Showing papers in "Pain in 2005"

Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4)

Abstract: Few studies have directly compared the clinical features of neuropathic and non-neuropathic pains. For this purpose, the French Neuropathic Pain Group developed a clinician-administered questionnaire named DN4 consisting of both sensory descriptors and signs related to bedside sensory examination. This questionnaire was used in a prospective study of 160 patients presenting with pain associated with a definite neurological or somatic lesion. The most common aetiologies of nervous lesions (n=89) were traumatic nerve injury, post herpetic neuralgia and post stroke pain. Non-neurological lesions (n=71) were represented by osteoarthritis, inflammatory arthropathies and mechanical low back pain. Each patient was seen independently by two experts in order to confirm the diagnosis of neuropathic or non-neuropathic pain. The prevalence of pain descriptors and sensory dysfunctions were systematically compared in the two groups of patients. The analysis of the psychometric properties of the DN4 questionnaire included: face validity, inter-rater reliability, factor analysis and logistic regression to identify the discriminant properties of items or combinations of items for the diagnosis of neuropathic pain. We found that a relatively small number of items are sufficient to discriminate neuropathic pain. The 10-item questionnaire developed in the present study constitutes a new diagnostic instrument, which might be helpful both in clinical research and daily practice.

Algorithm for neuropathic pain treatment:: an evidence based proposal.

Abstract: New studies of the treatment of neuropathic pain have increased the need for an updated review of randomized, double-blind, placebo-controlled trials to support an evidence based algorithm to treat neuropathic pain conditions. Available studies were identified using a MEDLINE and EMBASE search. One hundred and five studies were included. Numbers needed to treat (NNT) and numbers needed to harm (NNH) were used to compare efficacy and safety of the treatments in different neuropathic pain syndromes. The quality of each trial was assessed. Tricyclic antidepressants and the anticonvulsants gabapentin and pregabalin were the most frequently studied drug classes. In peripheral neuropathic pain, the lowest NNT was for tricyclic antidepressants, followed by opioids and the anticonvulsants gabapentin and pregabalin. For central neuropathic pain there is limited data. NNT and NNH are currently the best way to assess relative efficacy and safety, but the need for dichotomous data, which may have to be estimated retrospectively for old trials, and the methodological complexity of pooling data from small cross-over and large parallel group trials, remain as limitations.

Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain

Abstract: The P2X(7) purinoceptor is a ligand-gated cation channel, expressed predominantly by cells of immune origin, with a unique phenotype which includes release of biologically active inflammatory cytokine, interleukin (IL)-1beta following activation, and unique ion channel biophysics observed only in this receptor family. Here we demonstrate that in mice lacking this receptor, inflammatory (in an adjuvant-induced model) and neuropathic (in a partial nerve ligation model) hypersensitivity is completely absent to both mechanical and thermal stimuli, whilst normal nociceptive processing is preserved. The knockout animals were unimpaired in their ability to produce mRNA for pro-IL-1beta, and cytometric analysis of paw and systemic cytokines from knockout and wild-type animals following adjuvant insult suggests a selective effect of the gene deletion on release of IL-1beta and IL-10, with systemic reductions in adjuvant-induced increases in IL-6 and MCP-1. In addition, we show that this receptor is upregulated in human dorsal root ganglia and injured nerves obtained from chronic neuropathic pain patients. We hypothesise that the P2X(7) receptor, via regulation of mature IL-1beta production, plays a common upstream transductional role in the development of pain of neuropathic and inflammatory origin. Drugs which block this target may have the potential to deliver broad-spectrum analgesia.

Duloxetine vs. placebo in patients with painful diabetic neuropathy.

Abstract: The aim of this study was to examine the efficacy and safety of duloxetine, a balanced and potent dual reuptake inhibitor of serotonin and norepinephrine, in the management of diabetic peripheral neuropathic pain. Serotonin and norepinephrine are thought to inhibit pain via descending pain pathways. In a 12-week, multicenter, double-blind study, 457 patients experiencing pain due to polyneuropathy caused by Type 1 or Type 2 diabetes mellitus were randomly assigned to treatment with duloxetine 20 mg/d (20 mg QD), 60 mg/d (60 mg QD), 120 mg/d (60 mg BID), or placebo. The diagnosis was confirmed by a score of at least 3 on the Michigan Neuropathy Screening Instrument. The primary efficacy measure was the weekly mean score of the 24-h Average Pain Score, which was rated on an 11-point (0-10) Likert scale (no pain to worst possible pain) and computed from diary scores between two site visits. Duloxetine 60 and 120 mg/d demonstrated statistically significant greater improvement compared with placebo on the 24-h Average Pain Score, beginning 1 week after randomization and continuing through the 12-week trial. Duloxetine also separated from placebo on nearly all the secondary measures including health-related outcome measures. Significantly more patients in all three active-treatment groups achieved a 50% reduction in the 24-h Average Pain Score compared with placebo. Duloxetine treatment was considered to be safe and well tolerated with less than 20 percent discontinuation due to adverse events. Duloxetine at 60 and 120 mg/d was safe and effective in the management of diabetic peripheral neuropathic pain.

ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model.

Abstract: Activation of extracellular signal-regulated kinase (ERK), a mitogen activated-protein kinase (MAPK), in dorsal horn neurons contributes to inflammatory pain by transcription-dependent and -independent means. We have now investigated if ERK is activated in the spinal cord after a spinal nerve ligation (SNL) and if this contributes to the neuropathic pain-like behavior generated in this model. An L5 SNL induces an immediate (<10 min) but transient (<6 h) induction of phosphoERK (pERK) restricted to neurons in the superficial dorsal horn. This is followed by a widespread induction of pERK in spinal microglia that peaks between 1 and 3 days post-surgery. On Day 10, pERK is expressed both in astrocytes and microglia, but by Day 21 predominantly in astrocytes in the dorsal horn. In the L5 DRG SNL transiently induces pERK in neurons at 10 min, and in satellite cells on Day 10 and 21. Intrathecal injection of the MEK (ERK kinase) inhibitor PD98059 on Day 2, 10 or 21 reduces SNL-induced mechanical allodynia. Our results suggest that ERK activation in the dorsal horn, as well as in the DRG, mediates pain through different mechanisms operating in different cells at different times. The sequential activation of ERK in dorsal horn microglia and then in astrocytes might reflect distinct roles for these two subtypes of glia in the temporal evolution of neuropathic pain.

Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation.

Abstract: Activated glial cells (microglia and astroglia) in the spinal cord play a major role in mediating enhanced pain states by releasing proinflammatory cytokines and other substances thought to facilitate pain transmission. In the present study, we report that intrathecal administration of minocycline, a selective inhibitor of microglial cell activation, inhibits low threshold mechanical allodynia, as measured by the von Frey test, in two models of pain facilitation. In a rat model of neuropathic pain induced by sciatic nerve inflammation (sciatic inflammatory neuropathy, SIN), minocycline delayed the induction of allodynia in both acute and persistent paradigms. Moreover, minocycline was able to attenuate established SIN-induced allodynia 1 day, but not 1 week later, suggesting a limited role of microglial activation in more perseverative pain states. Our data are consistent with a crucial role for microglial cells in initiating, rather than maintaining, enhanced pain responses. In a model of spinal immune activation by intrathecal HIV-1 gp120, we show that the anti-allodynic effects of minocycline are associated with decreased microglial activation, attenuated mRNA expression of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-1beta-converting enzyme, TNF-alpha-converting enzyme, IL-1 receptor antagonist and IL-10 in lumbar dorsal spinal cord, and reduced IL-1beta and TNF-alpha levels in the CSF. In contrast, no significant effects of minocycline were observed on gp120-induced IL-6 and cyclooxygenase-2 expression in spinal cord or CSF IL-6 levels. Taken together these data highlight the importance of microglial activation in the development of exaggerated pain states.

Psychometric properties of the TSK-11: a shortened version of the Tampa Scale for Kinesiophobia.

Abstract: The Tampa Scale for Kinesiophobia (TSK) is one of the most frequently employed measures for assessing pain-related fear in back pain patients. Despite its widespread use, there is relatively little data to support the psychometric properties of the English version of this scale. This study investigated the psychometric properties of the English version of the TSK in a sample of chronic low back pain patients. Item analysis revealed that four items possessed low item total correlations (4, 8, 12, 16) and four items had response trends that deviated from a pattern of normal distribution (4, 9, 12, 14). Consequently, we tested the psychometric properties of a shorter version of the TSK (TSK-11), having excluded the six psychometrically poor items. The psychometric properties of this measure were compared to those of the original TSK. Both measures demonstrated good internal consistency (TSK: α=0.76; TSK-11: α=0.79), test–retest reliability (TSK: ICC=0.82, SEM=3.16; TSK-11: ICC=0.81, SEM=2.54), responsiveness (TSK: SRM=−1.19; TSK-11: SRM=−1.11), concurrent validity and predictive validity. In respect of specific cut-off scores, a reduction of at least four points on both measures maximised the likelihood of correctly identifying an important reduction in fear of movement. Overall, the TSK-11 possessed similar psychometric properties to the original TSK and offered the advantage of brevity. Further research is warranted to investigate the utility of the new instrument and the cut-off scores in a wider group of chronic pain patients in different clinical settings.

Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition

Abstract: A deficit of endogenous pain inhibitory systems has been suggested to contribute to some chronic pain conditions, one of them being fibromyalgia. The aim of the investigation was to test whether endogenous pain inhibitory systems were activated by a spatial summation procedure in 30 fibromyalgia, 30 chronic low back pain, and 30 healthy volunteers who participated in a cross-over trial (two sessions). Each session consisted of visual analog scale ratings of pain during the immersion of different surfaces of the arm in circulating noxious cold (12 degrees C) water. The arm was arbitrarily divided into eight segments from the fingertips to the shoulder. One session was ascending (from the fingertips to the shoulder) and the other was descending (from the shoulder to the fingertips); they included eight consecutive 2-min immersions separated by 5-min resting periods. For healthy and low back pain subjects, pain was perceived differently during the ascending and descending sessions (P=0.0001). The descending session resulted in lower pain intensity and unpleasantness. This lowering of the perception curve seems to be due to a full recruitment of inhibitory systems at the beginning of the descending session as opposed to a gradual recruitment during the ascending session. For fibromyalgia subjects, no significant differences were found between the increasing and decreasing sessions (P>0.05). These data support a deficit of endogenous pain inhibitory systems in fibromyalgia but not in chronic low back pain. The treatments proposed to fibromyalgia patients should aim at stimulating the activity of those endogenous systems.

Chronic spinal pain and physical-mental comorbidity in the United States: results from the national comorbidity survey replication.

Abstract: This paper investigates comorbidity between chronic back and neck pain and other physical and mental disorders in the US population, and assesses the contributions of chronic spinal pain and comorbid conditions to role disability. A probability sample of US adults (n=5692) was interviewed. Chronic spinal pain, other chronic pain conditions and selected chronic physical conditions were ascertained by self-report. Mood, anxiety and substance use disorders were ascertained with the Composite International Diagnostic Interview (CIDI). Role disability was assessed with questions about days out of role and with impaired role functioning. The 1 year prevalence of chronic spinal pain was 19.0%. The vast majority (87.1%) of people with chronic spinal pain reported at least one other comorbid condition, including other chronic pain conditions (68.6%), chronic physical conditions (55.3%), and mental disorders (35.0%). Anxiety disorders showed as strong an association with chronic spinal pain as did mood disorders. Common conditions not significantly comorbid with chronic spinal pain were diabetes, heart disease, cancer, and drug abuse. Chronic spinal pain was significantly associated with role disability after controlling for demographic variables and for comorbidities. However, comorbid conditions explained about one-third of the gross association of chronic spinal pain with role disability. We conclude that chronic spinal pain is highly comorbid with other pain conditions, chronic diseases, and mental disorders, and that comorbidity plays a significant role in role disability associated with chronic spinal pain. The societal burdens of chronic spinal pain need to be understood and managed within the context of comorbid conditions.

Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens

Abstract: Pregabalin binds with high affinity to the alpha2-delta subunit protein of voltage-gated calcium channels and, thereby, reduces release of excitatory neurotransmitters. This 12-week randomised, double-blind, multicentre, placebo-controlled, parallel-group study evaluated the efficacy and safety of pregabalin in patients with chronic postherpetic neuralgia (PHN) or painful diabetic peripheral neuropathy (DPN). Patients were randomised to placebo (n=65) or to one of two pregabalin regimens: a flexible schedule of 150, 300, 450, and 600 mg/day with weekly dose escalation based on patients' individual responses and tolerability (n=141) or a fixed schedule of 300 mg/day for 1 week followed by 600 mg/day for 11 weeks (n=132). Both flexible- and fixed-dose pregabalin significantly reduced endpoint mean pain score (primary outcome) versus placebo (P=0.002, P<0.001) and were significantly superior to placebo in improving pain-related sleep interference (P<0.001). The most common adverse events (AEs) for pregabalin-treated patients were dizziness, peripheral oedema, weight gain (not affecting diabetes control), and somnolence. These results are consistent with previous studies' demonstrating pregabalin's efficacy, tolerability, and safety for treatment of chronic neuropathic pain associated with DPN or PHN. Pregabalin dosing aimed at optimal balance of efficacy and tolerability provides significant pain relief and may reduce risks for AEs and therapy discontinuation.

Facing others in pain: the effects of empathy.

Abstract: Department of Experimental-Clinical and Health Psychology, Ghent University, Ghent, Belgium Research Institute for Psychology & Health, Utrecht, The Netherlands Department of Psychology, University of British Columbia, Vancouver, BC, Canada Academic Unit of Psychiatry & Behavioural Sciences, University of Leeds, Leeds, UK Department of Psychology, University of Montreal, Quebec, Canada Sub-Department of Clinical Health Psychology, University College London, London, UK Department of Psychology, Wayne State University, Detroit, MI, USA

Ketamine and postoperative pain--a quantitative systematic review of randomised trials.

Abstract: Ketamine, an N-methyl-D-aspartate receptor antagonist, is known to be analgesic and to induce psychomimetic effects. Benefits and risks of ketamine for the control of postoperative pain are not well understood. We systematically searched for randomised comparisons of ketamine with inactive controls in surgical patients, reporting on pain outcomes, opioid sparing, and adverse effects. Data were combined using a fixed effect model. Fifty-three trials (2839 patients) from 25 countries reported on a large variety of different ketamine regimens and surgical settings. Sixteen studies tested prophylactic intravenous ketamine (median dose 0.4 mg/kg, range (0.1-1.6)) in 850 adults. Weighted mean difference (WMD) for postoperative pain intensity (0-10 cm visual analogue scale) was -0.89 cm at 6 h, -0.42 at 12 h, -0.35 at 24 h and -0.27 at 48 h. Cumulative morphine consumption at 24 h was significantly decreased with ketamine (WMD -15.7 mg). There was no difference in morphine-related adverse effects. The other 37 trials tested in adults or children, prophylactic or therapeutic ketamine orally, intramuscularly, subcutaneously, intra-articulary, caudally, epidurally, transdermally, peripherally or added to a PCA device; meta-analyses were deemed inappropriate. The highest risk of hallucinations was in awake or sedated patients receiving ketamine without benzodiazepine; compared with controls, the odds ratio (OR) was 2.32 (95%CI, 1.09-4.92), number-needed-to-harm (NNH) 21. In patients undergoing general anaesthesia, the incidence of hallucinations was low and independent of benzodiazepine premedication; OR 1.49 (95%CI 0.18-12.6), NNH 286. Despite many published randomised trials, the role of ketamine, as a component of perioperative analgesia, remains unclear.

A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder.

Abstract: This was a 12-week, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, in 354 female patients with primary fibromyalgia, with or without current major depressive disorder. Patients (90% Caucasian; mean age, 49.6 years; 26% with current major depressive disorder) received duloxetine 60 mg once daily (QD) (N=118), duloxetine 60 mg twice daily (BID) (N=116), or placebo (N=120). The primary outcome was the Brief Pain Inventory average pain severity score. Response to treatment was defined as >or=30% reduction in this score. Compared with placebo, both duloxetine-treated groups improved significantly more (P or=30% in this score (duloxetine 60 mg QD (55%; P<0.001); duloxetine 60 mg BID (54%; P=0.002); placebo (33%)). The treatment effect of duloxetine on pain reduction was independent of the effect on mood and the presence of major depressive disorder. Compared with patients on placebo, patients treated with duloxetine 60 mg QD or duloxetine 60 mg BID had significantly greater improvement in remaining Brief Pain Inventory pain severity and interference scores, Fibromyalgia Impact Questionnaire, Clinical Global Impression of Severity, Patient Global Impression of Improvement, and several quality-of-life measures. Both doses of duloxetine were safely administered and well tolerated. In conclusion, both duloxetine 60 mg QD and duloxetine 60 mg BID were effective and safe in the treatment of fibromyalgia in female patients with or without major depressive disorder.

Trigeminal small-fiber sensory neuropathy causes burning mouth syndrome.

Abstract: Burning mouth syndrome is a common disorder that frequently affects women in the 5th-7th decade. It is characterized by persisting painful symptoms mainly involving the anterior two-thirds of the tongue. For several years it has been attributed to psychological causes. We investigated the innervation of the epithelium of the tongue to assess whether damage of peripheral nerve fibers underlies the pathogenesis of the disease. We examined 12 patients with clinically definite burning mouth syndrome for at least 6 months. We obtained superficial biopsies of the lateral aspect of the anterior two-thirds of the tongue from all patients and nine healthy controls. Immunohistochemical and confocal microscope co-localization studies were performed with cytoplasmatic, cytoskeletric, Schwann cell, and myelin markers for pathological changes. The density of epithelial nerve fibers was quantified. Patients showed a significantly lower density of epithelial nerve fibers than controls, with a trend toward correlation with the duration of symptoms. Epithelial and sub-papillary nerve fibers showed diffuse morphological changes reflecting axonal degeneration. Our study demonstrates that burning mouth syndrome is caused by a trigeminal small-fiber sensory neuropathy and that superficial biopsy of the tongue can be helpful in assessing the diagnosis. These findings shed light into the pathogenesis of this common disorder and could contribute to evaluate targeted therapies in patients.

The relationship between religion/spirituality and physical health, mental health, and pain in a chronic pain population

Abstract: This study sought to better understand the relationship between religion/spirituality and physical health and mental health in 122 patients with chronic musculoskeletal pain. The current study conceptualized religion/spirituality as a multidimensional factor, and measured it with a new measure of religion/spirituality for research on health outcomes (Brief Multidimensional Measure of Religion/Spirituality). Pain patients' religious and spiritual beliefs appear different than the general population (e.g. pain patients feel less desire to reduce pain in the world and feel more abandoned by God). Hierarchical multiple regression analyses revealed significant associations between components of religion/spirituality and physical and mental health. Private religious practice (e.g. prayer, meditation, consumption of religious media) was inversely related to physical health outcomes, indicating that those who were experiencing worse physical health were more likely to engage in private religious activities, perhaps as a way to cope with their poor health. Forgiveness, negative religious coping, daily spiritual experiences, religious support, and self-rankings of religious/spiritual intensity significantly predicted mental health status. Religion/spirituality was unrelated to pain intensity and life interference due to pain. This study establishes relationships between religion/spirituality and health in a chronic pain population, and emphasizes that religion/spirituality may have both costs and benefits for the health of those with chronic pain.

The measurement of postoperative pain: A comparison of intensity scales in younger and older surgical patients

Abstract: The psychometric properties of pain intensity scales for the assessment of postoperative pain across the adult lifespan have not been reported. The objective of this study was to compare the feasibility and validity of the Numeric Rating Scale (NRS), Verbal Descriptor Scale (VDS), and Visual Analog Scale (horizontal (VAS-H) and vertical (VAS-V) line orientation) for the assessment of pain intensity in younger and older surgical patients. At 24h following surgery, 504 patients, who were receiving i.v. morphine via patient-controlled analgesia, completed the pain intensity measures and the McGill Pain Questionnaire (MPQ) in a randomized order. They were asked which scale was easiest to complete, the most accurate measure, and which they would most prefer to complete in the future, as an index of face validity. The amount of opioid self-administered was recorded. Age differences in postoperative pain intensity were not found. However, elderly patients obtained lower MPQ scores and self-administered less morphine than younger people. Psychometric analyses suggested that the NRS was the preferred pain intensity scale. It had low error rates, and higher face, convergent, divergent and criterion validity than the other scales. Most importantly, its properties were not age-related. The VDS also had a favourable profile with low error rates and good face, convergent and criterion validity. Finally, difficulties with VAS use among the elderly were identified, including high rates of unscorable data and low face validity. Its use with elderly postoperative patients should be discouraged.

Age effects on pain thresholds, temporal summation and spatial summation of heat and pressure pain

Abstract: Experimental data on age-related changes in pain perception have so far been contradictory. It has appeared that the type of pain induction method is critical in this context, with sensitivity to heat pain being decreased whereas sensitivity to pressure pain may be even enhanced in the elderly. Furthermore, it has been shown that temporal summation of heat pain is more pronounced in the elderly but it has remained unclear whether age differences in temporal summation are also evident when using other pain induction methods. No studies on age-related changes in spatial summation of pain have so far been conducted. The aim of the present study was to provide a comprehensive survey on age-related changes in pain perception, i.e. in somatosensory thresholds (warmth, cold, vibration), pain thresholds (heat, pressure) and spatial and temporal summation of heat and pressure pain. We investigated 20 young (mean age 27.1 years) and 20 elderly (mean age 71.6 years) subjects. Our results confirmed and extended previous findings by showing that somatosensory thresholds for non-noxious stimuli increase with age whereas pressure pain thresholds decrease and heat pain thresholds show no age-related changes. Apart from an enhanced temporal summation of heat pain, pain summation was not found to be critically affected by age. The results of the present study provide evidence for stimulus-specific changes in pain perception in the elderly, with deep tissue (muscle) nociception being affected differently by age than superficial tissue (skin) nociception. Summation mechanisms contribute only moderately to age changes in pain perception.

Physical and psychological factors predict outcome following whiplash injury.

Abstract: Predictors of outcome following whiplash injury are limited to socio-demographic and symptomatic factors, which are not readily amenable to secondary and tertiary intervention. This prospective study investigated the predictive capacity of early measures of physical and psychological impairment on pain and disability 6 months following whiplash injury. Motor function (ROM; kinaesthetic sense; activity of the superficial neck flexors (EMG) during cranio-cervical flexion), quantitative sensory testing (pressure, thermal pain thresholds, brachial plexus provocation test), sympathetic vasoconstrictor responses and psychological distress (GHQ-28, TSK, IES) were measured in 76 acute whiplash participants. The outcome measure was Neck Disability Index scores at 6 months. Stepwise regression analysis was used to predict the final NDI score. Logistic regression analyses predicted membership to one of the three groups based on final NDI scores ( 30 moderate/severe pain and disability). Higher initial NDI score (1.007-1.12), older age (1.03-1.23), cold hyperalgesia (1.05-1.58), and acute post-traumatic stress (1.03-1.2) predicted membership to the moderate/severe group. Additional variables associated with higher NDI scores at 6 months on stepwise regression analysis were: ROM loss and diminished sympathetic reactivity. Higher initial NDI score (1.03-1.28), greater psychological distress (GHQ-28) (1.04-1.28) and decreased ROM (1.03-1.25) predicted subjects with persistent milder symptoms from those who fully recovered. These results demonstrate that both physical and psychological factors play a role in recovery or non-recovery from whiplash injury. This may assist in the development of more relevant treatment methods for acute whiplash.

Sustained sleep restriction reduces emotional and physical well-being.

Abstract: Background: Chronic insufficient sleep is a common finding in many pain-related and other medical diseases and is frequently experienced in the general population. Prolonged curtailment of nocturnal sleep has been studied for its adverse effect on cognitive functioning and subjective tiredness, but relatively little is known about its effect on mood and physical symptoms. Objective: In order to test whether sleep restriction to 50% of the habitual time over 12 days affects diurnal and day-to-day variation of subjective ratings of mood and physical symptoms, 108 adjectives and statements were self-rated using visual analog scales every 2 h during the waking period. Design: Randomized, 16-day controlled in-laboratory study. Setting: General Clinical Research Center (GCRC). Participants: Forty healthy subjects aged 21–40 years (14 females, 26 males). Intervention: Subjects were randomized to either 4 h of sleep per night (11pm–3am, N=22) or 8 h of sleep per night (11pm–7am, N=18) for 12 consecutive days. Main Outcome Measure: Changes in the factor-derived variables optimism-sociability, tiredness-fatigue, anger-aggression, bodily discomfort, and items constituting bodily discomfort were compared between groups. Results: Optimism-sociability progressively declined over consecutive days of sleep restriction by 15%. Bodily discomfort showed a slight, but significant interindividual increase of 3% across days of sleep restriction due to significant increases of generalized body pain, back pain, and stomach pain. Optimism-sociability and tiredness-fatigue showed diurnal variations with a quadratic function period within each day in both conditions. Conclusion: The data suggest that chronic insufficient sleep may contribute to the onset and amplification of pain and affect health by compromising optimistic outlook and psychosocial functioning.

Hypervigilance to pain: An experimental and clinical analysis

Abstract: A clinical feature of many chronic pain patients is persistent, distressing and preoccupying pain that cannot be explained easily by observable biomedical phenomena. Growing in popularity are explanations based on the idea of dysfunctional attentional processes. Patients are thought to display a ‘hypervigilance’ to pain and pain-associated information at the expense of the rest of life. Although seductive as an explanation for a class of effects, closer examination shows that there is a number of partial and competing explanations of this putative attentional effect, and different ways to operationalise it (Van Damme et al., 2004a,b). For just three examples: Puzzled by the observation that patients with widespread musculoskeletal pain have both lower pain and auditory thresholds than controls, McDermid et al. (1996) proposed that fibromyalgia patients are hypervigilant to stressors in general. In reviewing gender differences in pain experience, Rollman et al. (2004) suggested that hypervigilance may explain commonly found gender differences in the reporting of pain. In their model of fear-avoidance Vlaeyen and Linton (2000) presumed low back pain patients who fear (re)injury to be hypervigilant to pain; a hypervigilance that expedites escape and avoidance behavior. In this paper we offer conceptual clarification of the concept of vigilance, and propose a model of hypervigilance.

Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU

Abstract: Data from animal models indicate that neonatal stress or pain can permanently alter subsequent behavioral and/or physiological reactivity to stressors. However, cumulative effects of pain related to acute procedures in the neonatal intensive care unit (NICU) on later stress and/or pain reactivity has received limited attention. The objective of this study is to examine relationships between prior neonatal pain exposure (number of skin breaking procedures), and subsequent stress and pain reactivity in preterm infants in the NICU. Eighty-seven preterm infants were studied at 32 (±1 weeks) postconceptional age (PCA). Infants who received analgesia or sedation in the 72 h prior to each study, or any postnatal dexamethasone, were excluded. Outcomes were infant responses to two different stressors studied on separate days in a repeated measures randomized crossover design: (1) plasma cortisol to stress of a fixed series of nursing procedures; (2) behavioral (Neonatal Facial Coding System; NFCS) and cardiac reactivity to pain of blood collection. Among infants born ≤ 28 weeks gestational age (GA), but not 29–32 weeks GA, higher cumulative neonatal procedural pain exposure was related to lower cortisol response to stress and to lower facial (but not autonomic) reactivity to pain, at 32 weeks PCA, independent of early illness severity and morphine exposure since birth. Repeated neonatal procedural pain exposure among neurodevelopmentally immature preterm infants was associated with down-regulation of the hypothalamic–pituitary–adrenal axis, which was not counteracted with morphine. Differential effects of early pain on development of behavioral, physiologic and hormonal systems warrant further investigation.

Risk factors for acute pain and its persistence following breast cancer surgery.

Abstract: Although more severe acute postoperative pain increases the risk of chronic pain following breast cancer surgery, few studies have examined the characteristics of patients who develop greater acute pain. To identify risk factors for acute pain and its persistence one month following breast cancer surgery, a sample of 114 women scheduled for breast cancer surgery was assessed preoperatively for demographic, clinical, and emotional functioning variables that were hypothesized to be associated with acute pain severity. Clinically meaningful postoperative pain was assessed at follow-up interviews 2, 10, and 30 days after surgery. In univariate analyses, the risk of clinically meaningful acute pain was increased among women who were younger, unmarried, had more invasive surgeries, and had greater preoperative emotional distress. In multiple logistic regression analyses, greater preoperative anxiety was the only variable that made an independent contribution to predicting clinically meaningful acute pain at 2 days after surgery whereas younger age, being unmarried, and preoperative anxiety each made an independent contribution to predicting clinically meaningful acute pain that persisted from 2 to 30 days after surgery. These results increase understanding of neurobiologic mechanisms and psychosocial processes that contribute to the development of acute pain following breast cancer surgery and have implications for the development of interventions to prevent it.

Parent and family factors in pediatric chronic pain and disability: An integrative approach

Abstract: Chronic pain is a widespread developmental health issue that affects a large proportion of children and adolescents (Perquin et al., 2000; Roth-Isigkeit et al., 2005). Pain can lead to significant interference with daily functioning for many children and adolescents (Palermo, 2000; KashikarZuck et al., 2001) and increases their risk of having a chronic pain syndrome in adulthood (Fearon and Hotopf, 2001). The family has been described as an important context for understanding, assessing, and managing pediatric chronic pain (Chambers, 2003), and there is a growing body of research on family and parent factors in pediatric chronic pain and their relationship to child pain and functional outcomes, such as disability. In particular, there has been a recent surge of interest along two separate lines of research on the influence of parent and family factors on children’s pain and disability. The first line of research is the role of specific parental behaviors, such as parental modeling, solicitousness or reinforcement, in pediatric chronic pain. The second line of research is on the role of broader family level factors, such as functioning and cohesion, in children’s pain. We argue that research on parent and family factors in pediatric chronic pain has been hindered by conceptual confusion about what constitutes a parent or family factor, limited tests of specific family

The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients.

Abstract: Catechol-O-methyltransferase (COMT) inactivates dopamine, epinephrine and norepinephrine in the nervous system. A common functional polymorphism (Val158Met) leads to a three- to-four-fold variation in the COMT enzyme activity, the Met form displaying lower enzymatic activity. The Val158Met polymorphism affects pain perception, and subjects with the Met/Met genotype have the most pronounced response to experimental pain. Based on this information we analyzed the influence from the COMT Val158Met polymorphism on the efficacy of morphine in a cohort of patients suffering from cancer pain. We genotyped 207 Caucasian cancer patients on morphine treatment with respect to the Val158Met polymorphism and compared the morphine doses, serum concentrations of morphine and morphine metabolites between the genotype groups. Patients with the Val/Val genotype (n=44) needed more morphine (155+/-160 mg/24 h) when compared to the Val/Met (117+/-100 mg/24 h; n=96) and the Met/Met genotype (95+/-99 mg/24 h; n=67) groups (P=0.025). This difference was not explained by other factors such as duration of morphine treatment, performance status, time since diagnosis, perceived pain intensity, adverse symptoms, or time until death. These results suggest that genetic variation in the COMT gene may contribute to variability in the efficacy of morphine in cancer pain treatment.

Increased placebo analgesia over time in irritable bowel syndrome (IBS) patients is associated with desire and expectation but not endogenous opioid mechanisms

Abstract: A study was conducted to determine whether changes in expected pain levels, desire for pain relief, or anxiety contribute to an increase in placebo analgesia over time as well as to determine whether placebo analgesic effects of IBS patients are related to endogenous opioid mechanisms. Twenty-six women with IBS were exposed to rectal stimulation (35 or 55 mmHg for 30 s) and tested under natural history (NH), rectal placebo (RP) and rectal lidocaine (RL) conditions. During all conditions, 16 patients were given saline intravenously (to test for a placebo effect) and 10 patients were given naloxone intravenously (to test naloxone antagonism of the placebo effect) on a double blind basis. Patients rated expected pain level, desire for pain relief and anxiety at 2 and 22 min after the onset of NH, RP, and RL conditions and they rated actual pain intensity at 5-min intervals for 40 min. There was a large and significant placebo effect (P<0.001) that increased over time. Ratings of expected pain levels, desire for pain relief and anxiety decreased over time and contributed to more variance in placebo and lidocaine responses during the last half of the session. These changes suggest that a reduction in negative emotions may be central to placebo effects. There was no significant difference between psychological mediators (desire, expectation, anxiety) or the placebo effect in the saline and naloxone groups, indicating that neither the psychological mediators nor the placebo analgesic effect were associated with endogenous opioids in this clinically related paradigm.

Effect of Iyengar yoga therapy for chronic low back pain

Abstract: Low back pain is a significant public health problem and one of the most commonly reported reasons for the use of Complementary Alternative Medicine. A randomized control trial was conducted in subjects with non-specific chronic low back pain comparing Iyengar yoga therapy to an educational control group. Both programs were 16 weeks long. Subjects were primarily self-referred and screened by primary care physicians for study of inclusion/exclusion criteria. The primary outcome for the study was functional disability. Secondary outcomes including present pain intensity, pain medication usage, pain-related attitudes and behaviors, and spinal range of motion were measured before and after the interventions. Subjects had low back pain for 11.2G1.54 years and 48% used pain medication. Overall, subjects presented with less pain and lower functional disability than subjects in other published intervention studies for chronic low back pain. Of the 60 subjects enrolled, 42 (70%) completed the study. Multivariate analyses of outcomes in the categories of medical, functional, psychological and behavioral factors indicated that significant differences between groups existed in functional and medical outcomes but not for the psychological or behavioral outcomes. Univariate analyses of medical and functional outcomes revealed significant reductions in pain intensity (64%), functional disability (77%) and pain medication usage (88%) in the yoga group at the post and 3-month follow-up assessments. These preliminary data indicate that the majority of self-referred persons with mild chronic low back pain will comply to and report improvement on medical and functional pain-related outcomes from Iyengar yoga therapy. q 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

A prospective study of acceptance of pain and patient functioning with chronic pain

Abstract: Acceptance of chronic pain is emerging as an important concept in understanding ways that chronic pain sufferers can remain engaged with valued aspects of life. Recent studies have relied heavily on cross-sectional investigations at a single time point. The present study sought to prospectively investigate relations between acceptance of chronic pain and patient functioning. A sample of adults referred for interdisciplinary treatment of severe and disabling chronic pain was assessed twice, an average of 3.9 months apart. Results showed that pain and acceptance were largely unrelated. Pain at Time 2 was weakly related to measures of functioning at Time 2. On the other hand, acceptance at Time 1 was consistently related to patient functioning at Time 2. Those patients who reported greater acceptance at Time 1 reported better emotional, social, and physical functioning, less medication consumption, and better work status at Time 2. These data suggest that willingness to have pain, and to engage in activity regardless of pain, can lead to healthy functioning for patients with chronic pain. Treatment outcome and process studies may demonstrate the potential for acceptance-based clinical methods for chronic pain management.

The case for the inclusion of female subjects in basic science studies of pain.

Abstract: Sex differences in pain are of great interest to the public, and of recently increasing interest among researchers. The first author has studied the topic since 1992 in the laboratory of the late John C. Liebeskind, when a reanalysis of an already published data set by subject sex revealed a pharmacological effect of N-methyl-D-aspartate receptor blockade on swim stress-induced analgesia in male but not female mice. The postdoctoral fellow also working on these studies was not particularly enthusiastic about them, asserting only half in jest that ‘sex differences are to be enjoyed, not studied’ (Marek, personal communication). Nonetheless, the resulting paper (Mogil et al., 1993) prompted a cover illustration and an editorial in the journal Pain designed to ‘draw.attention to the issue’ (Ruda, 1993). There is little doubt that the attention of the pain research community has now effectively been drawn: in a recent issue of Pain (Vol. 114, No. 1–2, March 2005), no less than six of 30 primary research articles referred to sex differences or gonadal hormones in their title, and three more discussed sex differences within. Since 1994, the US National Institutes of Health has required that clinical trials supported by them include adequate representation of women. However, basic science studies continue to use male rodents almost exclusively as research subjects. A survey of 100 basic neuroscience papers from four prominent journals in 1991 revealed only 12 papers where both male and female subjects were used, and an astonishing 45 papers where the sex of the subject was not even specified (Berkley, 1992). Has anything

A role for the brainstem in central sensitisation in humans. Evidence from functional magnetic resonance imaging.

Abstract: Animal studies have established a role for the brainstem reticular formation, in particular the rostral ventromedial medulla (RVM), in the development and maintenance of central sensitisation and its clinical manifestation, secondary hyperalgesia. Similar evidence in humans is lacking, as neuroimaging studies have mainly focused on cortical changes. To fully characterise the supraspinal contributions to central sensitisation in humans, we used whole-brain functional magnetic resonance imaging at 3 T, to record brain responses to punctate mechanical stimulation in an area of secondary hyperalgesia. We used the heat/capsaicin sensitisation model to induce secondary hyperalgesia on the right lower leg in 12 healthy volunteers. A paired t-test was used to compare activation maps obtained during punctate stimulation of the secondary hyperalgesia area and those recorded during control punctate stimulation (same body site, untreated skin, separate session). The following areas showed significantly increased activation (Z>2.3, corrected P<0.01) during hyperalgesia: contralateral brainstem, cerebellum, bilateral thalamus, contralateral primary and secondary somatosensory cortices, bilateral posterior insula, anterior and posterior cingulate cortices, right middle frontal gyrus and right parietal association cortex. Brainstem activation was localised to two distinct areas of the midbrain reticular formation, in regions consistent with the location of nucleus cuneiformis (NCF) and rostral superior colliculi/periaqueductal gray (SC/PAG). The PAG and the NCF are the major sources of input to the RVM, and therefore in an ideal position to modulate its output. These results suggest that structures in the mesencephalic reticular formation, possibly the NCF and PAG, are involved in central sensitisation in humans.