PAIN

Editorial list

2012-05-01

Lower limb pain and locomotor disability

Sebastian Straube, Fiona Blyth — 2012-03-14

Cohort studies enable us to define health trajectories over time, and factors that may influence them. Implicitly or explicitly, cohort studies capture the effects of ageing as well. Recent evidence from a long-running British cohort study suggests that trajectories for lower body functional limitations are apparent in midlife (age 53) . Other evidence from longitudinal research on subgroups aged 100years or more suggests that prolonged survival is accompanied by a relative resistance to age-related disability . Given this intriguing and complex background, might pain be important in driving trajectories of disability over time?

Balancing ethics and science in pediatric pain intervention trials

R.N. Jean Solodiuk, M.D. Berde Charles — 2012-03-29

Researchers struggle with balancing the burden of research on a sample population with the benefits of advancing science to improve care for a larger population. This balance can be precarious in pediatric research as the burden may be endured by vulnerable subjects, unable to consent or assent. On the other hand, several years ago Fost described how overprotecting children from involvement in research has been a barrier to advancing pediatric medicine .

Who receives opioids for acute pain in emergency departments? Considering evidence, patient and provider preferences

Gilbert J. Fanciullo — 2012-03-26

In this issue of Pain, Platt-Mills et al. in a multicenter study of non-Hispanic whites report that there is a correlation between educational level and likelihood of receiving opioids in emergency departments (EDs) following minor motor vehicle collisions (MVC) . In a well controlled study, patients who had not graduated from at least high school received opioids 54% of the time compared to only 10% of the time in post college graduate educated individuals. Why did more educated patients receive opioids less frequently than their less well educated counterparts? How can we interpret the data and what are the implications for patient management?

Vanguard research in opioid-induced hyperalgesia – but guard the basics

Mads U. Werner — 2012-03-05

Few areas in contemporary pain research have gained so much attention as opioid-induced hyperalgesia (OIH []). A number of different definitions have been presented, but the most straightforward explanation seems to be “Patients receiving opioids to control their pain somewhat paradoxically may become more sensitive to pain [i.e. hyperalgesic] as a direct result of opioid therapy” . Studies in humans have been performed in several settings: in volunteers during short-term opioid infusion , patients in methadone substitution therapy , chronic pain patients during start of opioid therapy or during opioid tapering and in patients during perioperative exposure to opioids . Psychophysiological assessments with thermal, mechanical and electrical stimulation have been used either by direct assessments (pain threshold, suprathreshold pain perception, pain tolerance) or by indirect assessments (secondary hyperalgesia areas). Although new information concerning the opioid system have been uncovered in the fields of genetics, molecular engineering, neuroimaging and pharmacology, amazingly, there still are no controlled studies indicating any clinical relevance of OIH.

‘Hot Feet – Hot Brain’: Gene and brain dysfunction in erythromelalgia

David Borsook — 2012-03-14

There is now considerable evidence that alterations in voltage gated sodium channels contribute to pain processing. For example, Na(v) 1.7. sodium channel dysfunction has been associated with diminished pain (loss of channel function) and increased pain (gain of channel function) in erythromelalgia . Erythromelalgia was first described by the neurologist S. Weir Mitchell in 1878. Primary erythromelalgia is a disease of the extremities in which there is burning pain that is frequently aggravated by heat or by lowering the extremity. The syndrome of increased pain associated with Na(v) 1.7. is the first human disorder in which an ion channel mutation is associated with chronic neuropathic pain. As such these channelopathies have provided novel models for understanding pain pathophysiology, and are especially important as they occur in the human condition. In addition to molecular studies, brain imaging techniques are contributing to our understanding of the pathophysiology of these neuropathic pain conditions.

Pain, body, and space: What do patients with complex regional pain syndrome really neglect?

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.

The effect of changes in lower limb pain on the rate of progression of locomotor disability in middle and old age: Evidence from the NorStOP cohort with 6-year follow-up

Sara Muller, Elaine Thomas, George Peat — 2012-03-02

Summary: Lower limb pain is an important determinant of locomotor disability. Recurrent episodes of pain may have a cumulative effect on functional decline in later life.Abstract: Locomotor disability (LMD) is common at older ages, and can lead to other significant disability and mortality. Prevalent pain has been shown to be associated with LMD. This article aimed to assess the association between changes in lower limb pain status (ascertained from a manikin) and changes in the level of self-reported LMD in a sample of UK adults age ⩾50years, over a 6-year period (data collected at 3-year intervals). There was an average increase in the level of LMD over 6years. Reports of an onset of lower limb pain were associated with a relative increase in LMD, independently of sociodemographic factors and the onset of selected comorbid diseases. A dose-response relationship was observed between the onset of multiple lower limb joint involvement and more frequent or intense pain and larger increases in LMD. Becoming free from lower limb pain was associated with a relative decrease in LMD, but did not return LMD scores to the level of those who had remained pain-free throughout. This is consistent with a cumulative effect on LMD of recurrent episodes of pain. Lower limb pain may be a key target for prevention and rehabilitation to reduce years lived with disability in later life.

Warmth is analgesic in healthy newborns

Larry Gray, Colleen W. Lang, Stephen W. Porges — 2012-03-16

TOC Summary: Providing natural warmth to newborn infants during a painful procedure decreases crying and grimacing and ranks first compared to the standard treatments of sucrose or pacifier.Abstract: This study identifies a behavioral and nonpharmacologic means of preventing and reducing newborn pain. Our objective was to determine whether warmth is analgesic in newborn infants undergoing vaccination—a routine painful hospital procedure. We used a prospective randomized controlled trial of 47 healthy full-term newborn infants. Infants were randomized into 1 of 3 conditions prior to vaccination: warmth exposure, pacifier suckling, or sucrose taste. Crying, grimacing, and heart rate differences were analyzed between groups before, during, and after vaccination as outcome measures. Warmer infants cried significantly less than sucrose taste or pacifier suckling after vaccination. Heart rate patterns reflected this analgesia. Core temperature did not differ between study groups. Providing natural warmth to newborn infants during a painful procedure decreases the crying and grimacing on par with the “gold” standard treatments of sucrose or pacifier.

More educated emergency department patients are less likely to receive opioids for acute pain

2012-03-05

Summary: Of patients presenting to an emergency department for evaluation after a motor vehicle collision, those with higher educational attainment are less likely to receive opioids.Abstract: Inadequate treatment of pain in United States emergency departments (EDs) is common, in part because of the limited and idiosyncratic use of opioids by emergency providers. This study sought to determine the relationship between patient socioeconomic characteristics and the likelihood that they would receive opioids during a pain-related ED visit. We conducted a cross-sectional analysis of ED data obtained as part of a multicenter study of outcomes after minor motor vehicle collision (MVC). Study patients were non-Hispanic white patients between the ages of 18 and 65years who were evaluated and discharged home from 1 of 8 EDs in 4 states. Socioeconomic characteristics include educational attainment and income. Of 690 enrolled patients, the majority had moderate or severe pain (80%). Patients with higher education attainment had lower levels of pain, pain catastrophizing, perceived life threat, and distress. More educated patients were also less likely to receive opioids during their ED visit. Opioids were given to 54% of patients who did not complete high school vs 10% of patients with post-college education (χ2 test P<.001). Differences in the frequency of opioid administration between patients with the lowest educational attainment (39%, 95% confidence interval 22% to 60%) and highest educational attainment (13%, 95% confidence interval 7% to 23%) remained after adjustment for age, sex, income, and pain severity (P=.01). In this sample of post-MVC ED patients, more educated patients were less likely to receive opioids. Further study is needed to assess the generalizability of these findings and to determine the reason for the difference.

Modulation of remifentanil-induced postinfusion hyperalgesia by the β-blocker propranolol in humans

2012-02-24

Summary: The administration of remifentanil causes a postinfusion hyperalgesia to mechanical but not thermal stimuli. Concomitant infusion of the β-adrenergic receptor blocker propranolol with remifentanil prevents opioid-induced hyperalgesia to mechanical stimuli in human subjects.Abstract: Acute and chronic exposure to opioids has been associated with hyperalgesia in both animals and humans. A genetic analysis of opioid-induced hyperalgesia in mice linked the β2-adrenergic receptor to mechanical sensitization after opioid exposure. In humans, expansion of the area of mechanical hyperalgesia surrounding an experimentally induced lesion after the cessation of remifentanil infusion is a commonly used model of opioid hyperalgesia (remifentanil-induced postinfusion hyperalgesia, RPH). The purpose of our translational study was to test the hypothesis that the β-adrenergic receptor antagonist propranolol modulates the expression of RPH in humans. This double-blinded, randomized, placebo-controlled, crossover study was performed in 10 healthy human volunteers. During test sessions, intracutaneous electrical stimulation was used to generate areas of secondary mechanical hyperalgesia. The area of this sensitization was measured before, during, and after remifentanil infusion. Heat pain sensitivity was also followed. During one test session, subjects received propranolol infusion. We observed an average increase in the areas of secondary mechanical hyperalgesia to 141% of the baseline in subjects infused with remifentanil and placebo (P=0.00040). However, when remifentanil infusion was combined with propranolol, the area of secondary hyperalgesia after terminating remifentanil was not significantly different than the area before beginning the opioid infusion (P=0.13). Thermal hyperalgesia was not observed after remifentanil infusion. Propranolol infusion at the selected dose had minor hemodynamic effects. Concomitant infusion of propranolol with remifentanil prevented the expression of RPH. β-adrenergic receptor blockade may be a useful pharmacological strategy for preventing hyperalgesia in patients exposed to opioids.

Epidermal Langerhans cells in small fiber neuropathies

2012-02-23

Summary: Subjects with painful small fiber neuropathy, specially in the context of diabetics, had an increased number of the proinflammatory Langerhans cells at the skin.Abstract: We quantified the immune histiocytic Langerhans cells (LCs) in skin biopsy samples of patients with distal small fiber neuropathy (SFN). Patients were divided according to the presence or absence of neuropathic pain (burning pain) assessed by a visual analogue scale (VAS). We studied 13 diabetic patients (pain-DSFN), 7 nondiabetic patients (pain-SFN) who reported relevant neuropathic pain (VAS ⩾3), and 6 nondiabetic patients without neuropathic pain (no-pain-SFN). Using double immunofluorohistochemistry with the PGP 9.5 and the langerin/CD207, we quantified the intraepidermal nerve fibers density (IENFD) and LCs per square millimeter in the epidermis. A group of 10 skin samples from healthy subjects served as controls. Confocal analysis was performed to evaluate LC PGP 9.5-immunoreactivity. We found a mean value of 334.3LC/mm2 in controls, 310.2LC/mm2 in no-pain-SFN, 329.6LC/mm2 in pain-SFN and 484.3LC/mm2 in pain-DSFN (analysis of variance; P=.01). In patients, analysis of covariance adjusted by different covariables showed that the presence of diabetes (F=5.2, P=.03) was associated with an increased number of LC/mm2. There was a negative correlation between the IENFD and the number of LCs (r2=−0.13, P=.03). No statistically significant differences were found among groups of subjects either for the co-localization or for the number of LCs that were PGP 9.5-immunoreactive (analysis of variance; P>.05). These results indicate that patients with neuropathic pain in the context of SFN, specially those who had diabetes (DSFN), had an increased number of LCs in the epidermis that may play a role in the generation or maintenance of neuropathic pain.

An increase in spinal cord noradrenaline is a major contributor to the antihyperalgesic effect of antidepressants after peripheral nerve injury in the rat

Kunie Nakajima, Hideaki Obata, Nobuhisa Iriuchijima, Shigeru Saito — 2012-03-19

Summary: Increase in noradrenaline in the spinal cord plays an important role in the antihyperalgesic effects of SNRIs and SSRIs in rats with neuropathic pain.Abstract: Antidepressants are often used for the treatment of neuropathic pain. Clinical studies suggest that the efficacy of serotonin (5-HT) and noradrenaline (NA) reuptake inhibitors (SNRIs) for neuropathic pain is greater than that of selective 5-HT reuptake inhibitors (SSRIs). In the present study, we determined the efficacy and mechanisms involved in the antihyperalgesic effects of milnacipran, an SNRI, compared with paroxetine, an SSRI, and maprotiline, a selective NA reuptake inhibitor, using a rat model of neuropathic pain. Male Sprague-Dawley rats underwent spinal nerve ligation (SNL), and the withdrawal threshold to paw pressure was measured. Intraperitoneal injection of milnacipran (3–30mg/kg) produced a dose-dependent antihyperalgesic effect. The effect was reversed by intrathecal injection of the α2-adrenoceptor antagonist idazoxan (30μg), but not by various 5-HT receptor antagonists. Paroxetine produced an antihyperalgesic effect only at the highest dose tested (10mg/kg). This effect was reversed by intrathecal injection of both idazoxan and ondansetron (30μg), a 5-HT3 receptor antagonist. Maprotiline produced an antihyperalgesic effect (10 and 30mg/kg), and the effect was reversed by intrathecal idazoxan. In microdialysis studies, NA and 5-HT concentrations in the spinal dorsal horn were increased after injection of either milnacipran or paroxetine, and only NA was increased after maprotiline. Furthermore, the NA content in the spinal cord of SNL rats was greater than that in normal animals. These findings suggest that an increase in NA in the spinal cord plays an important role in the antihyperalgesic effects of not only NA reuptake inhibitors but also SSRIs.

Sickness absence because of musculoskeletal diagnoses and risk of all-cause and cause-specific mortality: A nationwide Swedish cohort study

Catarina Jansson, Ellenor Mittendorfer-Rutz, Kristina Alexanderson — 2012-03-15

Summary: In this nationwide study, associations between sickness absence because of musculoskeletal diagnoses and increased risks of all-cause and cause-specific premature death were observed.Abstract: Knowledge regarding mortality as a potential consequence of being sickness absent because of musculoskeletal diagnoses is almost nonexistent. The association between sickness absence because of musculoskeletal diagnoses and risk of premature death was examined in a prospective, nationwide, population-based cohort study based on Swedish registers. Included were all 4,760,987 individuals who were living in Sweden December 31, 2005, aged 20 to 64years, and not on disability or old-age pension. Those sickness absent in 2005 because of musculoskeletal diagnoses were compared to those sickness absent because of non-musculoskeletal diagnoses and to those with no sickness absence. Musculoskeletal diagnoses were categorized as follows: 1) artropathies/systemic connective tissue disorders; 2) dorsopathies; and 3) soft tissue disorders/osteopathies/chondropathies/other musculoskeletal disorders. All-cause mortality was followed from 2006 to 2009 and cause-specific mortality was followed from 2006 to 2008. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression. In models adjusted for socio-demographic factors, and morbidity, sickness absence because of all 3 categories of musculoskeletal diagnoses was associated with 1.3- to 1.5-fold increased risks of all-cause mortality (adjusted model, category 1 diagnoses, HR=1.50, 95% CI=1.38–1.63). Similar associations were observed among both women and men. Moreover, increased mortality risks due to tumors (HR=1.6–1.7), circulatory diseases (HR=1.2–1.5), mental disorders (HR=1.2–3.2), and suicide (HR=1.5–1.9) were observed among persons sickness absent because of musculoskeletal diagnoses. This nationwide cohort study reveals, for the first time, an increased risk of premature death among both women and men sickness absent because of musculoskeletal diagnoses after adjustment for several potential confounders.

Changes in regional gray matter volume in women with chronic pelvic pain: A voxel-based morphometry study

2012-03-05

Summary: Chronic pelvic pain, with and without endometriosis, is associated with changes in regional gray matter volume within the central pain system.Abstract: Chronic pelvic pain (CPP) is a highly prevalent pain condition, estimated to affect 15%–20% of women in the United States. Endometriosis is often associated with CPP, however, other factors, such as preexisting or concomitant changes of the central pain system, might contribute to the development of chronic pain. We applied voxel-based morphometry to determine whether women with CPP with and without endometriosis display changes in brain morphology in regions known to be involved in pain processing. Four subgroups of women participated: 17 with endometriosis and CPP, 15 with endometriosis without CPP, 6 with CPP without endometriosis, and 23 healthy controls. All patients with endometriosis and/or CPP were surgically confirmed. Relative to controls, women with endometriosis-associated CPP displayed decreased gray matter volume in brain regions involved in pain perception, including the left thalamus, left cingulate gyrus, right putamen, and right insula. Women with CPP without endometriosis also showed decreases in gray matter volume in the left thalamus. Such decreases were not observed in patients with endometriosis who had no CPP. We conclude that CPP is associated with changes in regional gray matter volume within the central pain system. Although endometriosis may be an important risk factor for the development of CPP, acting as a cyclic source of peripheral nociceptive input, our data support the notion that changes in the central pain system also play an important role in the development of chronic pain, regardless of the presence of endometriosis.

Pain-related fear predicts reduced spinal motion following experimental back injury

Zina Trost, Christopher R. France, Michael J. Sullivan, James S. Thomas — 2012-03-01

Summary: In healthy participants, pain-related fear at baseline predicted reduced lumbar flexion and perceived interference following induction of delayed-onset muscle soreness to the lower back.Abstract: The current study examined the prospective relationship between pain-related fear and altered motor behavior, as well as perceived interference, among 51 healthy participants following induction of delayed-onset muscle soreness (DOMS) to the trunk extensor muscles. Healthy participants without history of back pain completed standardized reaches to high and low targets at self-paced and rapid speeds before and after induction of acute low back pain using a DOMS paradigm. Pain-related fear was assessed prior to DOMS induction. Three-dimensional joint motions of the thoracic spine, lumbar spine, and hip were recorded using an electromagnetic tracking device. DOMS-induced differences between high- and low-fear participants were observed for lumbar spine flexion, but not for thoracic or hip flexion. Pain-related fear scores were not predictive of lumbar flexion during baseline, but predicted reduced lumbar flexion during self- and fast-paced trials to low target locations once DOMS was induced. Pain-related fear was likewise predictive of perceived interference in life activities following DOMS induction. The findings suggest that initially pain-free individuals with high pain-related fear adopt avoidant spinal strategies during common reaching movements shortly after injury is sustained, which may comprise a risk factor for future pain and disability.

Effect of NMDA NR2B antagonist on neuropathic pain in two spinal cord injury models

Youngkyung Kim, Hwi-young Cho, Young Ju Ahn, Junesun Kim, Young Wook Yoon — 2012-03-19

Summary: NR2B antagonists increased the mechanical nociceptive threshold after 2 experimental spinal cord injury models with no motor depression, and NR2B expression was increased in the spinal cord.Abstract: N-Methyl-d-aspartate (NMDA) receptors are thought to play an important role in the processes of central sensitization and pathogenesis of neuropathic pain, particularly after spinal cord injury (SCI). NMDA antagonists effectively reduce neuropathic pain, but serious side effects prevent their use as therapeutic drugs. NMDA NR2B antagonists have been reported to effectively reduce inflammatory and neuropathic pain. In this study, we investigated the effects of NR2B antagonists on neuropathic pain and the expression of NR2B in the spinal cord in 2 SCI models. SCI was induced at T12 by a New York University impactor (contusion) or by sectioning of the lateral half of the spinal cord (hemisection). Ifenprodil (100, 200, 500, 1000nmol) and Ro25-6981 (20, 50, 100, 200nmol) were intrathecally injected and behavioral tests were conducted. Ifenprodil increased the paw withdrawal threshold in both models but also produced mild motor depression at higher doses. Ro25-6981 increased the mechanical nociceptive threshold in a dose-dependent manner without motor depression. NR2B expression was significantly increased on both sides at the spinal segments of L1–2 and L4–5 in the hemisection model but did not change in the contusion model. Increased expression of NR2B in the hemisection model was reduced by intrathecal ifenprodil. These results suggest that intrathecal NMDA NR2B antagonist increased the mechanical nociceptive threshold after SCI without motor depression. A selective subtype of NMDA receptor, such as NR2B, may be a more selective target for pain control because NMDA receptors play a crucial role in the development and maintenance of chronic pain.

Women, but not men, report increasingly more pain during repeated (un)predictable painful electrocutaneous stimulation: Evidence for mediation by fear of pain

Ann Meulders, Debora Vansteenwegen, Johan W.S. Vlaeyen — 2012-03-09

Abstract: An abundance of animal research suggests that fear inhibits pain whereas anxiety increases it. Human studies on this topic are more scarce, and the existing evidence seems rather inconsistent. Therefore, we aimed to investigate the divergent effects of both negative emotional states—that is, pain-related fear and anxiety on pain sensitivity and unpleasantness. Possible sex-related differences were also under investigation, as well as the potential mediational role of fear of movement-related pain on the differences in pain intensity and unpleasantness between both sexes. We employed a voluntary joystick movement paradigm using movements as conditioned stimuli (CSs) and a painful electrocutaneous stimulus as the unconditioned stimulus. Healthy participants received predictable shocks in one condition and unpredictable shocks in another condition. The former procedure is known to induce fear of movement-related pain to the CS+ movement (movement consistently followed by pain), whereas the latter procedure induces (contextual) pain-related anxiety. Results showed that fear of movement-related pain indeed resulted in decreased pain intensity/unpleasantness ratings, while pain-related anxiety led to increased pain intensity/unpleasantness reports. Further, the anticipated sex difference was modulated by time. That is, women gradually reported more pain/unpleasantness, whereas men do not show such a sensitization effect. Moreover, this sex-specific sensitization is partially mediated by (conditioned) fear of movement-related pain. Women also report increasingly more fear of pain over conditioning blocks, while men do not. These results might be interesting in the light of the overrepresentation of women in a number of clinical pain conditions as well as anxiety disorders.

Spinal SIRPα1-SHP2 interaction regulates spinal nerve ligation-induced neuropathic pain via PSD-95-dependent NR2B activation in rats

Hsien-Yu Peng, Gin-Den Chen, Cheng-Yuang Lai, Ming-Chun Hsieh, Tzer-Bin Lin — 2012-03-19

Summary: Spinal SIRPα1-SHP2 interaction, which subsequently triggers SHP2/PSD-95/NR2B cascade, plays a pivotal role in neuropathic pain development caused by L5 spinal nerve ligation in rats.Abstract: The fact that neuropathic pain mechanisms are not well understood is a major impediment in the development of effective clinical treatments. We examined whether the interaction between signal regulatory protein alpha 1 (SIRPα1) and Src homology-2 domain-containing protein tyrosine phosphatase 2 (SHP2), and the downstream spinal SHP2/postsynaptic density 95 (PSD-95)/N-methyl-d-aspartate receptor NR2B subunit signaling cascade play a role in neuropathic pain. Following spinal nerve ligation (L5), we assessed tactile allodynia using the von Frey filament test and analyzed dorsal horn samples (L4-5) by Western blotting, reverse transcription polymerase chain reaction, coimmunoprecipitation, and immunofluorescence. Nerve ligation induced allodynia, SIRPα1, SHP2, phosphorylated SHP2 (pSHP2), and phosphorylated NR2B (pNR2B) expression, and SHP2-PSD-95, pSHP2-PSD-95, PSD-95-NR2B, and PSD-95-pNR2B coimmunoprecipitation in the ipsilateral dorsal horn. In allodynic rats, injury-induced SHP2 immunoreactivity was localized in the ipsilateral dorsal horn neurons and coincident with PSD-95 and NR2B immunoreactivity. SIRPα1 silencing using small interfering RNA (siRNA; 1, 3, or 5μg/rat for 7days) prevented injury-induced allodynia and the associated changes in protein expression, phosphorylation, and coimmunoprecipitation. Intrathecal administration of NSC-87877 (an SHP2 antagonist; 1, 10, or 100μM/rat) and SIRPα1-neutralizing antibodies (1, 10, or 30μg/rat) suppressed spinal nerve ligation-induced allodynia, spinal SHP2 and NR2B phosphorylation, and SHP2/phosphorylated SHP2-PSD-95 and PSD-95-NR2B/phosphorylated NR2B coprecipitation. SHP2 siRNA led to similar effects as the NSC-87877 and SIRPα1 antibody treatments, except it prevented the allodynia-associated spinal SHP2 expression. In conclusion, our results suggest that a spinal SIRPα1-SHP2 interaction exists that subsequently triggers SHP2/PSD-95/NR2B signaling, thereby playing a role in neuropathic pain development.

Psychological symptoms in children of parents with chronic pain—the HUNT study

Jannike Kaasbøll, Stian Lydersen, Marit S. Indredavik — 2012-03-23

Summary: Children with both parents experiencing chronic pain had twice the risk for reporting internalizing symptoms compared with children of parents without chronic pain.Abstract: The aim of the present study was to investigate the associations between parental chronic pain and anxiety, depression, and conduct problems in adolescents. The current study was based on cross-sectional surveys performed during 2006 to 2008 from the Nord Trøndelag Health Study (HUNT 3 and Young-HUNT 3). The sample consisted of 3227 adolescents aged 13 to 18years for whom information was available on parental chronic pain and health statuses. Separate analyses were conducted for girls and boys. The results indicated that if both parents experienced chronic pain, there was an increased risk of symptoms of anxiety and depression in girls (OR=2.17, CI=1.36–3.45, P=.001) and boys (OR=2.33, CI=1.17–4.63, P=.016) compared with children for whom neither parent had chronic pain. Girls had an increased risk of conduct problems in school if their mothers had chronic pain (OR=1.33, CI=1.02–1.74, P=.034). These results remained after adjusting for the possible effects of confounding factors and parental mental health. The results suggest that the presence of both maternal and paternal chronic pain is a high risk factor for internalizing symptoms in both girls and boys. The present study offers insights that should prove useful in clinical work and further large-scale research.

Cognitive correlates of “neglect-like syndrome” in patients with complex regional pain syndrome

Leonie Kolb, Christoph Lang, Frank Seifert, Christian Maihöfner — 2012-03-19

TOC summary: Patients with complex regional pain syndrome (CRPS) may have distinct parietal lobe dysfunction. Nevertheless, the “neglect-like syndrome” in CRPS patients is different from typical neglect patients.Abstract: Patients with complex regional pain syndrome (CRPS) often show distinct neurocognitive dysfunctions, which were initially termed “neglect-like symptoms.” So far, particularly the patients’ feelings about the affected extremity, motor, and sensory aspects of the “neglect-like symptoms” have been investigated, possibly pointing to a disturbed body schema. Because patients with classical neurological neglect show diminished awareness regarding the perception of their body, as well as of the space around them, our hypothesis was that CRPS patients exhibit some signs of personal neglect and extrapersonal visuospatial problems over and beyond those seen in patients simply suffering from limb pain. We used quantitative sensory testing and motor assessment aimed at detecting motor and sensory loss, a standardized questionnaire calculating a neglect score, and applied a detailed neuropsychological test battery assessing different parietal lobe functions, including visual neglect. We examined 20 CRPS patients and 2 matched control groups, one consisting of healthy subjects and the other one of patients with limb pain other than CRPS. Results show significant higher neglect scores for CRPS patients and the pain control group, but interestingly, CRPS patients and pain patients were indistinguishable. The results of the neuropsychological test battery did not demonstrate systematic variances, which would be indicative of a classical neurological neglect in CRPS patients, even though there were 3 CRPS patients who differed ⩾2 SD from the mean of our healthy control group, with poorer results in ⩾3 different tests. We assume that the “neglect-like syndrome” in most CRPS patients is different from typical neglect.

Viewing a needle pricking a hand that you perceive as yours enhances unpleasantness of pain

Marion Höfle, Michael Hauck, Andreas K. Engel, Daniel Senkowski — 2012-05-01

Summary: Viewing needle pricks enhances unpleasantness ratings and pupil dilation responses to concurrent painful and nonpainful stimuli. Situational expectations about needle pricks primarily affect intensity ratings.Abstract: “Don’t look and it won’t hurt” is commonly heard advice when receiving an injection, which implies that observing needle pricks enhances pain perception. Throughout our lives, we repeatedly learn that sharp objects cause pain when penetrating our skin, but situational expectations, like information given by the clinician prior to an injection, may also influence how viewing needle pricks affects forthcoming pain. How both previous experiences and acute situational expectations related to viewing needle pricks modulate pain perception is unknown. We presented participants with video clips of a hand perceived as their own being either pricked by a needle or touched by a Q-tip, while concurrently applying painful or nonpainful electrical stimuli. Intensity and unpleasantness ratings, as well as pupil dilation responses, were monitored. Effects of situational expectations about the strength of electrical stimuli were investigated by manipulating the contingency between clips and electrical stimuli across experimental blocks. Participants were explicitly informed about the contingency. Intensity ratings of electrical stimuli were higher when a clip was associated with expectation of painful compared to nonpainful stimuli, suggesting that situational expectations about forthcoming pain bias perceived intensity. Unpleasantness ratings and pupil dilation responses were higher when participants viewed a needle prick, compared to when they viewed a Q-tip touch, suggesting that previous experiences with viewing needle pricks primarily act upon perceived unpleasantness. Thus, remote painful experiences with viewing needle pricks, together with information given prior to an injection, differentially shape the impact of viewing a needle prick on pain perception.

Is touch gating due to sensory or cognitive interference?

Daniel E. Harper, Mark Hollins — 2012-03-15

Summary: Multiple lines of evidence show that touch gating, an impairment in tactile sensitivity induced by pain, is a form of sensory rather than cognitive interference.Abstract: Touch gating, the attenuation of tactile sensitivity in the presence of pain, is a well-documented phenomenon, but its mechanism is unknown. The ability of pain to capture attention suggests that touch gating may be an example of distraction, but the fact that pain raises tactile but not auditory thresholds argues that touch gating is a form of somatosensory interaction. Therefore, the present study was carried out to determine whether touch gating is the result of sensory or cognitive interference. Touch gating was repeatedly produced by delivering a colocalized painful heat stimulus (45°C) during forced-choice measurements of vibration threshold on the palm. Noxious heat significantly increased thresholds compared with those measured at normal skin temperature, and this interference did not decline over the course of an extended series of experiments during which pain intensity significantly habituated. Touch gating was thus related to the constant physical intensity, rather than to the changing subjective intensity, of the noxious stimulus. For comparison, a form of unambiguously cognitive interference, the Stroop effect, was also measured repeatedly; it declined significantly across sessions, unlike touch gating interference. Finally, touch gating was not correlated with measures of participants’ distractibility, fear of pain, hypervigilance, or anxiety, variables previously found to influence pain on a cognitive level. Taken together, the results suggest that touch gating is a robust, stimulus-locked form of sensory interaction, rather than a transitory result of distraction or other cognitive processes.

Intrathecal cannabilactone CB2R agonist, AM1710, controls pathological pain and restores basal cytokine levels

2012-03-19

Summary: Spinal AM1710 suppresses allodynia with corresponding anti-inflammatory and anti-MAGL (monoacylglycerol lipase) effects in the spinal cord and dorsal root ganglia.Abstract: Spinal glial and proinflammatory cytokine actions are strongly implicated in pathological pain. Spinal administration of the anti-inflammatory cytokine interleukin (IL)-10 abolishes pathological pain and suppresses proinflammatory IL-1β and tumor necrosis factor alpha (TNF-α). Drugs that bind the cannabinoid type-2 receptor (CB2R) expressed on spinal glia reduce mechanical hypersensitivity. To better understand the CB2R-related anti-inflammatory profile of key anatomical nociceptive regions, we assessed mechanical hypersensitivity and protein profiles following intrathecal application of the cannabilactone CB2R agonist, AM1710, in 2 animal models; unilateral sciatic nerve chronic constriction injury (CCI), and spinal application of human immunodeficiency virus-1 glycoprotein 120 (gp120), a model of peri-spinal immune activation. In CCI animals, lumbar dorsal spinal cord and corresponding dorsal root ganglia (DRG) were evaluated by immunohistochemistry for expression of IL-10, IL-1β, phosphorylated p38-mitogen-activated-kinase (p-p38MAPK), a pathway associated with proinflammatory cytokine production, glial cell markers, and degradative endocannabinoid enzymes, including monoacylglycerol lipase (MAGL). AM1710 reversed bilateral mechanical hypersensitivity. CCI revealed decreased IL-10 expression in dorsal spinal cord and DRG, while AM1710 resulted in increased IL-10, comparable to controls. Adjacent DRG and spinal sections revealed increased IL-1β, p-p38MAPK, glial markers, and/or MAGL expression, while AM1710 suppressed all but spinal p-p38MAPK and microglial activation. In spinal gp120 animals, AM1710 prevented bilateral mechanical hypersensitivity. For comparison to immunohistochemistry, IL-1β and TNF-α protein quantification from lumbar spinal and DRG homogenates was determined, and revealed increased DRG IL-1β protein levels from gp120, that was robustly prevented by AM1710 pretreatment. Cannabilactone CB2R agonists are emerging as anti-inflammatory agents with pain therapeutic implications.

Subthalamic deep brain stimulation modulates small fiber–dependent sensory thresholds in Parkinson’s disease

2012-03-29

TOC summary: Subthalamic nucleus deep brain stimulation contributes to relieve pain associated with Parkinson’s disease and specifically modulates small fiber–mediated sensations.Abstract: The effects of deep brain stimulation of the subthalamic nucleus on nonmotor symptoms of Parkinson’s disease (PD) rarely have been investigated. Among these, sensory disturbances, including chronic pain (CP), are frequent in these patients. The aim of this study was to evaluate the changes induced by deep brain stimulation in the perception of sensory stimuli, either noxious or innocuous, mediated by small or large nerve fibers. Sensory detection and pain thresholds were assessed in 25 PD patients all in the off-medication condition with the stimulator turned on or off (on- and off-stimulation conditions, respectively). The relationship between the changes induced by surgery on quantitative sensory testing, spontaneous CP, and motor abilities were studied. Quantitative sensory test results obtained in PD patients were compared with those of age-matched healthy subjects. Chronic pain was present in 72% of patients before vs 36% after surgery (P=.019). Compared with healthy subjects, PD patients had an increased sensitivity to innocuous thermal stimuli and mechanical pain, but a reduced sensitivity to innocuous mechanical stimuli. In addition, they had an increased pain rating when painful thermal stimuli were applied, particularly in the off-stimulation condition. In the on-stimulation condition, there was an increased sensitivity to innocuous thermal stimuli but a reduced sensitivity to mechanical or thermal pain. Pain provoked by thermal stimuli was reduced when the stimulator was turned on. Motor improvement positively correlated with changes in warm detection and heat pain thresholds. Subthalamic nucleus deep brain stimulation contributes to relieve pain associated with PD and specifically modulates small fiber–mediated sensations.

Induced fear reduces the effectiveness of a placebo intervention on pain

Peter Solvoll Lyby, June Thorvaldsen Forsberg, Ole Åsli, Magne Arve Flaten — 2012-04-05

TOC summary: Induced fear abolished placebo analgesia in reported pain intensity and the acoustic startle reflex, and this effect was strongest in subjects highest in self-reported fear.Abstract: Fear was induced by the anticipation of electric shock in order to investigate whether fear reduced the effectiveness of a placebo intervention on reported pain and the acoustic startle reflex. Thirty-three subjects participated in a 3 Condition (Natural History [NH], Placebo [P], Placebo+Fear [PF])×3 Test (Pretest, Posttest 1, Posttest 2) within-subject design, tested on 3 separate days. Measures of fear were fear of pain (FOP), measured by the Fear of Pain Questionnaire (FPQ-III); fear-potentiated startle; and a self-report measure that assessed the effectiveness of the fear induction procedure. In the pain intensity data, there was a trend towards a placebo effect. This trend was abolished by induced fear, and was most pronounced in subjects who were highest in measures of fear. The placebo manipulation also caused a reduction in startle reflex amplitude. This effect was abolished by induced fear, and was strongest amongst high FOP subjects. In conclusion, induced fear abolished placebo analgesia, and this effect was strongest in subjects who had high scores on measures of fear.

Imaging the neural correlates of neuropathic pain and pleasurable relief associated with inherited erythromelalgia in a single subject with quantitative arterial spin labelling

2012-02-27

Summary: Using a composite diagnostic-neuroimaging approach, this study shows the modulatory effects of pleasant cooling on pain-related cortical regions in a subject suffering from inherited erythromelalgia.Abstract: We identified a patient with severe inherited erythromelalgia secondary to an L858F mutation in the voltage-gated sodium channel Nav1.7. The patient reported severe ongoing foot pain, which was exquisitely sensitive to limb cooling. We confirmed this heat hypersensitivity using quantitative sensory testing. Additionally, we employed a novel perfusion imaging technique in a simple block design to assess her baseline erythromelalgia pain vs cooling relief. Robust activations of key pain, pain-affect, and reward-related centres were observed. This combined approach allowed us to confirm the presence of a temperature-sensitive channelopathy of peripheral neurons and to investigate the neural correlates of tonic neuropathic pain and relief in a single subject.

Neuropsychology and complex regional pain syndrome

David J. Libon, Guillermo Alexander, Robert J. Schwartzman — 2012-03-09

We read with interest the case report of Robinson et al. describing a CRPS patient with object-orientation agnosia. The authors present novel information on a little-studied neurobehavioral syndrome. In their introduction, Robinson et al. correctly point out that there has been little systematic study regarding neurocognitive deficits associated with CRPS. However, my colleagues and I would like to call attention to several experimental studies conducted in our laboratory. Libon et al. conducted a large multivariate analysis of CRPS patients (n=137) demonstrating the existence of a dysexecutive syndrome for at least a portion of patients. Another portion of our patients presented with global neurocognitive deficits. Koffler et al. studied a group of CRPS patients with neuropsychological tests before and after 5-day coma treatment with ketamine, midazolam, and clonidine. After treatment, these patients could be maintained on no medication.

Katz et al., Efficacy and safety of tanezumab in the treatment of chronic low back pain [Pain 2011;152:2248–2258] and Hill, Blocking the effects of NGF as a route to safe and effective pain relief – fact or fancy? [Pain 2011;152:2200–2201]

P.W. Ackermann — 2012-03-26

With their article, Katz et al. corroborate the idea that blockage of nerve growth factor (NGF) provides much more effective pain relief than traditional therapy with nonsteroidal antiinflammatory drugs . The authors treated chronic low back pain with a single dose of a humanised monoclonal antibody, tanezumab, and found no serious adverse events.

Response to letter by Ackermann

2012-03-29

We thank Dr. Ackermann for his thoughtful response to our recent paper and appreciate his contribution. We thank the editor for the opportunity to respond. A tremendous amount of work has been done in the tanezumab clinical program to understand the joint safety issues and to identify appropriate patient populations for further study. After imposition of a clinical hold by the US Food and Drug Administration (FDA), all studies impacted by this hold were closed out for results analysis; an analysis plan was developed for joint-related safety adverse events, and the emerging benefit-risk profile has been assessed. The goal of this work has been not only to clarify the joint safety signal and its consequences, its prevalence, and identity of subpopulations of patients in which it occurs, but also to identify the mechanism that triggers such events. As part of this work, an expert external adjudication committee evaluated case documentation data for all cases reported as osteonecrosis in a blinded fashion and provided diagnoses based on predefined diagnostic criteria. Also, further nonclinical assessments of bone and joint safety have been conducted. We look forward to discussing these data at the recently announced FDA Advisory Committee meeting in March 2012. We hope that Dr. Ackermann will contribute to the ongoing dialog to identify and clarify the process. Hopefully, the scientific community will stay tuned to the story of tanezumab and other anti-nerve growth factor (NGF) agents.

To the Editor:

Raymond G. Hill — 2012-03-27

I thank Professor Ackerman for his comments on the neuronal actions of nerve growth factor (NGF) on controlling joint homeostasis as part of the debate as to whether inhibition of the effects of NGF can be a safe way of controlling pain in patients suffering from joint damage. Whilst agreeing with him that we should be cautious when using therapies that interfere with the actions of multifunctional peptides such as Substance P and calcitonin gene-related peptide , I would also make a plea that evaluation of such therapies should not be abandoned because of such theoretical concerns. After all, it is possible to argue, on the basis of published work, that nonsteroidal antiinflammatory drugs and coxibs impair bone healing and thus, these substances should be contraindicated in conditions involving joint damage. These substances remain the mainstay of analgesic therapy for those with osteoarthritis without unwanted consequences for bone integrity in the vast majority of patients. I also reiterate my point that perhaps what we really need are small-molecule therapeutic agents with a relatively brief duration of action to increase the safety of studies in which the consequences of blocking the actions of NGF are evaluated. Part of the problem in deciding whether or not to continue studies with tanezumab is its extremely long duration of action . It is interesting to note in this context that it has recently been found possible to pharmacologically inhibit the action of NGF by blocking its production from proNGF .