicin, significant hyperalgesia was found to distension of the gut (a 28% reduction pressure in pain threshold). No significant manifestations were found after application of glycerol and saline. Application of capsaicin to the human ileum induces pain and mechanical hyperalgesia. Specific activation of nociceptors in the gut mucosa provides new possibilities to study clinical relevant visceral pain mechanisms.     

Dysmenorrhoea is associated with hypersensitivity in the sigmoid colon and rectum

Dysmenorrhoea patients experience intense visceral pain during menstruation. Recurrent and/or intense visceral pain can induce facilitation of somatic and visceral nociceptive processing which can lead to viscero-somatic (referred) and viscero-visceral hyperalgesia. Our aim was to study if dysmenorrhoea is associated with hypersensitivity in the referred somatic skin area or in the large bowel, i.e., viscero-visceral hyperalgesia. We measured skin sensitivity in the referred area of the sigmoid colon as well as stimulus-response relationships in the sigmoid colon and rectum. The latter were measured using mechanical (balloon) distension applied via a Barostat in 11 dysmenorrhoea patients without gastro-intestinal complaints and 10 healthy and age matched women, again without gastrointestinal complaints. We found no skin hypersensitivity in the colonic referred area. In contrast, significantly lower distension volumes were seen at each threshold in dysmenorrhoea patients, particularly in the sigmoid colon. The mean reduction in colonic distension volume thresholds for dysmenorrhoea patients vs. controls was 57% at the detection threshold and 39% at the pain threshold. There were no differences in compliance between the groups. These findings suggest that, despite the absence of overt gastro-intestinal symptoms or viscero-somatic sensitisation, dysmenorrhoea patients demonstrate intestinal hypersensitivity. This can be regarded as the result of centrally mediated viscero-visceral hyperalgesia due to recurrent intense menstrual pain.     

The effects of racemic ketamine on painful stimulation of skin and viscera in human subjects

Evidence suggests that NMDA receptors may have a differential role in the modulation of visceral and somatic pain. Specifically, animal data indicate an analgesic role of NMDA-R antagonists in acute visceral but not acute somatic pain. In humans analgesic effects are documented in acute somatic pain, while the role of NMDA-R antagonists in acute visceral pain is still questionable. We, therefore, conducted a study in humans comparing the analgesic effects of ketamine in an experimental model of visceral and cutaneous pain. In a double-blind, randomized, cross-over study, 11 healthy volunteers (3M, 8F) participated in two experimental sessions in which they evaluated perceptions induced by balloon distention of the distal esophagus and contact heat on the upper chest during continuous computer-controlled i.v. infusion of either ketamine (60 and 120 ng/mL) or saline. Two stimulus intensities producing non-painful and painful sensation were used for each stimulus modality. Subjects reported maximum pain intensity and unpleasantness on visual analog scales (VAS). For noxious visceral stimulation, low dose ketamine produced significant attenuation of both pain intensity and unpleasantness. In contrast, for noxious cutaneous stimulation, ketamine reduced pain unpleasantness, but not perceived intensity. In addition, ketamine did not alter the perception of innocuous stimuli in either modality. Our results confirm the analgesic effects of low-dose ketamine, with minimal side effects, on acute visceral pain and indicate a similar but smaller effect on acute cutaneous pain. A decrease in the unpleasantness but not in the intensity of cutaneous pain may reflect the differential effect of NMDA-R antagonists for the two pain states observed in animal models.     

Neural mechanisms mediating the effects of expectation in visceral placebo analgesia: an fMRI study in healthy placebo responders and nonresponders

This functional magnetic resonance imaging study analysed the behavioural and neural responses during expectation-mediated placebo analgesia in a rectal pain model in healthy subjects. In N = 36 healthy subjects, the blood oxygen level-dependent (BOLD) response during cued anticipation and painful rectal stimulation was measured. Using a within-subject design, placebo analgesia was induced by changing expectations regarding the probability of receiving an analgesic drug to 0%, 50%, and 100%. Placebo responders were identified by median split based on pain reduction (0% to 100% conditions), and changes in neural activation correlating with pain reduction in the 0% and 100% conditions were assessed in a regions-of-interest analysis. Expectation of pain relief resulted in overall reductions in pain and urge to defecate, and this response was significantly more pronounced in responders. Within responders, pain reduction correlated with reduced activation of dorsolateral and ventrolateral prefrontal cortices, somatosensory cortex, and thalamus during cued anticipation (paired t tests on the contrast 0% > 100%); during painful stimulation, pain reduction correlated with reduced activation of the thalamus. Compared with nonresponders, responders demonstrated greater placebo-induced decreases in activation of dorsolateral prefrontal cortex during anticipation and in somatosensory cortex, posterior cingulate cortex, and thalamus during pain. In conclusion, the expectation of pain relief can substantially change perceived painfulness of visceral stimuli, which is associated with activity changes in the thalamus, prefrontal, and somatosensory cortices. Placebo analgesia constitutes a paradigm to elucidate psychological components of the pain response relevant to the pathophysiology and treatment of chronic abdominal pain.     

Hyperalgesia and functional sensory loss in restless legs syndrome

Pain and other sensory signs in patients with restless legs syndrome (RLS) are still poorly understood, as most investigations focus on motor system dysfunctions. This study aimed to investigate somatosensory changes in patients with primary RLS and the restoration of somatosensory function by guideline-based treatment. Forty previously untreated RLS patients were investigated unilaterally over hand and foot using quantitative sensory testing (QST) and were compared with 40 age- and gender-matched healthy subjects. The predominant finding in RLS patients was 3- to 4-fold increase of sensitivity to pinprick stimuli in both extremities (hand: P < .05; foot: P < .001), a sensory pathway involved in withdrawal reflexes. Pinprick hyperalgesia was not paralleled by dynamic mechanical allodynia. Additional significant sensory changes were tactile hypoesthesia in both extremities (hand: P < .05; foot P < .01) and dysesthesia to non-noxious cold stimuli (paradoxical heat sensation), which was present in the foot in an unusually high proportion (14 of 40 patients; P < .01). In 8 patients, follow-up QST 2 to 20 months after treatment with l-DOPA (L-3,4-dihydroxyphenylalanine) revealed a significant reduction of pinprick hyperalgesia (−60%, P < .001), improved tactile detection (+50%, P < .05), and disappearance of paradoxical heat sensation in half of the patients. QST suggested a type of spinal or supraspinal central sensitization differing from neuropathic pain or human experimental models of central sensitization by the absence of dynamic mechanical allodynia. Reversal of pinprick hyperalgesia by l-DOPA may be explained by impaired descending inhibitory dopaminergic control on spinal nociceptive neurons. Restoration of tactile sensitivity and paradoxical heat sensations suggest that they were functional disturbances resulting from central disinhibition.