PAIN - Articles in Press

No pain no gain? Pursuing a competing goal inhibits avoidance behavior - Corrected Proof

2012-02-02

Summary: Pursuing valuable goals reduces pain-related avoidance behavior and the relation between fear and avoidance. This shows the need for a dynamic, contextual-motivational view on disability.Abstract: This experiment investigated pain-related avoidance behavior in context of competing goals. Participants (N=56) were presented trials of 2 different tasks of which 1 task could produce pain. They were free to decide whether or not to perform trials of these tasks. In half of the participants, a competing goal was activated by instructing them that they would receive a monetary reward corresponding to the number of pain task trials actually performed (competition group). In the other half of the participants, no competing goal was installed (control group). Results showed that the competition group showed less frequent avoidance behavior than the control group. Furthermore, the association between pain-related avoidance behavior and fear of pain was smaller in the competition group than in the control group. The findings indicate that the emergence of pain-related avoidance behavior depends upon the motivational context, and that the association between pain-related fear and avoidance is not stable. This study has implications for our understanding of disability, and points to the need to consider avoidance behavior within a broad context of multiple, often competing, goals.

Calcium/calmodulin dependent kinase II contributes to persistent central neuropathic pain following spinal cord injury - Corrected Proof

2012-02-01

Summary: Activated neuronal CaMKII is a critical component of the intracellular signaling pathways that contribute to neuropathic pain and persistent neuronal hyperexcitability after spinal cord injury.Abstract: Chronic central neuropathic pain after central nervous system injuries remains refractory to therapeutic interventions. A novel approach would be to target key intracellular signaling proteins that are known to contribute to continued activation by phosphorylation of kinases, transcription factors, and/or receptors that contribute to changes in membrane excitability. We demonstrate that one signaling kinase, calcium/calmodulin-dependent kinase II (CaMKII), is critical in maintaining aberrant dorsal horn neuron hyperexcitability in the neuropathic pain condition after spinal cord injury (SCI). After contusion SCI at spinal level T10, activated CaMKII (phosphorylated, pCaMKII) expression is significantly upregulated in the T7/8 spinal dorsal horn in neurons, but not glial cells, and in oligodendrocytes in the dorsal column in the same rats that displayed at-level mechanical allodynia. Furthermore, identified spinothalamic neurons demonstrated significant increases of pCaMKII after SCI compared to sham-treated control animals. However, neither astrocytes nor microglia showed pCaMKII expression in either sham-treated or SCI rats. To demonstrate causality, treatment of SCI rats with KN-93, which prevents CaMKII activation, significantly attenuated at-level mechanical allodynia and aberrant wide dynamic range neuronal activity evoked by brush, pressure, and pinch stimuli and a graded series of von Frey stimuli, respectively. Persistent CaMKII activation contributes to chronic central neuropathic pain by mechanisms that involve maintained hyperexcitability of wide dynamic range dorsal horn neurons. Furthermore, targeting key signaling proteins is a novel, useful therapeutic strategy for treating chronic central neuropathic pain.

Dependence scores predict prognosis of medication overuse headache: a prospective cohort from the Akershus study of chronic headache - Corrected Proof

2012-01-27

Summary: Prognosis regarding out-patient detoxification from medication overuse and improvement of chronic headache is predicted by Severity of Dependence Scale scores in subjects with medication overuse headache. Those with high scores at baseline are less likely to improve and may require in-patient treatment.Abstract: Medication overuse headache (MOH) is a chronic headache that is common in the general population. It has characteristics similar to drug dependence, and detoxification is established as the main treatment. The majority of MOH cases are in contact with general practitioners. Our objective was to investigate whether the Severity of Dependence Scale (SDS) score could be used as predictor for the prognosis of MOH in the general population.In a cross-sectional epidemiological survey, an age- and gender-stratified sample of 30,000 persons 30 to 44 years of age was recruited via a posted questionnaire. Those individuals with self-reported chronic headache (⩾15 days per month) were interviewed by neurological residents at Akershus University Hospital, Oslo. The International Classification of Headache Disorders was used. Those with MOH were re-interviewed by telephone 2 to 3 years after the initial interview. SDS scores and medication information were collected at baseline and follow-up. The main outcomes were SDS scores, termination of MOH and chronic headache from baseline to follow-up. We found the predominant overused analgesics in this sample to be simple analgesics. At follow-up, 65% of participants no longer had medication overuse, and 37% had changed to episodic headache (<15 days per month). The SDS score at baseline successfully predicted improvement for primary MOH, but not secondary MOH. The SDS scores decreased slightly from baseline to follow-up in those who stopped medication overuse, but were still significantly higher than in subjects with chronic headache without medication overuse at baseline. We conclude that the SDS score can predict successful prognosis related to detoxification of primary MOH but not in secondary MOH.

Is there a potential role for attention bias modification in pain patients? Results of 2 randomised, controlled trials - Corrected Proof

2012-01-27

Summary: Attention bias modification resulted in positive outcomes compared to placebo in 2 randomised, controlled trials in patients with acute and chronic pain.Abstract: Potential applications of attention bias modification (ABM) for acute and chronic pain patients are investigated. In study 1, 54 acute back pain patients (46 of whom completed the study) were recruited at their initial physiotherapy session and randomised to receive 1 session of ABM or placebo. Patients were followed up 3months later. Participants who were randomised to receive ABM reported less average (P=0.001) and current pain (P=0.008) and experienced pain for fewer days (P=0.01) than those who received placebo. In study 2, 34 chronic pain patients were recruited and randomly assigned to receive either 4 sessions of ABM (n=22) or placebo (n=12), followed by 8 sessions of cognitive behavioural treatment (CBT). After ABM, there was a significant group-by-time effect for disability. By 6-month follow-up, differences had emerged between the 2 training groups, such that the ABM group had shown greater reductions in anxiety sensitivity and disability than the placebo group. Although the results of these studies show that there is potential in the application of ABM to pain conditions, the mechanisms of treatment could not be established. Neither group showed an initial bias towards the word stimuli or a training effect, and only in the acute pain group were changes in biases related to outcome. Nonetheless, the fact that 2 independent samples showed a positive effect of ABM on clinical outcomes suggests that ABM is worthy of future study as an intervention for pain patients.

Insomnia, sleep quality, pain, and somatic symptoms: sex differences and shared genetic components - Corrected Proof

Jihui Zhang, Siu-Ping Lam, S.X. Li, N.L. Tang, M.W.M. Yu, A.M. Li, Yun-Kwok Wing — 2012-01-25

TOC summary: A shared genetic predisposition might underlie the associations of insomnia and sleep quality with pain and somatic symptoms. Insomnia seems to modulate the sex differences in pain and somatic symptoms, especially in the adult population.Abstract: This study investigated the sex differences, and the shared genetic and environmental factors underlying the associations of sleep disturbances (insomnia and sleep quality) with pain and somatic symptoms in both adolescents and middle-aged adults. We recruited 259 adolescents (69 with current insomnia) and their parents (256 middle-aged adults, 78 with current insomnia). Insomnia severity and sleep quality were measured by the Insomnia Severity Inventory (ISI) and Pittsburgh Sleep Quality Index (PSQI), respectively. Pain and somatic symptoms were measured by the Somatic Symptom Inventory and Visual Analogue Scale for overall pain. Subjects with insomnia scored higher on all measures of pain and somatic symptoms than non-insomnia patients, in both adolescents and adults (P<.001). Both pain and somatic measures were associated with ISI and PSQI scores after controlling for age, sex, depressive and anxiety symptoms. There was an interaction effect between insomnia and female sex on pain and somatic symptoms (P<.05), especially in adults. Pain and somatic symptoms ran in family with moderate heritability (range h2=0.15–0.42). The phenotypic associations of ISI and PSQI with pain and somatic measures were both contributed by genetic (range pG=0.41–0.96) and environmental (range pE=0.27–0.40) factors with a major genetic contribution. In summary, insomnia and poor sleep quality are closely associated with pain and somatic symptoms. Insomnia seems to modulate the sex differences in pain and somatic symptoms, especially in the adult population. A shared genetic predisposition might underlie the associations of insomnia and sleep quality with pain and somatic symptoms.

Which domains should be included in a cancer pain classification system? Analyses of longitudinal data - Corrected Proof

2012-01-24

Summary: Pain intensity, incident pain, pain localisation, and cancer diagnosis are important domains to include in an international cancer pain classification system.Abstract: The overall aim of the present study was to further develop an evidence-based platform for the content of an international cancer pain classification system. Data from a multicentre, observational longitudinal study of cancer patients were analysed. Analyses were carried out in 2 samples: (A) Cross-sectional data of patients on opioids at inclusion, and (B) patients just admitted to palliative care. Outcome measures in the models we investigated were pain on average, worst pain, and pain relief at inclusion, and at day 14, respectively. Uni- and multivariate regression models were applied to test the explicative power on pain outcomes of a series of known pain domains, including incident pain, psychological distress, neuropathic pain, pain localisation, sleep disturbances, total morphine equivalent daily dose (MEDD), and cancer diagnosis. In the 2 analyses, 1529 (A) and 352 (B) patients were included, respectively. Incident pain, pain localisation, MEDD, use of nonsteroidal antiinflammatory drugs, and sleep were associated with one or more of the pain outcomes in analysis A, while initial pain intensity, initial pain relief, incident pain, localisation of pain, cancer diagnosis, and age were predictors in the longitudinal analysis. Identified domains explained 16% to 24% of the variability of the pain outcome. Initial pain intensity emerged as the strongest predictor of pain outcome after 2weeks, and incident pain was confirmed to be a relevant domain. The regression models explained only a minor part of the variability of pain outcomes.

Impact of parental catastrophizing and contextual threat on parents’ emotional and behavioral responses to their child’s pain - Corrected Proof

Line Caes, Tine Vervoort, Zina Trost, Liesbet Goubert — 2012-01-24

Summary: Heightened contextual threat induces elevated levels of parental psychophysiological distress in response to child pain, and is associated with more pain-attending talk in catastrophizing parents.Abstract: Limited research has addressed processes underlying parents’ empathic responses to their child’s pain. The present study investigated the effects of parental catastrophizing, threatening information about the child’s pain, and child pain expression upon parental emotional and behavioral responses to their child’s pain. A total of 56 school children participated in a heat pain task consisting of 48 trials while being observed by 1 of their parents. Trials were preceded by a blue or yellow circle, signaling possible pain stimulation (i.e., pain signal) or no pain stimulation (i.e., safety signal). Parents received either neutral or threatening information regarding the heat stimulus. Parents’ negative emotional responses when anticipating their child’s pain were assessed using psychophysiological measures— i.e., fear-potentiated startle and corrugator EMG activity. Parental behavioral response to their child’s pain (i.e., pain attending talk) was assessed during a 3-minute parent–child interaction that followed the pain task. The Child Facial Coding System (CFCS) was used to assess children’s facial pain expression during the pain task. Results indicated that receiving threatening information was associated with a stronger parental corrugator EMG activity during pain signals in comparison with safety signals. The same pattern was found for parental fear-potentiated startle reflex, particularly when the child’s facial pain expression was high. In addition, parents who reported high levels of catastrophizing thought about their child’s pain engaged, in comparison with low-catastrophizing parents, in more pain-attending talk when they received threatening information. The findings are discussed in the context of affective-motivational theories of pain.

Pain’s peptide signature - Corrected Proof

Michael Costigan — 2012-01-24

Chronic pain, and especially persistent pain caused by an identifiable lesion to the nervous system (neuropathic pain), is a clinical concern of intense ongoing research. There is clearly a need for improved therapies. Multiple mechanisms have been discovered and illuminated within this field (reviewed in ) and medical research has in a few notable cases, such as gabapentin, resulted in tangible benefit . Much work remains, however, in order that the mechanisms that underlie the generation of neuropathic pain can be elucidated and novel therapies developed rationally. Within the last few decades, genomic science has been added to the tool box of methods that can be used to define and understand this disease. Among these methods are cloning, transcript abundance quantification, genetic trait association, and genetic manipulation of model organisms. As technology improves, each of these methods aspires to be genome-wide, which will allow us, in theory, to peer at will into the innermost workings of an organism ( and references within this issue). These nucleic acid based methods have become so fashionable that it is rare to see a research article that does not contain them. Unfortunately, this focus on DNA and RNA often ignores the fact that a cell is made of protein and that the principle method of communication within the nervous system is electrical, i.e. via action potentials. Of course the body is the product of genes, proteins and physiology and each mechanism must be considered in context, which is why the advent of protein quantification en masse is such an exciting step forward.

Acute experimental endotoxemia induces visceral hypersensitivity and altered pain evaluation in healthy humans - Corrected Proof

2012-01-20

Summary: A systemic, endotoxin-induced immune activation leads to decreased visceral sensory and pain thresholds and altered subjective pain ratings in healthy humans.Abstract: Growing evidence suggests that systemic immune activation plays a role in the pathophysiology of pain in functional bowel disorders. By implementing a randomized crossover study with an injection of endotoxin or saline, we aimed to test the hypothesis that endotoxin-induced systemic inflammation increases visceral pain sensitivity in humans. Eleven healthy men (mean±standard error of the mean age 26.6±1.1 years) received an intravenous injection of either lipopolysaccharide (LPS; 0.4ng/kg) or saline on 2 otherwise identical study days. Blood samples were collected 15min before and 1, 2, 3, 4, and 6h after injection to characterize changes in immune parameters including proinflammatory cytokines. Rectal sensory and pain thresholds and subjective pain ratings were assessed with barostat rectal distensions 2h after injection. LPS administration induced an acute inflammatory response indicated by transient increases in tumor necrosis factor alpha, interleukin 6, and body temperature (all P<.001). The LPS-induced immune activation increased sensitivity to rectal distensions as reflected by significantly decreased visceral sensory and pain thresholds (both P<.05) compared to saline control. Visceral stimuli were rated as more unpleasant (P<.05) and inducing increased urge to defecate (P<.01). Pain thresholds correlated with interleukin 6 at +1h (r=0.60, P<.05) and +3h (r=0.67, P<.05) within the LPS condition. This report is novel in that it demonstrates that a transient systemic immune activation results in decreased visceral sensory and pain thresholds and altered subjective pain ratings. Our results support the relevance of inflammatory processes in the pathophysiology of visceral hyperalgesia and underscore the need for studies to further elucidate immune-to-brain communication pathways in gastrointestinal disorders.

Metallothionein deficiency in the injured peripheral nerves of complex regional pain syndrome as revealed by proteomics - Corrected Proof

2012-01-16

Summary: This work, for the first time, revealed molecules central in intractable pain in complex regional pain syndrome (CRPS). Metallothionein, a very strong free radical scavenger and an anti-inflammatory mediator is lacked in the affected nerves of CRPS. This work may shed a light in pathology of this intractable algetic disorder and open a new paradigm in this difficult condition.Abstract: Complex regional pain syndrome (CRPS) is characterized by persistent and severe pain after trauma or surgery; however, its molecular mechanisms in the peripheral nervous system are poorly understood. Using proteomics, we investigated whether injured peripheral nerves of CRPS patients have altered protein profiles compared with control nerves. We obtained nerve samples from 3 patients with CRPS-2 who underwent resection of part of an injured peripheral nerve. Sural nerves from fresh cadavers with no history of trauma or neuropathic pain served as controls. Proteomic analysis showed that the number and functional distribution of proteins expressed in CRPS and control nerves was similar. Interestingly, metallothionein was absent in the injured nerves of CRPS-2, although it was readily detected in control nerves. Western blotting further confirmed the absence of metallothionein in CRPS-2 nerves, and immunohistochemistry corroborated the deficiency of metallothionein expression in injured nerves from 5 of 5 CRPS patients and 2 of 2 patients with painful neuromas. In contrast, all control nerves, including 5 sural nerves from fresh cadavers and 41 nerves obtained from surgically resected tumors, expressed MT. Furthermore, expression of S100 as a marker for Schwann cells, and neurofilament M as a marker of axons was comparable in both CRPS-2 and controls.Metallothioneins are zinc-binding proteins that are probably involved in protection against injury and subsequent regeneration after CNS damage. Their absence from the injured peripheral nerves of patients with CRPS-2 suggests a potential pathogenic role in generating pain in the damaged peripheral nerves.

White matter microstructural alterations in migraine: A diffusion-weighted MRI study - Corrected Proof

2012-01-16

Summary: White matter disintegration, as measured by diffusion-weighted MRI, is reported in migraineurs, and is speculated to be either a marker of possible white matter disintegration or maladaptive plasticity.Abstract: Migraine is a common and disabling neurological disease. The pathomechanism that underlies the disorder is not entirely understood, and reliable biomarkers are missing. In the current analysis we looked for microstructural alterations of the brain white matter in migraine patients by means of diffusion-weighted magnetic resonance imaging. The measurements were carried out with a novel approach based on fine-tuned nonlinear registration and nonparametric permutation test in an alignment-invariant tract representation (Tract-Based Spatial Statistics). We found reduced fractional anisotropy in the right frontal white matter cluster of migraine patients. In the same region we also found increased mean diffusivity and increased radial diffusivity. The probabilistic tractography showed connection of this cluster to other parts of the pain network (orbitofrontal cortex, insula, thalamus, dorsal midbrain). We speculate that these findings reflect maladaptive plastic changes or white matter disintegration.

Pain, body, and space: what do patients with complex regional pain syndrome really neglect? - Corrected Proof

Valéry Legrain, Janet H. Bultitude, Annick L. De Paepe, Yves Rossetti — 2012-01-16

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Space is an important dimension in perception. It helps to perceive the relative position between objects including one’s own body in order to guide interaction with the outer world. The brain is able to process spatial information according to different frames of reference. A first dissociation can be made between egocentric and allocentric representations . The egocentric, subject-centered frame of reference enables spatial representations of objects depending on their position relative to the perceiver’s body. In this case, left and right are defined according to the midline of the body or of specific body parts. In representations that depend on an allocentric frame of reference, the perception of position in space is independent of the observer. Space is then perceived in terms of positions between objects or between parts of the same objects. Another important distinction is the dissociation between personal, peripersonal and extrapersonal spaces . Personal space corresponds to the space of the body, peripersonal space to the immediate space surrounding the body allowing direct manipulation of proximal objects, and extrapersonal space to the far space in which objects are reached by limb movements.

Effects of mitochondrial poisons on the neuropathic pain produced by the chemotherapeutic agents, paclitaxel and oxaliplatin - Corrected Proof

Wen Hua Xiao, Gary J. Bennett — 2012-01-16

Summary: The mitochondrial poisons, rotenone, oligomycin, and auranofin, significantly increase chemotherapy-evoked neuropathic pain at doses that have no effect on the responses of normal rats.Abstract: The dose-limiting side effect of taxane, platinum-complex, and other kinds of anticancer drugs is a chronic, distal, bilaterally symmetrical, sensory peripheral neuropathy that is often accompanied by neuropathic pain. Work with animal models of these conditions suggests that the neuropathy is a consequence of toxic effects on mitochondria in primary afferent sensory neurons. If this is true, then additional mitochondrial insult ought to make the neuropathic pain worse. This prediction was tested in rats with painful peripheral neuropathy due to the taxane agent, paclitaxel, and the platinum-complex agent, oxaliplatin. Rats with established neuropathy were given 1 of 3 mitochondrial poisons: rotenone (an inhibitor of respiratory Complex I), oligomycin (an inhibitor of adenosine triphosphate synthase), and auranofin (an inhibitor of the thioredoxin-thioredoxin reductase mitochondrial antioxidant defense system). All 3 toxins significantly increased the severity of paclitaxel-evoked and oxaliplatin-evoked mechano-allodynia and mechano-hyperalgesia while having no effect on the mechano-sensitivity of chemotherapy-naïve rats. Chemotherapy-evoked painful peripheral neuropathy is associated with an abnormal spontaneous discharge in primary afferent A fibers and C fibers. Oligomycin, at the same dose that exacerbated allodynia and hyperalgesia, significantly increased the discharge frequency of spontaneously discharging A fibers and C fibers in both paclitaxel-treated and oxaliplatin-treated rats, but did not evoke any discharge in naïve control rats. These results implicate mitochondrial dysfunction in the production of chemotherapy-evoked neuropathic pain and suggest that drugs that have positive effects on mitochondrial function may be of use in its treatment and prevention.

Fear avoidance and neuroimaging: Falsification or just failure to confirm? - Corrected Proof

Tim V. Salomons, Karen D. Davis — 2012-01-16

I am visiting Chicago for the first time and see three blue taxicabs. Based on these observations I hypothesise that all Chicago cabs are blue. Karl Popper argued that this type of inductive inference (in which a general rule is derived from a set of observations) cannot be the basis for building a strong scientific theory. No number of confirmatory blue taxi sightings would prove my hypothesis true. Popper instead argued for a deductive approach where a prediction is derived from the theory and investigators seek data to falsify the prediction. Thus, the most rigorous way to test my theory would be to look for Chicago cabs that are not blue, rather than simply counting blue taxicabs.

Mindfulness, functioning and catastrophizing after multidisciplinary pain management for chronic low back pain - Corrected Proof

2012-01-13

Summary: Relationships between self-reports of mindfulness, catastrophizing, disability and depression were explored before and after a multidisciplinary cognitive-behavioural intervention for chronic pain.Abstract: We examined mindfulness in people with chronic low back pain who were attending a multidisciplinary pain management programme. Participants completed questionnaires at baseline (n=116) and after a 3-month cognitive-behaviourally informed multidisciplinary intervention (n=87). Self-reported mindfulness was measured before and after the intervention, and relationships were explored between mindfulness, disability, affect and pain catastrophizing. Mindfulness increased following participation in the intervention, and greater mindfulness was predictive of lower levels of disability, anxiety, depression and catastrophizing, even when pain severity was controlled. Mediator analyses suggested that the relationship between mindfulness and disability was mediated by catastrophizing. It is possible that cognitive-behavioural interventions and processes can affect both catastrophizing and mindfulness.

Pain-related bias in the classification of emotionally ambiguous facial expressions in mothers of children with chronic abdominal pain - Corrected Proof

Christina Liossi, Paul White, Natasha Croome, Popi Hatira — 2012-01-13

Summary: Mothers of children with chronic abdominal pain show a pain bias towards ambiguous emotional expressions which possibly contributes to the maintenance of this condition.Abstract: This study sought to determine whether mothers of young people with chronic abdominal pain (CAP) compared to mothers of pain-free children show a pain recognition bias when they classify facial emotional expressions. One hundred demographically matched mothers of children with CAP (n=50) and control mothers (n=50) were asked to identify different emotions expressed by adults in 2 experiments. In experiment 1, participants were required to identify the emotion in a series of facial images that depicted 100% intensity of the following emotions: Pain, Sadness, Anger, Fear, Happiness, and Neutral. In experiment 2, mothers were required to identify the predominant emotion in a series of computer-interpolated (“morphed”) facial images. In this experiment, pain was combined with Sad, Angry, Fearful, Happy, and Neutral facial expressions in different proportions—that is, 90%:10%, 70%:30%, 50%:50%, 30%:70%, 10%:90%. All participants completed measures of state and trait anxiety, depression, and anxiety sensitivity. In experiment 1, there was no difference in the performance of the 2 groups of mothers. In experiment 2, it was found that overall mothers of children with CAP were classifying ambiguous emotional expressions predominantly as pain. Mean response times for CAP and control groups did not differ significantly. Mothers of children with CAP did not report more anxiety, depression, and anxiety sensitivity compared to control mothers. It is concluded that mothers of children with CAP show a pain bias when interpreting ambiguous emotional expressions, which possibly contributes to the maintenance of this condition in children via specific parenting behaviours.

The challenges of prognosis in cancer pain - Corrected Proof

Eduardo Bruera — 2012-01-13

In this issue of PAIN, Knudsen et al. report on their cross-sectional evaluation and longitudinal follow up of patients with cancer pain treated in a large number of Italian clinical programs. They identified a number of independent predictors of pain intensity and pain relief. Initial pain intensity was the most important and consistent predictor. Other domains included initial pain relief, incident pain, pain location, type of cancer, and younger age. Unfortunately, the models only explained between 16% and 24% of the variability of the pain outcome. This study has made an important contribution in highlighting our limited understanding of contributors to successful cancer pain control.

A systematic literature review of 10years of research on sex/gender and pain perception – Part 2: Do biopsychosocial factors alter pain sensitivity differently in women and men? - Corrected Proof

2012-01-11

Summary: Ecological validity of laboratory findings in healthy humans about the role of certain biopsychological factors on sex differences in pain perception needs to be assessed/improved.Abstract: This systematic review summarizes the results of 10years of laboratory research on pain and sex/gender. An electronic search strategy was designed by a medical librarian to access multiple databases. A total of 172 articles published between 1998 and 2008 were retrieved, analyzed, and synthesized. The second set of results presented in this review (129 articles) examined various biopsychosocial factors that may contribute to differences in pain sensitivity between healthy women and men. The results revealed that the involvement of hormonal and physiological factors is either inconsistent or absent. Some studies suggest that temporal summation, allodynia, and secondary hyperalgesia may be more pronounced in women than in men. The evidence to support less efficient endogenous pain inhibitory systems in women is mixed and does not necessarily apply to all pain modalities. With regard to psychological factors, depression may not mediate sex differences in pain perception, while the role of anxiety is ambiguous. Cognitive and social factors appear to partly explain some sex-related differences. Finally, past individual history may be influential in female pain responses. However, these conclusions must be treated with much circumspection for various methodological reasons. Furthermore, some factors/mechanisms remain understudied in the field. There is also a need to assess and improve the ecological validity of findings from laboratory studies on healthy subjects, and perhaps a change of paradigm needs to be considered at this point in time to better understand the factors that influence the experience of women and men who suffer from acute or chronic pain.

Evoked bursting in injured Aβ dorsal root ganglion neurons: A mechanism underlying tactile allodynia - Corrected Proof

2012-01-11

Summary: The evoked bursting discharges of the Aβ dorsal root ganglion neurons may contribute to the development of allodynia after nerve injury.Abstract: Chronic compression of rat dorsal root ganglion (CCD) produced tactile allodynia accompanied with hyperexcitability of the myelinated Aβ dorsal root ganglion (DRG) neurons. The Aβ DRG neuron hyperexcitability exhibits as bursting discharges in response to peripherally evoked action potentials (evoked bursting [EB]). The incidence of EB was significantly increased after chronic compression of DRG (CCD) (43.3%) vs control (13.3%). EB was maintained by oscillation of the membrane potential, and its duration was increased when the membrane potential was depolarized. EB was found to coexist in some neurons with spontaneous bursting (SB), but EB always occurred at a more negative membrane potential than SB. Afterdischarges of the wide dynamic range neurons of the dorsal horn in the spinal cord in response to electrical stimulation of Aβ afferent nerve fibers were suppressed by blocking EB of the DRG neurons. CCD neurons with EB exhibited increased current density of persistent sodium current (INap) and hyperpolarization-activated cation current (Ih) and decreased α-dendrotoxin (α-DTX) sensitive current (IDTX). The increased Ih activated by afterhyperpolarization of peripheral afferent action potential was necessary for EB generation and a balance between IDTX and INap might be necessary for EB maintenance. This study may suggest a role of EB of myelinated DRG neurons in development of allodynia after nerve injury and a potential pharmaceutical therapy in treating neuropathic allodynia.

Neural correlates of fear of movement in high and low fear-avoidant chronic low back pain patients: An event-related fMRI study - Corrected Proof

2012-01-09

Summary: High and low fear-avoidant chronic low back pain patients did not differ with regard to brain activation when they viewed photographs of aversive movements.Abstract: The fear-avoidance model postulates that in chronic low back pain (CLBP) a fear of movement is acquired in the acute phase, which leads to subsequent avoidance of physical activity and contributes to the pain syndrome’s becoming chronic. In the present event-related functional magnetic resonance imaging (fMRI) study of the neural correlates of the fear of movement, 60 women (30 CLBP patients, 15 healthy controls, and 15 women with spider phobia; mean age 46.8±9.8 years) participated. The CLBP patients were divided into a high and low fear-avoidant group on the basis of the Tampa Scale of Kinesiophobia. The participants viewed photographs depicting neutral and aversive (back-stressing) movements, generally fear-inducing and neutral pictures from the International Affective Picture System, and pictures of spiders while fMRI data were acquired. It was hypothesized that the high fear-avoidant CLBP patients would show fear-related activations when viewing the aversive movements and that they would differ from CLBP patients with low fear-avoidance and controls in this regard. No such activations were found for high or low fear-avoidant CLBP patients. The random-effects analysis showed no differences between high and low fear-avoidant CLBP patients or high fear-avoidant CLBP patients and controls. Normal fear-related activations were present in the high fear-avoidant CLBP patients for the generally fear-inducing pictures, demonstrating the validity of the stimulation paradigm and a generally unimpaired fear processing of the high fear-avoidant CLBP patients. Our findings do not support the fear component of the fear avoidance model.

Opioids added to local anesthetics for single-shot intrathecal anesthesia in patients undergoing minor surgery: A meta-analysis of randomized trials - Corrected Proof

Daniel M. Pöpping, Nadia Elia, Emmanuel Marret, Manuel Wenk, Martin R. Tramèr — 2012-01-09

Summary: Morphine, and to a lesser extent fentanyl, added to intrathecal bupivacaine prolong postoperative analgesia. With morphine, the risk of respiratory depression cannot be ruled out.Abstract: Opioids are widely used as additives to local anesthetics for intrathecal anesthesia. Benefit and risk remain unclear. We systematically searched databases and bibliographies to February 2011 for full reports of randomized comparisons of any opioid added to any intrathecal local anesthetic with the local anesthetic alone in adults undergoing surgery (except cesarean section) and receiving single-shot intrathecal anesthesia without general anesthesia. We included 65 trials (3338 patients, 1932 of whom received opioids) published between 1983 and 2010. Morphine (0.05–2mg) and fentanyl (10–50μg) added to bupivacaine were the most frequently tested. Duration of postoperative analgesia was prolonged with morphine (weighted mean difference 503min; 95% confidence interval [CI] 315 to 641) and fentanyl (weighted mean difference 114min; 95% CI 60 to 168). Morphine decreased the number of patients needing opioid analgesia after surgery and decreased pain intensity to the 12th postoperative hour. Morphine increased the risk of nausea (number needed to harm [NNH] 9.9), vomiting (NNH 10), urinary retention (NNH 6.5), and pruritus (NNH 4.4). Fentanyl increased the risk of pruritus (NNH 3.3). With morphine 0.05 to 0.5mg, the NNH for respiratory depression varied between 38 and 59 depending on the definition of respiratory depression chosen. With fentanyl 10 to 40μg, the risk of respiratory depression was not significantly increased. For none of these effects, beneficial or harmful, was there evidence of dose-responsiveness. Consequently, minimal effective doses of intrathecal morphine and fentanyl should be sought. For intrathecal buprenorphine, diamorphine, hydromorphone, meperidine, methadone, pentazocine, sufentanil, and tramadol, there were not enough data to allow for meaningful conclusions.

Similar alteration of motor unit recruitment strategies during the anticipation and experience of pain - Corrected Proof

Kylie Tucker, Anna-Karin Larsson, Stina Oknelid, Paul Hodges — 2011-12-30

Summary: Motoneuron discharge is altered during anticipation of pain as well as pain itself, does not fully resolve after pain has ceased, and may underlie long-term musculoskeletal changes.Abstract: A motor unit consists of a motoneurone and the multiple muscle fibres that it innervates, and forms the final neural pathway that influences movement. Discharge of motor units is altered (decreased discharge rate and/or cessation of firing; and increased discharge rate and/or recruitment of new units) during matched-force contractions with pain. This is thought to be mediated by nociceptive (pain) input on motoneurones, as demonstrated in animal studies. It is also possible that motoneurone excitability is altered by pain related descending inputs, that these changes persist after noxious stimuli cease, and that direct nociceptive input is not necessary to induce pain related changes in movement. We aimed to determine whether anticipation of pain (descending pain related inputs without nociceptor discharge) alters motor unit discharge, and to observe motor unit discharge recovery after pain has ceased. Motor unit discharge was recorded with fine-wire electrodes in the quadriceps of 9 volunteers. Subjects matched isometric knee-extension force during anticipation of pain (anticipation: electrical shocks randomly applied over the infrapatellar fat-pad); pain (hypertonic saline injected into the fat-pad); and 3 intervening control conditions. Discharge rate of motor units decreased during pain (P<.001) and anticipation (P<.01) compared with control contractions. De-recruitment of 1 population of units and new recruitment of another population were observed during both anticipation and pain; some changes in motor unit recruitment persisted after pain ceased. This challenges the fundamental theory that pain-related changes in muscle activity result from direct nociceptor discharge, and provides a mechanism that may underlie long-term changes in movement/chronicity in some musculoskeletal conditions.

Persistent antinociception through repeated self-injury in patients with borderline personality disorder - Corrected Proof

2011-12-26

Summary: Pain suppression in borderline personality disorder correlates with recency of self-injury, but not with psychometric scales, suggesting a state of acquired antinociception from repeated self-injury.Abstract: Patients with borderline personality disorder, mostly female, exhibit severe autoaggressive behavior, namely an intentionally performed, nonsuicidal self-injury and severe blunting of pain perception, the mechanism of which is hitherto not understood. Because the nociceptive system displays a high degree of plasticity, the aim of this study was to analyze the relationship of pain perception to self-injurious behavior. Pain perception of mechanical and chemical noxious stimuli was studied by quantitative sensory testing in 22 patients (15 female, 7 male) with borderline personality disorder (BPD) according to DSM-IV and 22 age- and gender-matched controls. BPD patients exhibited a significantly higher pain threshold to pinprick stimuli (2.7 times higher than healthy control subjects), and significantly lower pain ratings to mechanical (pinprick, −28%) and chemical (capsaicin, −38%) stimulation. Capsaicin-induced pain decayed significantly faster in BPD patients (τ=49seconds) than in controls (τ=76seconds). These alterations of pain perception were generally present in the female, but not in the male subgroup of BPD patients. Analysis of pain intensity vs unpleasantness suggested that primarily the unpleasantness aspect of the pain experience was reduced. Blunting of pain sensation was significantly predicted by the recency of self-injurious behavior (multiple r=0.58). In line with recent data, we suggest an excess of endogenous antinociception in BPD patients resulting from self-inflicted multiple injuries. This exaggerated pain control is conceived to operate via an uncoupling of the evaluative or emotional–affective from the sensory-discriminative dimension of pain.

Contribution of spinal galectin-3 to acute herpetic allodynia in mice - Corrected Proof

2011-12-26

Summary: The present study presents galectin-3 as a new molecule involved in the spinal processes of acute herpetic pain in mice.Abstract: To identify endogenous factors involved in herpetic pain, we performed genome-wide microarray analysis of the spinal cord of mice that suffered from herpetic allodynia induced by inoculation with herpes simplex virus type 1, which revealed marked induction of galectin-3, a β-galactoside-binding lectin. Therefore, we investigated the role of galectin-3 in herpetic allodynia. The expression levels of galectin-3 mRNA and protein were increased with a temporal pattern similar to that of herpetic allodynia. Galectin-3-expressing cells were mainly localized in the superficial dorsal horn, round in shape, and positive for the macrophage/microglia markers Iba-1 and F4/80. In the deep dorsal horn, there were Iba-1-positive cells with ramified and stout processes, which were negative for galectin-3. In the superficial dorsal horn, there were many CD3-positive T cells, but most of the galectin-3-expressing cells were negative for CD3. Galectin-3-expressing cells were negative for the neuronal marker NeuN and the astrocyte marker glial fibrillary acidic protein antibody. Deficiency in galectin-3 markedly reduced herpetic allodynia, without showing an effect on herpes zoster-like skin lesions. Intrathecal injection of galectin-3 produced mechanical allodynia in naive mice, and intrathecal injections of anti-galectin-3 antibodies significantly reduced herpetic allodynia. The present results suggest that galectin-3 in infiltrating macrophages and/or resident microglia in the spinal dorsal horn contributes to herpetic allodynia. Galectin-3 may be a new therapeutic target for the treatment of herpes zoster-associated pain.

Pain today – Disability tomorrow - Corrected Proof

Pekka Mäntyselkä — 2011-12-26

Chronic pain is common and tends to be persistent in the population . People with chronic pain very often have poor self-rated health . Poor self-rated health is a strong predictor of disability retirement . Not surprisingly, therefore, the largest proportion of costs related to pain is indirect, i.e. costs arising from absence through sick leave and disability retirement .

Targeting A-type K+ channels in primary sensory neurons for bone cancer pain in a rat model - Corrected Proof

Kai-Zheng Duan, Qian Xu, Xiao-Meng Zhang, Zhi-Qi Zhao, Yan-Ai Mei, Yu-Qiu Zhang — 2011-12-22

Summary: Bone cancer induced dynamic changes of A-type K+ channels in dorsal root ganglion neurons. Diclofenac antagonized bone cancer pain by upregulating peripheral A-type K+ channels.Abstract: Cancer pain is one of the most severe types of chronic pain, and the most common cancer pain is bone cancer pain. The treatment of bone cancer pain remains a clinical challenge. Here, we report firstly that A-type K+ channels in dorsal root ganglion (DRG) are involved in the neuropathy of rat bone cancer pain and are a new target for diclofenac, a nonsteroidal anti-inflammatory drug that can be used for therapy for this distinct pain. There are dynamically functional changes of the A-type K+ channels in DRG neurons during bone cancer pain. The A-type K+ currents that mainly express in isolectin B4-positive small DRG neurons are increased on post-tumor day 14 (PTD 14), then faded but still remained at a higher level on PTD 21. Correspondingly, the expression levels of A-type K+ channel Kv1.4, Kv3.4, and Kv4.3 showed time-dependent changes during bone cancer pain. Diclofenac enhances A-type K+ currents in the DRG neurons and attenuates bone cancer pain in a dose-dependent manner. The analgesic effect of diclofenac can be reversed or prevented by A-type K+ channel blocker 4-AP or pandinotoxin-Kα, also by siRNA targeted against rat Kv1.4 or Kv4.3. Repeated diclofenac administration decreased soft tissue swelling adjacent to the tumor and attenuated bone destruction. These results indicate that peripheral A-type K+ channels were involved in the neuropathy of rat bone cancer pain. Targeting A-type K+ channels in primary sensory neurons may provide a novel mechanism-based therapeutic strategy for bone cancer pain.

Compound action potentials recorded in the human spinal cord during neurostimulation for pain relief - Corrected Proof

2011-12-22

Summary: Aβ sensory nerve fibres are recruited during therapeutic spinal cord stimulation and the Aβ potential amplitude correlates with the degree of coverage of the painful area.Abstract: Electrical stimulation of the spinal cord provides effective pain relief to hundreds of thousands of chronic neuropathic pain sufferers. The therapy involves implantation of an electrode array into the epidural space of the subject and then stimulation of the dorsal column with electrical pulses. The stimulation depolarises axons and generates propagating action potentials that interfere with the perception of pain. Despite the long-term clinical experience with spinal cord stimulation, the mechanism of action is not understood, and no direct evidence of the properties of neurons being stimulated has been presented. Here we report novel measurements of evoked compound action potentials from the spinal cords of patients undergoing stimulation for pain relief. The results reveal that Aβ sensory nerve fibres are recruited at therapeutic stimulation levels and the Aβ potential amplitude correlates with the degree of coverage of the painful area. Aβ-evoked responses are not measurable below a threshold stimulation level, and their amplitude increases with increasing stimulation current. At high currents, additional late responses are observed. Our results contribute towards efforts to define the mechanism of spinal cord stimulation. The minimally invasive recording technique we have developed provides data previously obtained only through microelectrode techniques in spinal cords of animals. Our observations also allow the development of systems that use neuronal recording in a feedback loop to control neurostimulation on a continuous basis and deliver more effective pain relief. This is one of numerous benefits that in vivo electrophysiological recording can bring to a broad range of neuromodulation therapies.

A systematic literature review of 10years of research on sex/gender and experimental pain perception – Part 1: Are there really differences between women and men? - Corrected Proof

2011-12-22

Summary: Relatively limited support is provided to the hypothesis that healthy women have greater pain sensitivity than men in most experimental pain modalities.Abstract: The purpose of this systematic review was to summarize and critically appraise the results of 10years of human laboratory research on pain and sex/gender. An electronic search strategy was designed by a medical librarian and conducted in multiple databases. A total of 172 articles published between 1998 and 2008 were retrieved, analyzed, and synthesized. The first set of results (122 articles), which is presented in this paper, examined sex difference in the perception of laboratory-induced thermal, pressure, ischemic, muscle, electrical, chemical, and visceral pain in healthy subjects. This review suggests that females (F) and males (M) have comparable thresholds for cold and ischemic pain, while pressure pain thresholds are lower in F than M. There is strong evidence that F tolerate less thermal (heat, cold) and pressure pain than M but it is not the case for tolerance to ischemic pain, which is comparable in both sexes. The majority of the studies that measured pain intensity and unpleasantness showed no sex difference in many pain modalities. In summary, 10years of laboratory research have not been successful in producing a clear and consistent pattern of sex differences in human pain sensitivity, even with the use of deep, tonic, long-lasting stimuli, which are known to better mimic clinical pain. Whether laboratory studies in healthy subjects are the best paradigm to investigate sex differences in pain perception is open to question and should be discussed with a view to enhancing the clinical relevance of these experiments and developing new research avenues.

Paclitaxel therapy potentiates cold hyperalgesia in streptozotocin-induced diabetic rats through enhanced mitochondrial reactive oxygen species production and TRPA1 sensitization - Corrected Proof

2011-12-16

Summary: Paclitaxel potentiates cold hyperalgesia in streptozotocin-induced diabetic rats through the combination of paclitaxel-induced increase in mitochondrial reactive oxygen species and diabetes-related overexpression of TRPA1.Abstract: Diabetes comorbidities include disabling peripheral neuropathy (DPN) and an increased risk of developing cancer. Antimitotic drugs, such as paclitaxel, are well known to facilitate the occurrence of peripheral neuropathy. Practitioners frequently observe the development or co-occurrence of enhanced DPN, especially cold sensitivity, in diabetic patients during chemotherapy. Preclinical studies showed that reactive oxygen species (ROS) and cold activate transient receptor potential ankyrin-1 (TRPA1) cation channels, which are involved in cold-evoked pain transduction signaling in DPN. Additionally, paclitaxel treatment has been associated with an accumulation of atypical mitochondria in the sensory nerves of rats. We hypothesized that paclitaxel might potentiate cold hyperalgesia by increasing mitochondrial injuries and TRPA1 activation. Thus, the kinetics of paclitaxel-induced cold hyperalgesia, mitochondrial ROS production, and TRPA1 expression were evaluated in dorsal root ganglia of normoglycemic and streptozotocin-induced diabetic rats. In diabetic rats, paclitaxel significantly enhanced cold hyperalgesia in comparison to normoglycemic paclitaxel-treated control rats. These effects were prevented by N-acetyl-cysteine, a reducing agent, and by HC030031, an antagonist of TRPA1. In diabetic and control rats, paclitaxel treatment was associated with an accumulation of atypical mitochondria and a 2-fold increase in mitochondrial ROS production. Moreover, mRNA levels of glutathione peroxidase 4 and glutathione-S-reductase were significantly lower in diabetic groups treated with paclitaxel. Finally, TRPA1 gene expression was enhanced by 45% in diabetic rats. Paclitaxel potentiation of cold hyperalgesia in diabetes may result from the combination of increased mitochondrial ROS production and poor radical detoxification induced by paclitaxel treatment and diabetes-related overexpression of TRPA1.

Sensory signs in complex regional pain syndrome and peripheral nerve injury - Corrected Proof

2011-12-12

Summary: QST revealed more similarities than differences between CRPS-I, CRPS-II, and PNI: sensory loss occurred in 63% of CRPS-I and sensory gain in 81% of PNI patients.Abstract: This study determined patterns of sensory signs in complex regional pain syndrome (CRPS) type I and II and peripheral nerve injury (PNI). Patients with upper-limb CRPS-I (n=298), CRPS-II (n=46), and PNI (n=72) were examined with quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain. The majority of patients (66%–69%) exhibited a combination of sensory loss and gain. Patients with CRPS-I had more sensory gain (heat and pressure pain) and less sensory loss than patients with PNI (thermal and mechanical detection, hypoalgesia to heat or pinprick). CRPS-II patients shared features of CRPS-I and PNI. CRPS-I and CRPS-II had almost identical somatosensory profiles, with the exception of a stronger loss of mechanical detection in CRPS-II. In CRPS-I and -II, cold hyperalgesia/allodynia (28%–31%) and dynamic mechanical allodynia (24%–28%) were less frequent than heat or pressure hyperalgesia (36%–44%, 67%–73%), and mechanical hypoesthesia (31%–55%) was more frequent than thermal hypoesthesia (30%–44%). About 82% of PNI patients had at least one type of sensory gain. QST demonstrates more sensory loss in CRPS-I than hitherto considered, suggesting either minimal nerve injury or central inhibition. Sensory profiles suggest that CRPS-I and CRPS-II may represent one disease continuum. However, in contrast to recent suggestions, small fiber deficits were less frequent than large fiber deficits. Sensory gain is highly prevalent in PNI, indicating a better similarity of animal models to human patients than previously thought. These sensory profiles should help prioritize approaches for translation between animal and human research.

Urologic chronic pelvic pain - Corrected Proof

Jeannette M. Potts, Christopher K. Payne — 2011-12-07

Urologic chronic pelvic pain (UCPP), primarily interstitial cystitis (IC)/painful bladder syndrome (PBS) in men and women, and chronic prostatitis (CP)/chronic pelvic pain syndrome (CPPS) in men, were initially regarded as bladder and prostate diseases. Decades of research have failed to establish infectious or other clear etiologies; in fact, bladder/prostate inflammation is uncommon. Most patients are best characterized as having a functional somatic syndrome (FSS). Current theory focuses on hyperesthesia/allodynia and pelvic floor muscle dysfunction (PFD).

Cognitive dimensions of anger in chronic pain - Corrected Proof

2011-12-05

Anger has long been recognized as an integral part of pain experience . Reviews highlight the deleterious effect of anger on social, clinical, and functional outcomes . Anger has been discussed as an aversive emotional state ranging from mild irritation to fury , and comprising specific cognitive attributions and action tendencies . Anecdotal and empirical data suggest that anger is commonplace among chronic pain sufferers . In their 2003 review, Greenwood et al. identified anger as an important target of research and behavioral management; since that review, research has highlighted biopsychosocial mechanisms through which anger may affect pain experience . However, to date, no systematic line of research has addressed the cognitive dimensions of anger in chronic pain. We believe that elucidating these facets of anger in pain sufferers might strengthen the empirical foundation for more effective treatment. Although not exhaustive, the current review highlights potential sources of anger among pain sufferers by drawing on conceptualizations from existing social psychological theory and newly evolving lines of research. On this basis, we discuss the role of anger in treatment settings, and possible frameworks for research and intervention.

Examining the role of positive and negative affect in recovery from spine surgery - Corrected Proof

2011-11-28

Summary: Multivariable mixed-model linear regression analyses illustrated the unique relation between postoperative positive affect and functional status and postoperative negative affect and pain interference and disability after spine surgery.Abstract: Consistent evidence supports a significant association between lower positive affect and higher negative affect and increased pain and disability in adults with chronic pain. However, examining this relation in surgical populations has received little empirical consideration. The primary purpose of this study was to determine whether preoperative and postoperative positive and negative affect predict pain, disability, and functional status after spine surgery. A secondary objective was to assess the relation of depression to postoperative outcomes compared with positive and negative affect. Participants were 141 patients treated by spine surgery for lumbar or cervical degeneration. Data collection occurred at baseline and 6weeks and 3months postoperatively. Affect was measured with the Positive and Negative Affect Schedule. Multivariable mixed-model linear regression analyses found that preoperative variables were not predictive of postoperative pain, disability and functional status. However, multivariable postoperative analysis found that 6-week positive affect predicted functional status, and 6-week negative affect predicted pain interference and pain-related disability at 3months following surgery. Postoperative depression demonstrated statistically significant and stronger associations with pain intensity, pain interference, and pain-related disability at 3-month follow-up, as compared with negative affect. Results suggest that positive affect and depression are important variables to target when seeking to improve postoperative outcomes in a spine surgery population. Recommendations include postoperative screening for positive affect and depression, and treating depression as well as focusing on rehabilitation strategies to bolster positive affect so as to improve functional outcomes after spine surgery.

One man’s risk factor is another man’s outcome : Difference in risk factor profiles for chronic postsurgical pain maintenance vs transition - Corrected Proof

Joel Katz — 2011-11-21

Chronic postsurgical pain develops in an alarming proportion of patients . Although we now know more than we ever did about chronic postsurgical pain, we are still in the Dark Ages when it comes to predicting who will go onto develop it and who will recover uneventfully. We know little about the risk and protective factors leading to chronicity. The article by Seebach et al. in this issue of PAIN is noteworthy for its prospective, longitudinal approach to studying the psychosocial recovery trajectory in patients after spine surgery. The authors’ main objective was to evaluate the extent to which preoperative and postoperative positive and negative affect predicted several outcomes measured at 6weeks and 3months after discharge. They conducted separate regression analyses to evaluate whether positive affect (a putative protective factor) and negative affect and depression scores (two putative risk factors) predicted four related, but different, outcome variables at different times after surgery; namely, pain intensity, pain interference, disability and functional status (after controlling for relevant covariates). The results showed that none of the three putative protective or risk factors predicted any of the four outcome variables 6weeks and 3months after surgery. In contrast, 6-week postoperative positive affect predicted 3-month functional status and 6-week negative affect predicted 3-month disability. Moreover, 6-week depression scores predicted 3-month pain intensity, pain interference and pain-related disability but not functional status.

WITHDRAWN: Response from authors - Corrected Proof

Edzard Ernst, Myeong Soo Lee — 2011-05-10

This article has been withdrawn at the request of the author and has being approved by the editor. The Publisher apologizes for any inconvenience this may cause.The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy