Showing papers in "Pain in 2006"

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values

Abstract: The nationwide multicenter trials of the German Research Network on Neuropathic Pain (DFNS) aim to characterize the somatosensory phenotype of patients with neuropathic pain. For this purpose, we have implemented a standardized quantitative sensory testing (QST) protocol giving a complete profile for one region within 30 min. To judge plus or minus signs in patients we have now established age- and gender-matched absolute and relative QST reference values from 180 healthy subjects, assessed bilaterally over face, hand and foot. We determined thermal detection and pain thresholds including a test for paradoxical heat sensations, mechanical detection thresholds to von Frey filaments and a 64 Hz tuning fork, mechanical pain thresholds to pinprick stimuli and blunt pressure, stimulus/response-functions for pinprick and dynamic mechanical allodynia, and pain summation (wind-up ratio). QST parameters were region specific and age dependent. Pain thresholds were significantly lower in women than men. Detection thresholds were generally independent of gender. Reference data were normalized to the specific group means and variances (region, age, gender) by calculating z-scores. Due to confidence limits close to the respective limits of the possible data range, heat hypoalgesia, cold hypoalgesia, and mechanical hyperesthesia can hardly be diagnosed. Nevertheless, these parameters can be used for group comparisons. Sensitivity is enhanced by side-to-side comparisons by a factor ranging from 1.1 to 2.5. Relative comparisons across body regions do not offer advantages over absolute reference values. Application of this standardized QST protocol in patients and human surrogate models will allow to infer underlying mechanisms from somatosensory phenotypes.

Systematic review of the psychometric properties, interpretability and feasibility of self-report pain intensity measures for use in clinical trials in children and adolescents.

Abstract: The aim of this study was to systematically review the psychometric properties, interpretability and feasibility of self-report pain intensity measures for children and adolescents for use in clinical trials evaluating pain treatments. Databases were searched for self-report measures of single-item ratings of pain intensity for children aged 3-18 years. A total of 34 single-item self-report measures were found. The measures' psychometric properties, interpretability and feasibility, were evaluated independently by two investigators according to a set of psychometric criteria. Six single-item measures met the a priori criteria and were included in the final analysis. While these six scales were determined as psychometrically sound and show evidence of responsivity, they had varying degrees of interpretability and feasibility. No single scale was found to be optimal for use with all types of pain or across the developmental age span. Specific recommendations regarding the most psychometrically sound and feasible measures based on age/developmental level and type of pain are discussed. Future research is needed to strengthen the measurement of pain in clinical trials with children.

A sham-controlled, phase II trial of transcranial direct current stimulation for the treatment of central pain in traumatic spinal cord injury

Abstract: Past evidence has shown that motor cortical stimulation with invasive and non-invasive brain stimulation is effective to relieve central pain. Here we aimed to study the effects of another, very safe technique of non-invasive brain stimulation--transcranial direct current stimulation (tDCS)--on pain control in patients with central pain due to traumatic spinal cord injury. Patients were randomized to receive sham or active motor tDCS (2mA, 20 min for 5 consecutive days). A blinded evaluator rated the pain using the visual analogue scale for pain, Clinician Global Impression and Patient Global Assessment. Safety was assessed with a neuropsychological battery and confounders with the evaluation of depression and anxiety changes. There was a significant pain improvement after active anodal stimulation of the motor cortex, but not after sham stimulation. These results were not confounded by depression or anxiety changes. Furthermore, cognitive performance was not significantly changed throughout the trial in both treatment groups. The results of our study suggest that this new approach of cortical stimulation can be effective to control pain in patients with spinal cord lesion. We discuss potential mechanisms for pain amelioration after tDCS, such as a secondary modulation of thalamic nuclei activity.

Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network.

Abstract: Placebo analgesia is one of the most striking examples of the cognitive modulation of pain perception and the underlying mechanisms are finally beginning to be understood. According to pharmacological studies, the endogenous opioid system is essential for placebo analgesia. Recent functional imaging data provides evidence that the rostral anterior cingulate cortex (rACC) represents a crucial cortical area for this type of endogenous pain control. We therefore hypothesized that placebo analgesia recruits other brain areas outside the rACC and that interactions of the rACC with these brain areas mediate opioid-dependent endogenous antinociception as part of a top-down mechanism. Nineteen healthy subjects received and rated painful laser stimuli to the dorsum of both hands, one of them treated with a fake analgesic cream (placebo). Painful stimulation was preceded by an auditory cue, indicating the side of the next laser stimulation. BOLD-responses to the painful laser-stimulation during the placebo and no-placebo condition were assessed using event-related fMRI. After having confirmed placebo related activity in the rACC, a connectivity analysis identified placebo dependent contributions of rACC activity with bilateral amygdalae and the periaqueductal gray (PAG). This finding supports the view that placebo analgesia depends on the enhanced functional connectivity of the rACC with subcortical brain structures that are crucial for conditioned learning and descending inhibition of nociception.

Critical issues on opioids in chronic non-cancer pain: an epidemiological study.

Abstract: The aim of the study was epidemiologically to evaluate the long-term effects of opioids on pain relief, quality of life and functional capacity in long-term/chronic non-cancer pain. The study was based on data from the 2000 Danish Health and Morbidity Survey. As part of a representative National random sample of 16,684 individuals (>16 years of age), 10,066 took part in an interview and completed a self-administered questionnaire. Cancer patients were excluded. The interview and the self-administered questionnaire included questions on chronic/long-lasting pain (>6 months), health-related quality of life (SF-36), use of the health care system, functional capabilities, satisfaction with medical pain treatment and regular or continuous use of medications. Participants reporting pain were divided into opioid and non-opioid users. The analyses were adjusted for age, gender, concomitant use of anxiolytics and antidepressants and pain intensity. Pain relief, quality of life and functional capacity among opioid users were compared with non-opioid users. Opioid usage was significantly associated with reporting of moderate/severe or very severe pain, poor self-rated health, not being engaged in employment, higher use of the health care system, and a negative influence on quality of life as registered in all items in SF-36. Because of the cross-sectional nature causative relationships cannot be ascertained. However, it is remarkable that opioid treatment of long-term/chronic non-cancer pain does not seem to fulfil any of the key outcome opioid treatment goals: pain relief, improved quality of life and improved functional capacity.

Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction.

Abstract: Paclitaxel chemotherapy frequently induces neuropathic pain during and often persisting after therapy. The mechanisms responsible for this pain are unknown. Using a rat model of paclitaxel-induced painful peripheral neuropathy, we have performed studies to search for peripheral nerve pathology. Paclitaxel-induced mechano-allodynia and mechano-hyperalgesia were evident after a short delay, peaked at day 27 and finally resolved on day 155. Paclitaxel- and vehicle-treated rats were perfused on days 7, 27 and 160. Portions of saphenous nerves were processed for electron microscopy. There was no evidence of paclitaxel-induced degeneration or regeneration as myelin structure was normal and the number/density of myelinated axons and C-fibres was unaltered by paclitaxel treatment at any time point. In addition, the prevalence of ATF3-positive dorsal root ganglia cells was normal in paclitaxel-treated animals. With one exception, at day 160 in myelinated axons, total microtubule densities were also unaffected by paclitaxel both in C-fibres and myelinated axons. C-fibres were significantly swollen following paclitaxel at days 7 and 27 compared to vehicle. The most striking finding was significant increases in the prevalence of atypical (swollen and vacuolated) mitochondria in both C-fibres (1.6- to 2.3-fold) and myelinated axons (2.4- to 2.6-fold) of paclitaxel-treated nerves at days 7 and 27. Comparable to the pain behaviour, these mitochondrial changes had resolved by day 160. Our data do not support a causal role for axonal degeneration or dysfunction of axonal microtubules in paclitaxel-induced pain. Instead, our data suggest that a paclitaxel-induced abnormality in axonal mitochondria of sensory nerves contributes to paclitaxel-induced pain.

Pain activates cortical areas in the preterm newborn brain.

Abstract: To study the patterns of supraspinal pain processing in neonates, we hypothesized that acute pain causes haemodynamic changes associated with activation of the primary somatosensory cortex. Forty preterm neonates at 28–36 weeks of gestation (mean = 32.0) and at 25–42 h (mean = 30.7) of age w

Affective components and intensity of pain correlate with structural differences in gray matter in chronic back pain patients

Abstract: Although chronic back pain is one of the most frequent reasons for permanent impairment in people under 65, the neurobiological mechanisms of chronification remain vague. Evidence suggests that cortical reorganisation, so-called functional plasticity, may play a role in chronic back pain patients. In the search for the structural counterpart of such functional changes in the CNS, we examined 18 patients suffering from chronic back pain with voxel-based morphometry and compared them to 18 sex and age matched healthy controls. We found a significant decrease of gray matter in the brainstem and the somatosensory cortex. Correlation analysis of pain unpleasantness and the intensity of pain on the day of scanning revealed a strong negative correlation (i.e. a decrease in gray matter with increasing unpleasantness/increasing intensity of pain) in these areas. Additionally, we found a significant increase in gray matter bilaterally in the basal ganglia and the left thalamus. These data support the hypothesis that ongoing nociception is associated with cortical and subcortical reorganisation on a structural level, which may play an important role in the process of the chronification of pain.

Gabapentin and postoperative pain – a systematic review of randomized controlled trials

Abstract: The objective of this systematic review was to evaluate the efficacy and tolerability of perioperative gabapentin administration for the control of acute postoperative pain. We searched Medline (1966–2006), the Cochrane Library (2006), Scopus, CINAHL and bibliographies from clinical trials and review articles. We included randomized controlled trials (RCTs) comparing gabapentin with inactive controls in surgical patients. Sixteen valid RCTs were included. Weighted mean difference (WMD) for postoperative pain intensity (0–100 mm visual analogue scale) was −16.55 mm at 6 h and −10.87 mm at 24 h for treatment with a single preoperative dose of gabapentin 1200 mg. Cumulative opioid consumption at 24 h was also significantly decreased with gabapentin (WMD, −27.90 mg). When gabapentin was administered at doses less than 1200 mg, pain intensity was also lower at 6 h (WMD, −22.43 mm) and 24 h (WMD, −13.18 mm). Cumulative 24 h opioid consumption was also lower (WMD, −7.25 mg). Gabapentin was associated with an increased risk of sedation (Peto OR 3.86; 95% CI 2.50–5.94) but less opioid-related side effects such as vomiting (Peto OR 0.58; 95% CI 0.39–0.86) and pruritus (Peto OR 0.27; 95% CI 0.10–0.74). In conclusion, gabapentin has an analgesic and opioid-sparing effect in acute postoperative pain management when used in conjunction with opioids.

How prior experience shapes placebo analgesia.

Abstract: Some studies indicate that placebo analgesia is stronger when pre-conditioning with effective analgesic treatments is performed, thereby suggesting that the placebo response is a learning phenomenon. Here we further tested this hypothesis in order to better understand when and how previous experience affects the placebo analgesic response. To do this, we used a conditioning procedure whereby the intensity of painful stimulation was reduced surreptitiously, so as to make the subjects believe that an analgesic treatment was effective. This procedure induced strong placebo responses after minutes, and these responses, albeit reduced, lasted up to 4-7 days. In addition, in a second group of subjects we repeated the same conditioning procedure 4-7 days after a totally ineffective analgesic treatment, and found that the placebo responses were remarkably reduced compared to the first group. Thus we obtained small, medium and large placebo responses, depending on several factors, such as the previous positive or negative experience of an analgesic treatment and the time lag between the treatment and the placebo responses. We also ran extinction trials, and found that these effects did not undergo extinction in a time span of several minutes. These findings indicate that placebo analgesia is finely tuned by prior experience and these effects may last, albeit reduced, several days. These results emphasize that the placebo effect is a learning phenomenon in which many factors come into play, and may explain the large variability of the placebo responses that is found in many studies.

Cortical responses to pain in healthy individuals depends on pain catastrophizing.

Abstract: The personal experience of pain is complex and depends on physiological and psychological factors. From this latter category, pain catastrophizing plays an important role in pain behavior and response. We aimed to determine the effect of pain catastrophizing on central nociceptive processing in healthy individuals. Functional MRI was performed during two pain intensity levels evoked by electrical median nerve stimulation in 22 healthy individuals. Pain catastrophizing scores were determined for all subjects. Pain catastrophizing was not related to activity in regions associated with sensory-discriminative aspects of pain, such as the primary or secondary somatosensory cortex. Instead, during mild pain, there was a relationship between catastrophizing and activity in cortical regions associated with affective, attention, and motor aspects of pain, including dorsolateral prefrontal, insula, rostral anterior cingulate, premotor, and parietal cortices. During more intense pain, prefrontal cortical regions implicated in the top-down modulation of pain were negatively correlated with catastrophizing. These findings can be viewed from the framework of an attention model of pain catastrophizing, whereby a cortical vigilance network is engaged during mild pain, but diminished prefrontal cortical modulation impedes disengaging from and suppressing pain during more intense pain. These findings may also implicate catastrophizing in the progression to or persistence of chronic pain.

Long-term alteration of pain sensitivity in school-aged children with early pain experiences

Abstract: While animal studies suggest that neonatal pain experiences induce long-term alterations in pain sensitivity, no such data exist in humans. Changes in pain sensitivity in school-aged children (9–14 years) who were born preterm or fullterm, had been hospitalized for a prolonged period of time

Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli

Abstract: Variations in the gene encoding catechol-O-methyltransferase (COMT) are linked to individual differences in pain sensitivity. A single nucleotide polymorphism (SNP) in codon 158 (val(158)met), which affects COMT protein stability, has been associated with the human experience of pain. We recently demonstrated that three common COMT haplotypes, which affect the efficiency of COMT translation, are strongly associated with a global measure of pain sensitivity derived from individuals' responses to noxious thermal, ischemic, and pressure stimuli. Specific haplotypes were associated with low (LPS), average (APS), or high (HPS) pain sensitivity. Although these haplotypes included the val(158)met SNP, a significant association with val(158)met variants was not observed. In the present study, we examined the association between COMT genotype and specific pain-evoking stimuli. Threshold and tolerance to thermal, ischemic, and mechanical stimuli, as well as temporal summation to heat pain, were determined. LPS/LPS homozygotes had the least, APS/APS homozygotes had average, and APS/HPS heterozygotes had the greatest pain responsiveness. Associations were strongest for measures of thermal pain. However, the rate of temporal summation of heat pain did not differ between haplotype combinations. In contrast, the val(158)met genotype was associated with the rate of temporal summation of heat pain, but not with the other pain measures. This suggests that the val(158)met SNP plays a primary role in variation in temporal summation of pain, but that other SNPs of the COMT haplotype exert a greater influence on resting nociceptive sensitivity. Here, we propose a mechanism whereby these two genetic polymorphisms differentially affect pain perception.

Functional assessment of pediatric pain patients: Psychometric properties of the Functional Disability Inventory

Abstract: The Functional Disability Inventory (FDI; Walker LS, Greene JW. The functional disability inventory: measuring a neglected dimension of child health status. J Pediatr Psychol 1991;16:39–58) assesses activity limitations in children and adolescents with a variety of pediatric conditions. This study evaluated the psychometric properties of the FDI in pediatric pain patients. Participants included 596 patients with chronic abdominal pain, ages 8–17, and a subset of their parents (n = 151) who completed the FDI and measures of pain, limitations in school activities, and somatic and depressive symptoms at a clinic visit. Test–retest reliability was high at 2 weeks (child report, .74; parent-report, .64) and moderate at 3 months (child report, .48; parent report, .39). Internal consistency reliability was excellent, ranging from .86 to .91. Validity was supported by significant correlations of child- and parent-report FDI scores with measures of school-related disability, pain, and somatic symptoms. Study results add to a growing body of empirical literature supporting the reliability and validity of the FDI for functional assessment of pediatric patients with chronic pain.

Idiopathic pain disorders--pathways of vulnerability.

Abstract: Idiopathic pain disorders (IPDs) consist of such conditions as temporomandibular joint disorders (TMJD), fibromyalgia syndrome (FMS), irritable bowel syndrome (IBS), chronic headaches, interstitial cystitis, chronic pelvic pain, chronic tinnitus, whiplash-associated disorders, and vulvar vestibulitis (VVS). IPDs commonly aggregate as ‘‘comorbid’’ conditions that are characterized by a complaint of pain as well as a mosaic of abnormalities in motor function, autonomic balance, neuroendocrine function, and sleep. Although the mechanisms that underlie the majority of these conditions are poorly understood, IPDs have been associated with a state of pain amplification and psychological distress (McBeth et al., 2001; Bradley and McKendree-Smith, 2002; Verne and Price, 2002; Gracely et al., 2004).

Greater occipital nerve injection in primary headache syndromes--prolonged effects from a single injection.

Abstract: Most patients with primary headache syndromes who have frequent attacks of pain have tenderness in the sub-occipital region. Injection of the greater occipital nerve (GON) with local anesthetic and corticosteroids has been widely used in clinical practice for many years, yet there is no clear understanding of its mechanisms of action. Moreover, there is no current gold-standard of practice regarding GON injections in the management of headache. We audited of our practice to generate hypotheses about the range of primary headaches that might benefit, to determine response rates to power future studies, and to assess whether we should continue to do this procedure. Twenty-six of fifty-seven injections in 54 migraineurs yielded a complete or partial response that lasted for the partial response a median of 30 days. For cluster headache 13 of 22 injections yielded a complete or partial response lasting for a median of 21 days for the partial response. Tenderness over the GON was strongly predictive of outcome, although local anesthesia after the injection was not. The presence or absence of medication overuse did not predict outcome. Apart from two patients with a small patch of alopecia the injection was well tolerated. GON injection is a useful tool in some patients that provides interim relief while other approaches are explored. It is remarkable that in all conditions in which an effect is observed the response time so much exceeds the local anesthetic effect that the mechanism of action may well be through changes in brain nociceptive pathways.

Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy)

Abstract: CRPS-I consists of post-traumatic limb pain and autonomic abnormalities that continue despite apparent healing of inciting injuries. The cause of symptoms is unknown and objective findings are few, making diagnosis and treatment controversial, and research difficult. We tested the hypotheses that CRPS-I is caused by persistent minimal distal nerve injury (MDNI), specifically distal degeneration of small-diameter axons. These subserve pain and autonomic function. We studied 18 adults with IASP-defined CRPS-I affecting their arms or legs. We studied three sites on subjects' CRPS-affected and matching contralateral limb; the CRPS-affected site, and nearby unaffected ipsilateral and matching contralateral control sites. We performed quantitative mechanical and thermal sensory testing (QST) followed by quantitation of epidermal neurite densities within PGP9.5-immunolabeled skin biopsies. Seven adults with chronic leg pain, edema, disuse, and prior surgeries from trauma or osteoarthritis provided symptom-matched controls. CRPS-I subjects had representative histories and symptoms. Medical procedures were unexpectedly frequently associated with CRPS onset. QST revealed mechanical allodynia (P<0.03) and heat-pain hyperalgesia (P<0.04) at the CRPS-affected site. Axonal densities were highly correlated between subjects' ipsilateral and contralateral control sites (r=0.97), but were diminished at the CRPS-affected sites of 17/18 subjects, on average by 29% (P<0.001). Overall, control subjects had no painful-site neurite reductions (P=1.00), suggesting that pain, disuse, or prior surgeries alone do not explain CRPS-associated neurite losses. These results support the hypothesis that CRPS-I is specifically associated with post-traumatic focal MDNI affecting nociceptive small-fibers. This type of nerve injury will remain undetected in most clinical settings.

Epidemiology and treatment of neuropathic pain: the UK primary care perspective.

Abstract: The true incidence of neuropathic pain is unknown, but it is believed to be under-diagnosed and treated inadequately, despite the availability of drugs with proven efficacy. Our objective was to report the epidemiology and drug treatment of neuropathic pain as managed by UK primary care physicians. A descriptive analysis of the epidemiology of incident post-herpetic neuralgia (n=12,386); trigeminal neuralgia (8268); phantom limb pain (451) and painful diabetic neuropathy (4719) and prescription treatment at diagnosis from computerised UK general practice records (GPRD): January 1992 to April 2002. Incidences per 100,000 person years observation of 40 (95% CI 39-41) for post-herpetic neuralgia, 27 (26-27) for trigeminal neuralgia, 1 (1-2) for phantom limb pain and 15 (15-16) for painful diabetic neuropathy are reported, with rates decreasing over time for phantom limb pain and post-herpetic neuralgia and increasing for painful diabetic neuropathy. Drugs were initiated at first diagnosis record for 46-66% of conditions, usually one item, with antidepressants included in 30% of prescriptions, anticonvulsants in 20% and opioid analgesics in 20%. The most commonly prescribed items were the same across conditions; amitriptyline, carbamazepine, coproxamol, codydramol and codeine+paracetamol. Carbamazepine was prescribed to 58% of the trigeminal neuralgia cohort. In 2600 patients followed to stable therapy, there was a median of one to two drug changes. We provide the primary care managed incidence of four neuropathic pain conditions. For commonly prescribed treatments, changes in therapy are less frequent when initial therapy was with antidepressants or anticonvulsants rather than conventional analgesics.

Parent attention versus distraction: Impact on symptom complaints by children with and without chronic functional abdominal pain

Abstract: The objective of this study was to assess the impact of parent attention and distraction on symptom complaints by children with and without chronic functional abdominal pain. The water load symptom provocation task was used to induce visceral discomfort in pediatric patients with abdominal pain (N=104) and well children (N=119), ages 8-16 years. Parents were randomly assigned and trained to interact with their children according to one of three conditions: Attention, Distraction, or No Instruction. Children's symptom complaints and parents' responses were audiotaped and coded. Children completed a self-report measure of gastrointestinal (GI) symptoms before and after interacting with their parents. Parents' and children's perceptions of their interaction were assessed. Compared to the No Instruction condition, symptom complaints by pain patients and well children nearly doubled in the Attention condition and were reduced by half in the Distraction condition. The effect of attention on symptom complaints was greater for female pain patients than for male patients or well children. Findings for self-report GI symptoms were similar to those for audiotaped symptom complaints. Both pain patients and well children in the Distraction condition rated parents as making them feel better compared to ratings for the Attention condition. Parents of pain patients rated distraction as having greater potential negative impact on their children than attention. Parents' responses to children's symptom complaints can significantly increase or decrease those complaints. Girls with functional abdominal pain are particularly vulnerable to the symptom-reinforcing effects of parental attention.

Parental catastrophizing about their child's pain. The parent version of the Pain Catastrophizing Scale (PCS-P): a preliminary validation.

Abstract: Numerous studies have found evidence for the role of catastrophizing about pain in adjustment to pain in both adults and children. However, the social context influencing pain and pain behaviour has been largely ignored. Especially in understanding the complexities of childhood pain, family processes may be of major importance. In line with the crucial role of pain catastrophizing in explaining adjustment and disability in adults and children, this study investigates the role of parental catastrophic thinking about their child’s pain in explaining child disability and parental distress. To study parental catastrophizing, a parent version of the Pain Catastrophizing Scale (PCS-P) was developed. An oblique three-factor structure emerged to best fit the data in both a sample of parents of schoolchildren (N = 205) and in a sample of parents of children with chronic pain (N = 107). Moreover, this three-factor structure was found to be invariant across both parent samples. Further, in the clinical sample, parents’ catastrophic thinking about their child’s pain had a significant contribution in explaining (a) childhood illness-related parenting stress, parental depression and anxiety, and (b) the child’s disability and school attendance, beyond the child’s pain intensity.

Loss of expectation-related mechanisms in Alzheimer's disease makes analgesic therapies less effective.

Abstract: Expectation/placebo-related mechanisms and specific effects of therapies show additive effects, such that a therapy is less effective if the placebo component is absent. So far, the placebo component has been disrupted experimentally by using covert administrations of treatments. Here, we show for the first time that disruption of expectation/placebo-related analgesic mechanisms may occur in a clinical condition, Alzheimer's disease (AD). In order to assess the placebo component of a therapy, we used the recently developed open-hidden paradigm. A local anesthetic was applied, either overtly or covertly, to the skin of AD patients to reduce burning pain after venipuncture. The placebo (psychological) component is represented by the difference between the analgesic effect after open (expected) and after hidden (unexpected) application. We correlated the placebo component with both cognitive status and functional connectivity among different brain regions. We found that AD patients with reduced Frontal Assessment Battery scores showed reduced placebo component of the analgesic treatment. We also found that the disruption of the placebo component occurred when reduced connectivity of the prefrontal lobes with the rest of the brain was present. Remarkably, the loss of these placebo-related mechanisms reduced treatment efficacy, such that a dose increase was necessary to produce adequate analgesia. These findings highlight the active role of cognition and prefrontal lobes in the therapeutic outcome and underscore the need of considering a possible revision of the therapeutic approach in Alzheimer patients in order to compensate for the loss of the endogenous expectation and placebo mechanisms.

To what extent do we share the pain of others? Insight from the neural bases of pain empathy.

Abstract: In the representationalist framework generally adopted in cognitive neuroscience, pain is conceived as a subjective experience triggered by the activation of a mental representation of actual or potential tissue damage (nociception) This representation may involve somatic sensory features, as well as affective-motivational reactions associated with the promotion of protective or recuperative visceromotor and behavioral responses Mental representation of nociception may provide the primary referent from which a rich associative network can be established to evoke the notion of pain in the absence of a nociceptive stimulus Here, we adopt the notion of a mental representation of pain as a means to relate the experience of pain in oneself to the perception of pain in others We review the functional neuroimaging studies supporting the hypothesis that the perception of pain in others relies at least partly on the activation of a mental representation of pain in the Self, and thus on common neural systems However, we also demonstrate that there are

Physical and Psychological Factors Maintain Long-term Predictive Capacity Post-Whiplash Injury

Abstract: Higher initial levels of pain and disability, older age, cold hyperalgesia, impaired sympathetic vasoconstriction and moderate post-traumatic stress symptoms have been shown to be associated with poor outcome 6 months following whiplash injury. This study prospectively investigated the predictive capacity of these variables at a long-term follow-up. Sixty-five of an initial cohort of 76 acutely injured whiplash participants were followed to 2–3 years post-accident. Motor function (ROM; kinaesthetic sense; activity of the superficial neck flexors (EMG) during cranio-cervical flexion), quantitative sensory testing (pressure, thermal pain thresholds and brachial plexus provocation test), sympathetic vasoconstrictor responses and psychological distress (GHQ-28, TSK and IES) were measured. The outcome measure was Neck Disability Index (NDI) scores. Participants with ongoing moderate/severe symptoms at 2–3 years continued to manifest decreased ROM, increased EMG during cranio-cervical flexion, sensory hypersensitivity and elevated levels of psychological distress when compared to recovered participants and those with milder symptoms. The latter two groups showed only persistent deficits in cervical muscle recruitment patterns. Higher initial NDI scores (OR 1.00–1.1), older age (OR 1.00–1.13), cold hyperalgesia (OR 1.1–1.13) and post-traumatic stress symptoms (OR 1.03–1.2) remained significant predictors of poor outcome at long-term follow-up (r 2 = 0.56). The robustness of these physical and psychological factors suggests that their assessment in the acute stage following whiplash injury will be important. 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Mechanisms underlying development of spatially distributed chronic pain (fibromyalgia).

Abstract: Chronic fibromyalgia (FM) pain is prevalent (estimated as high as 13%), predominantly affects women, and is associated with a variety of focal pain conditions. Ongoing FM pain is referred to deep tissues and is described as widespread but usually is maximally located within a restricted region such as the shoulders. Palpation of deep tissues reveals an enhanced nociceptive sensitivity that is not restricted to regions of clinical pain. Similarly, psychophysical testing reveals allodynia and hyperalgesia for cutaneous stimulation at locations beyond regions of clinical pain referral. The combination of widely distributed clinical pain and generalized hypersensitivity is highly disabling, but no satisfactory treatment is regularly prescribed. A thorough understanding of mechanisms will likely be required to develop and document adequate therapies. The generalized hypersensitivity associated with FM has focused considerable interest on central (CNS) mechanisms for the disorder. These include central sensitization, central disinhibition and a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis. However, the central effects associated with FM can be produced by a peripheral source of pain. Chronic nociceptive input induces central sensitization, magnifying pain, and it activates the HPA and the sympathetic nervous system. Chronic sympathetic activation indirectly sensitizes peripheral nociceptors and sets up a vicious cycle. Thus, it appears that central mechanisms of FM pain are dependent on abnormal peripheral input(s) for development and maintenance of this condition. A substantial literature defines peripheral-CNS-peripheral interactions that are integral to FM pain. These reciprocal actions and related phenomena of relevance to FM pain are reviewed here, leading to suggestions for testing of therapeutic approaches.

Lumbar instrumented fusion compared with cognitive intervention and exercises in patients with chronic back pain after previous surgery for disc herniation: a prospective randomized controlled study.

Abstract: The effectiveness of lumbar fusion for chronic low back pain after surgery for disc herniation has not been evaluated in a randomized controlled trial. The aim of the present study was to compare the effectiveness of lumbar fusion with posterior transpedicular screws and cognitive intervention and exercises. Sixty patients aged 25-60 years with low back pain lasting longer than 1 year after previous surgery for disc herniation were randomly allocated to the two treatment groups. Experienced back surgeons performed transpedicular fusion. Cognitive intervention consisted of a lecture intended to give the patient an understanding that ordinary physical activity would not harm the disc and a recommendation to use the back and bend it. This was reinforced by three daily physical exercise sessions for 3 weeks. The primary outcome measure was the Oswestry Disability Index (ODI). Outcome data were analyzed on an intention-to-treat basis. Ninety-seven percent of the patients, including seven of eight patients who had either not attended treatment (n=5) or changed groups (n=2), completed 1-year follow-up. ODI was significantly improved from 47 to 38 after fusion and from 45 to 32 after cognitive intervention and exercises. The mean difference between treatments after adjustment for gender was -7.3 (95% CI -17.3 to 2.7, p=0.15). The success rate was 50% in the fusion group and 48% in the cognitive intervention/exercise group. For patients with chronic low back pain after previous surgery for disc herniation, lumbar fusion failed to show any benefit over cognitive intervention and exercises.

An experimental study of shared sensitivity to physical pain and social rejection

Abstract: Recent evidence points to a possible overlap in the neural systems underlying the distressing experience that accompanies physical pain and social rejection (Eisenberger et al., 2003). The present study tested two hypotheses that stem from this suggested overlap, namely: (1) that baseline sensitivity to physical pain will predict sensitivity to social rejection and (2) that experiences that heighten social distress will heighten sensitivity to physical pain as well. In the current study, participants’ baseline cutaneous heat pain unpleasantness thresholds were assessed prior to the completion of a task that manipulated feelings of social distress. During this task, participants played a virtual ball-tossing game, allegedly with two other individuals, in which they were either continuously included (social inclusion condition) or they were left out of the game by either never being included or by being overtly excluded (social rejection conditions). At the end of the game, three pain stimuli were delivered and participants rated the unpleasantness of each. Results indicated that greater baseline sensitivity to pain (lower pain unpleasantness thresholds) was associated with greater self-reported social distress in response to the social rejection conditions. Additionally, for those in the social rejection conditions, greater reports of social distress were associated with greater reports of pain unpleasantness to the thermal stimuli delivered at the end of the game. These results provide additional support for the hypothesis that pain distress and social distress share neurocognitive substrates. Implications for clinical populations are discussed. � 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Assessment and analysis of mechanical allodynia-like behavior induced by spared nerve injury (SNI) in the mouse.

Abstract: Experimental models of peripheral nerve injury have been developed to study mechanisms of neuropathic pain. In the spared nerve injury (SNI) model in rats, the common peroneal and tibial nerves are injured, producing consistent and reproducible pain hypersensitivity in the territory of the spared sural nerve. In this study, we investigated whether SNI in mice is also a valid model system for neuropathic pain. SNI results in a significant decrease in withdrawal threshold in SNI-operated mice. The effect is very consistent between animals and persists for the four weeks of the study. We also determined the relative frequency of paw withdrawal for each of a series of 11 von Frey hairs. Analysis of response frequency using a mixed-effects model that integrates all variables (nerve injury, paw, gender, and time) shows a very stable effect of SNI over time and also reveals subtle divergences between variables, including gender-based differences in mechanical sensitivity. We tested two variants of the SNI model and found that injuring the tibial nerve alone induces mechanical hypersensitivity, while injuring the common peroneal and sural nerves together does not induce any significant increase in mechanical sensitivity in the territory of the spared tibial nerve. SNI induces a mechanical allodynia-like response in mice and we believe that our improved method of assessment and data analysis will reveal additional internal and external variability factors in models of persistent pain. Use of this model in genetically altered mice should be very effective for determining the mechanisms involved in neuropathic pain.

Developing patient-reported outcome measures for pain clinical trials: IMMPACT recommendations

Abstract: a University of Washington, Seattle, WA 98195, USA b University of Rochester School of Medicine and Dentistry, Rochester, NY, USA c United States Food and Drug Administration, Rockville, MD, USA d Northwestern University, Chicago, IL, USA e Johnson and Johnson, Raritan, NY, USA f AstraZeneca, Wilmington, DE, USA g University of California San Diego, La Jolla, CA, USA h Merck and Company, Blue Bell, PA, USA i University of Texas, M.D. Anderson Cancer Center, USA j American Chronic Pain Association, Rocklin, CA, USA k Allergan, Inc, Irvine, CA, USA l National Institute of Dental and Craniofacial Research, Bethesda, MD, USA m University of Pennsylvania, Philadelphia, PA, USA n Johns Hopkins University, Baltimore, MD, USA o University Health Network and University of Toronto, Toronto, Canada p Novartis Pharmaceuticals, East Hanover, NJ, USA q VA Connecticut Healthcare System, West Haven, CT, USA r Yale University, New Haven, CT, USA s Celgene Corporation, Warren, NJ, USA t Pfizer Global Research and Development, Ann Arbor, MI, USA u Dalhousie University, Halifax, Nova Scotia, Canada v London Regional Cancer Centre, London, Ont., Canada

Pathologic alterations of cutaneous innervation and vasculature in affected limbs from patients with complex regional pain syndrome.

Abstract: Complex regional pain syndromes (CRPS, type I and type II) are devastating conditions that can occur following soft tissue (CRPS type I) or nerve (CRPS type II) injury. CRPS type I, also known as reflex sympathetic dystrophy, presents in patients lacking a well-defined nerve lesion, and has been questioned as to whether or not it is a true neuropathic condition with an organic basis. As described here, glabrous and hairy skin samples from the amputated upper and lower extremity from two CRPS type I diagnosed patients were processed for double-label immunofluorescence using a battery of antibodies directed against neural-related proteins and mediators of nociceptive sensory function. In CRPS affected skin, several neuropathologic alterations were detected, including: (1) the presence of numerous abnormal thin caliber NF-positive/MBP-negative axons innervating hair follicles; (2) a decrease in epidermal, sweat gland, and vascular innervation; (3) a loss of CGRP expression on remaining innervation to vasculature and sweat glands; (4) an inappropriate expression of NPY on innervation to superficial arterioles and sweat glands; and (5) a loss of vascular endothelial integrity and extraordinary vascular hypertrophy. The results are evidence of widespread cutaneous neuropathologic changes. Importantly, in these CRPS type I patients, the myriad of clinical symptoms observed had detectable neuropathologic correlates.

The role of values in a contextual cognitive-behavioral approach to chronic pain.

Abstract: Chronic pain can dominate all concerns for individuals suffering with it, leaving much of their time focused on trying to reduce pain rather than living their life, as they would most want to do, according to their values. The purpose of this study was to examine these processes, the degree of success patients have in following their values as guides for their actions, and relations between values-based action and other aspects of daily functioning. For this study we designed a brief inventory of patient values in domains of family, intimate relations, friends, work, health, and growth or learning. One hundred forty, consecutive, adult patients referred to a pain management unit completed this inventory in addition to measures of pain, disability, depression, pain-related anxiety, and acceptance of pain. Results showed that highest importance was placed on values in the domains of family and health and the least importance in friends and growth or learning. Highest success was reported in domains of family and friends and the least success in health and growth or learning. Significant correlations of overall success with measures of avoidance and acceptance of pain supported the validity of scores from the values measure. Success in living according to values was correlated with measures of disability, depression, and pain-related anxiety. Regression analysis showed that success at living according to values predicted variance in functioning independent of acceptance of pain, supporting its incremental utility in a contextual analysis of chronic pain and its potential importance in treatment for chronic pain.