Brain activity modifications following spinal cord stimulation for chronic neuropathic pain: A systematic review

Abstract

Background and objective

Spinal cord stimulation (SCS) is believed to exert supraspinal effects; however, these mechanisms are still far from fully elucidated. This systematic review aims to assess existing neurophysiological and functional neuroimaging literature to reveal current knowledge regarding the effects of SCS for chronic neuropathic pain on brain activity, to identify gaps in knowledge, and to suggest directions for future research.

Databases and data treatment

Electronic databases and hand-search of reference lists were employed to identify publications investigating brain activity associated with SCS in patients with chronic neuropathic pain, using neurophysiological and functional neuroimaging techniques (fMRI, PET, MEG, EEG). Studies investigating patients with SCS for chronic neuropathic pain and studying brain activity related to SCS were included. Demographic data (age, gender), study factors (imaging modality, patient diagnoses, pain area, duration of SCS at recording, stimulus used) and brain areas activated were extracted from the included studies.

Results

Twenty-four studies were included. Thirteen studies used neuroelectrical imaging techniques, eight studies used haemodynamic imaging techniques, two studies employed both neuroelectrical and haemodynamic techniques separately, and one study investigated cerebral neurobiology.

Conclusions

The limited available evidence regarding supraspinal mechanisms of SCS does not allow us to develop any conclusive theories. However, the studies included appear to show an inhibitory effect of SCS on somatosensory evoked potentials, as well as identifying the thalamus and anterior cingulate cortex as potential mediators of the pain experience. The lack of substantial evidence in this area highlights the need for large-scale controlled studies of this kind.

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An uncommon case of sternoclavicular septic arthritis

bmj;351/sep30_15/h4967/FIG1F1fig1An 85 year old woman taking immunosuppressants for an exacerbation of Crohn’s disease described increasing left shoulder pain. Shoulder and chest radiographs were...

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Concordance of phantom- and residual limb pain phenotypes in double amputees: evidence for the contribution of distinct and common individual factors

Most, but not all, limb amputees develop phantom limb pain (PLP) and/or residual limb pain (RLP), and large inter-individual differences in pain intensity and course are apparent. The present cross-sectional study of 122 double amputees investigated the possible role of genetic factors in PLP and RLP, assuming that strong individual predisposition will result in high intra-individual concordance in pain phenotype. Intra-individual concordance was observed in 116 (95%) subjects for development of PLP; and in 110 subjects (90%) for development of RLP.

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Smaller amygdala volumes in patients with chronic low back pain as compared to healthy control subjects

Although preclinical and clinical data strongly support an association between amygdala and chronic pain by the presence of mood and cognitive disturbances in affected individuals, little attention has been paid to morphometric measurement of the structure in patients with chronic low back pain (CLBP). In the present study, MR volumetric and surface analysis, using FMRIB's integrated registration and segmentation tool (FIRST), were performed to compare structural MR imaging data obtained from 33 patients with CLBP to those obtained from 33 demographically similar healthy controls.

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My brain reads pain in your face, before knowing your gender

Humans are expert at recognizing facial features whether they are variable (emotions) or unchangeable (gender). Due to its huge communicative value, pain might be detected faster in faces than unchangeable features. Based on this assumption, we aimed at finding a presentation time that will enable subliminal discrimination of pain facial expression without permitting gender discrimination. To this purpose, we compared in 80 subjects the time needed (50, 100 ,150 or 200ms) to discriminate masked static pain faces among anger and neutral faces with that needed to discriminate male from female faces.

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Treatment as Usual and Routine Care in Research and Clinical Practice

An evidence-based review of systemic treatments for itch

Abstract

Background and objective

Many treatment modalities are used for itch treatment in daily medical practices without adequate evidence of their efficacy. The purpose of this study was to provide an evidence-based review of the literature as to the clinical benefits of systemic anti-itch treatments.

Databases and data treatment

We performed a systematic review and, when appropriate, meta-analysis from available placebo-controlled randomized controlled trails (RCTs). A systematic search of the literature was performed using Pub Med, Cochrane Library and EMBASE. The primary outcome was the change in the itch score comparing the intervention group and placebo group. The meta-analysis method was used to calculate the pooled outcome of each treatment modality.

Results

Twenty-six eligible RCTs were included. We found evidence for the effectiveness of: naltrexone (in cholestatic itch and atopic eczema), nalfurafine (in uraemic itch), gabapentin (in uraemic itch) and ursodeoxycholic acid (in intrahepatic cholestasis of pregnancy). The results of two RCTs with naltrexone in uremic itch are conflicting. On the other hand, we did not find any benefit from ondansetron (in cholestatic and uraemic itch), ergocalciferol (in uraemic itch), colesevelam (in cholestatic itch) or gabapentin (in cholestatic itch). The possible effectiveness of sertraline, paroxetine, cromolyn sodium, zinc sulphate, omega-3 fatty acid, montelukast, doxepin and rifampin need to be confirmed from future large studies, because the available evidence is insufficient.

Conclusions

The findings from this study suggest the effective therapeutic approaches for itch. The major limitations are that there are small numbers of available RCTs and methodological differences across studies.

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Placebo and nocebo effects on itch: effects, mechanisms, and predictors

Abstract

Placebo and nocebo effects have been extensively studied in the field of pain and more recently also on itch. In accordance with placebo research on pain, expectancy learning via verbal suggestion or conditioning has shown to induce placebo and nocebo effects on itch, in which the combination of both procedures seems most promising. Moreover, itch can also be transferred ‘contagiously’ in which suggestion and social behavioural learning seem to play a role. With regard to predictors of placebo and nocebo responding on itch and contagious itch, preliminary evidence suggests a role for individual psychological characteristics and personality traits regarding negative outcome expectancies. Although findings on placebo and nocebo effects on itch seem comparable to pain, we have only just begun to understand the underlying mechanisms and predictors of placebo and nocebo effects on itch.

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Many parallels between itch and pain research

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The pathogenesis of Prurigo nodularis – ‘Super-Itch’ in exploration

Abstract

Prurigo nodularis (PN) is characterized by multiple hyperkeratotic nodules, papules and the presence of intensive pruritus. This leads to an impaired quality of life and high burden due not only to the severe itch but also the chronic, skin lesions and lack of treatment options.

The pathogenesis of PN is not completely clarified. Previous studies have demonstrated just how important the interaction between cutaneous nerve fibres and immune cells is. Besides a reduced intraepidermal nerve fibre density, there are increased dermal levels of neuropeptides such as substance P, calcitonin gene-related peptide and nerve growth factor, as well as a predominant presence of eosinophils and mast cells. An interaction of these factors results in a complex relationship which will be discussed in this article.

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Pruritus in psoriasis: An update

Abstract

Background and objective

Psoriasis is one of the most common chronic inflammatory skin diseases, found in about 1–3% of the general population. Pruritus affects about 60–90% of patients with psoriasis. The aim of this review was to summarize current knowledge about the pathogenesis and treatment of this symptom in psoriasis patients.

Results

Majority of psoriatic patients consider pruritus as the most bothersome symptom. The pathogenesis of pruritus is still unknown but the major concept of its origin is focused on neurogenic inflammation. Possible itch mediators include neuropeptides released from dermal nerve endings upon various stimuli, which were found to be abnormally expressed in itchy psoriatic plaques. Another important phenomenon supporting the idea of neurogenic inflammation as a key player in pruritus accompanying psoriasis is abnormal innervations of psoriatic skin. Possibly increased innervation density in psoriasis may decrease the threshold for pruritic stimuli. It is also suggested that pruritus in psoriasis might be related to abnormal functioning of the peripheral opioid system. Despite the high frequency of pruritus in psoriasis, to date there is no single antipruritic therapy dedicated specifically to treat itch in this disease.

Conclusions

Neurogenic inflammation seems to be important for itchiness in psoriasis. Treatment of pruritus in patients with psoriasis should be directed towards the resolution of skin lesions, as disease remission usually is linked with pruritus relief.

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Malignancy-associated pruritus

Abstract

Malignancy-associated pruritus can be the result of a neoplasm's local effect on tissue or due to the systemic reaction to malignancy. A systemic reaction to malignancy has been termed ‘paraneoplastic itch’ and can be the first sign of an underlying malignancy. Paraneoplastic itch is most commonly caused by lymphoproliferative malignancies, and severity of itch correlates with stage of disease in Hodgkin's lymphoma and polycythemia vera. Non-melanoma skin cancer is the most common type of malignancy-associated pruritus, and recent data indicate that pruritus is associated with more than one-third of non-melanoma skin cancers. Cutaneous T-cell lymphomas (CTCL), particularly more advanced stages, cause intractable pruritus and recent investigations into the pathophysiology of CTCL-associated itch have implicated cyotokine interleukin-31 as a putative mediator. Treatments that reduce itch in CTCL patients, such as histone deacetylase inhibitors (HDACi), Mogamulizumab, a novel monoclonal antibody against chemokine receptor type-4, and oral corticosteroids, have demonstrated a correlation between their anti-pruritic effect and reduced serum levels of interleukin-31.

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Epidemiology of uraemic itch: New data

Abstract

Chronic itch (CI) is a frequent and impairing symptom in haemodialysis (HD) patients. Within the last decades, worldwide variations were reported in the prevalence of itch in HD patients, ranging from 10 to 77%. Regional differences and especially the irregular pattern of itch in HD may explain why CI is still not well perceived and underestimated in HD patients. The pathogenesis is still unclear and therapy is ineffective in the majority of cases. There is a great diversity of prevalence estimates of itch used in different studies as well, as the study population greatly differs, especially when investigating CI in HD. Due to the demographic situation with a rising number of aged patients and increasing survival rates in HD, the number of HD patients will continuously grow, especially in the Western countries. Up to now, representative epidemiological data on CI in HD were missing. GEHIS (German Epidemiological Hemodialysis Itch Study) was established in 2012 as a representative prospective cross-sectional study. Eight hundred and sixty HD patients from a randomly selected cluster sample were included. The primary outcome measures were different prevalence measures of CI. The point prevalence was 25.2%, the 12-month prevalence was 27.2% and the lifetime prevalence of CI was 35.2%. General health status and health-related quality of life (HRQOl) were significantly impaired in those with CI. Due to the comparability of standards in HD quality, these results can be transferred to Western countries. This study demonstrates that CI is a frequent, long-lasting burden in HD patients affecting every fourth HD patient (point prevalence) and more than every third HD patient at some point in their lifetime.

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Evolving understanding on the aetiology of thermally provoked itch

Abstract

Background and objectives

Itch is one of the major symptoms in dermatology clinics, and severely impairs the quality of life. Itch is frequently produced by environmental stimuli, especially heat or warmth. Changes of temperature on the skin surface and noxious heat stimuli augment and develop itch, respectively. Thermally provoked itch is sometimes intractable with existing treatments.

Data bases and data treatment

Recent researches, linking heat sensation and itch, were searched in MEDLINE literature database through PubMed.

Results

Recent studies of the transient receptor potential cation channel subfamily vanilloid type 1 (TRPV1), the calcitonin gene-related peptide (CGRP) and the vesicular glutamate transporter 2 (VGLUT2), which link noxious heat and itch, contribute to a much better understanding of the thermally evoked itch process. From a clinical perspective, a warm sensation is a major provocative factor for subjects with atopic dermatitis. The accumulation of artemin (also known as enovin or neublastin) in the dermis of lesional skin can possibly provide a pathological mechanism for warmth-provoked itch.

Conclusions

This mini-review describes recent results of both basic and clinical research related to thermally provoked itch.

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Role of personality and expectations for itch and scratching induced by audiovisual itch stimuli

Abstract

Itch is an unpleasant, bodily sensation, which – similar to pain – evokes behavioral reactions. As a response to itch, people start scratching. There are different ways to provoke itch and subsequent scratching in experimental settings. A non-invasive method to induce itch and scratching is the presentation of itch-related (audio-) visual stimulus material, like slide-supported lectures on skin diseases or crawling insects. Also, watching videos showing other people scratching provokes itch and the desire to scratch. In this review, we focus on psychological factors, which were shown to be associated with itch and scratching provoked by (audio-) visual itch stimuli. First, we summarize the findings on the relationship between personality characteristics and (audio-) visually induced itch. Agreeableness and self-consciousness were shown to be associated with induced itch and scratching in patients with chronic skin diseases, while neuroticism was linked to induced itch in healthy subjects. Second, we present results of a recent study, in which we altered the expectations towards audio-visually induced itch and scratching by changing the information given on upcoming itch stimuli. It was shown that subjects being informed about itch stimuli in a neutral way displayed a shorter scratch duration in itch inducing situations than subjects having catastrophizing expectations. Also, the increase in scratch duration and in the number of scratch movements induced by audiovisual itch stimuli was higher when the patients were not informed about itch induction. Thus, in itch patients neither catastrophizing nor trivializing symptoms seems to be helpful.

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Re: ”High variability of the subjective visual vertical test of vertical perception, in some people with neck pain – Should this be a standard measure of cervical proprioception?”

We read with interest the article on increased variability in neck pain subjects when aligning a rod to vertical using the computerised rod-and-frame test (Treleaven & Takasaki, 2015). This prompted us to re-examine data we previously published on visual vertical and neck pain, also using the computerised rod-and-frame test (Bagust, et al, 2005; Docherty et al, 2012). Using analysis similar to that employed by Treleaven & Takasaki (2015) and Nyborg (1974), for determining Variable Error (VE) and Response Consistency (σ) respectively, we have calculated Variability as SD around the mean signed rod alignment error when the surrounding frame was tilted 18° from gravitational vertical in both clockwise and counter clockwise directions (Table 1).

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Effect of Deep Intramuscular Stimulation and Transcranial Magnetic Stimulation on Neurophysiological Biomarkers in Chronic Myofascial Pain Syndrome

Abstract

Objective

The aim was to assess the neuromodulation techniques effects (repetitive transcranial magnetic stimulation [rTMS] and deep intramuscular stimulation therapy [DIMST]) on pain intensity, peripheral, and neurophysiological biomarkers chronic myofascial pain syndrome (MPS) patients.

Design

Randomized, double blind, factorial design, and controlled placebo-sham clinical trial.

Setting

Clinical trial in the Laboratory of Pain and Neuromodulation at Hospital de Clínicas de Porto Alegre (NCT02381171).

Subjects

We recruited women aged between 19- and 75-year old, with MPS diagnosis.

Methods

Patients were randomized into four groups: rTMS + DIMST, rTMS + sham-DIMST, sham-rTMS + DIMST, sham-rTMS + sham-DIMST; and received 10 sessions for 20 minutes each one (rTMS and DIMST). Pain was assessed by visual analogue scale (VAS); neurophysiological parameters were assessed by transcranial magnetic stimulation; biochemical parameters were: BDNF, S100β, lactate dehydrogenase, inflammatory (TNF-α, IL6, and IL10), and oxidative stress parameters.

Results

We observed the pain relief assessed by VAS immediately assessed before and after the intervention (P < 0.05, F_(1,3)= 3.494 and F_(1,3)= 4.656, respectively); in the sham-rTMS + DIMST group and both three active groups in relation to sham-rTMS + sham-DIMST group, respectively. There was an increase in the MEP after rTMS + sham-DIMST (P < 0.05). However, there was no change in all-peripheral parameters analyzed across the treatment (P > 0.05).

Conclusion

Our findings add additional evidence about rTMS and DIMST in relieving pain in MPS patients without synergistic effect. No peripheral biomarkers reflected the analgesic effect of both techniques; including those related to cellular damage. Additionally, one neurophysiological parameter (increased MEP amplitude) needs to be investigated.

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Cervical transforaminal with low-dose local anesthetic is not a safeguard for neurological complications

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Physiotherapy commenced within the first four weeks post spinal surgery is safe and effective: a systematic review and meta-analysis

Pain and Health-Related Quality of Life after Pediatric Inpatient Surgery

Around 4 million children undergo inpatient surgery in the U.S. each year, however little is known about the impact of surgery and postoperative pain on children’s health-related quality of life (HRQOL) during the weeks and months after surgery. We measured pain and HRQOL in a large, heterogeneous pediatric postsurgical population from baseline to 1-month follow-up. Over a 20-month period, parents of 915 children age 2-18 years (Mean=9.6 years), 50% male, 56% white, admitted to surgical services at a children’s hospital enrolled in the study.

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A Systematic Review of Predictors and Moderators of Improvement in Cognitive-Behavioral Therapy for Panic Disorder and Agoraphobia

Cognitive-Behavioral Therapy for Sleep Disturbances in Treating Posttraumatic Stress Disorder Symptoms: A Meta-Analysis of Randomized Controlled Trials

Comprehensive Treatments for Social Cognitive Deficits in Schizophrenia: A Critical Review and Effect-Size Analysis of Controlled Studies

Frontostriatal Gating of Tinnitus and Chronic Pain

A case of unusual hand pain in general practice

A 34 year old white man presented to his general practitioner with a one year history of progressive bilateral hand pain. There was no trauma history or previous arthropathy. He consumed 84 units of...

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Treating youth in pain: Comparing tailored behavioural medicine treatment provided by physical therapists in primary care with physical exercises

Abstract

Objectives

To study the efficacy of tailored behavioural medicine treatment within a physical therapy framework.

Methods

The study was a randomized controlled study (RCT): tailored behavioural medicine treatment (EXT) delivered by physical therapists (PTs) was compared with exercise-based treatment (CT). Thirty-two adolescents (mean age 14.3 years) with persistent pain participated. Data on pain-related disability and school attendance (primary outcomes), pain intensity, catastrophizing, fear of movement and self-efficacy were collected.

Results

The pain-related disability measured by the Functional Disability Inventory (FDI) resulted in mean score change of EXT = −18 and CT = −11, respectively. A significant change within both groups was found (EXT p = 0.003, CT p = 0.001), and a large effect size for FDI between the conditions was demonstrated (AUC of 0.77). For school attendance post-treatment, no difference was found between conditions. For secondary outcomes, a significant improvement in pain intensity and pain catastrophizing was found for the EXT and self-efficacy for the CT groups but no statistically significant difference between the two conditions was detected. Caution should be given to the small sample size, as it may affect the interpretation and generalizability of the results.

Conclusion

In this study, differences between tailored behavioural medicine treatment delivered by PTs and exercise-based treatment could not be demonstrated, although the effect size was large. Patients who received either treatment demonstrated significant changes over time in pain-related disability. The low number of participants and suboptimal tailoring of the psychological components may partly explain the failure to demonstrate differences between groups, and future studies are warranted.

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Multisociety Letter to the Agency for Healthcare Research and Quality: Serious Methodological Flaws Plague Technology Assessment on Pain Management Injection Therapies for Low Back Pain

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Daily associations between male partner responses, pain during intercourse, and anxiety in women with vulvodynia and their partners

Vulvodynia is a prevalent vulvovaginal pain condition that disrupts the sexual and psychological health of affected women and their partners. Cross-sectional and daily experience studies suggest that partner responses to this pain influence the psychological and sexual sequelae of affected couples. However, their daily impact on pain and anxiety remain unknown. Using a daily diary method, 69 women (M age = 28.12, SD = 6.68) diagnosed with vulvodynia and their cohabiting partners (M age = 29.67, SD = 8.10) reported on male partner responses to women’s pain and anxiety symptoms on sexual intercourse days (M = 6.54, SD = 4.99) over eight weeks.

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Treatment of Postherpetic Neuralgia with Gastroretentive Gabapentin: Interaction of Patient Demographics, Disease Characteristics, and Efficacy Outcomes

To understand how patient demographics and patient-reported disease characteristics relate to successful management of postherpetic neuralgia (PHN), integrated data from Phase 3 and Phase 4 studies of patients with PHN (n=546) who received once-daily gastroretentive gabapentin (G-GR, 1800 mg) were analyzed. There were widespread, networked, positive correlations among efficacy endpoints—pain qualities on the Visual Analog Scale (VAS) and Brief Pain Inventory (BPI), measures of pain interference on the BPI, and Patient Global Impression of Change (PGIC)—most likely characterized by positive feedback loops, in which pain interferes with patient functioning, and poor functioning enhances pain.

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Expectancies Mediate the Relations Between Pain Catastrophizing, Fear of Movement and Return to Work Outcomes Following Whiplash Injury

Pain catastrophizing and fear of movement have been identified as key predictors of prolonged work disability following whiplash injury. However, little is known about the processes by which pain catastrophizing and fear of movement impact on return to work. This study investigated the mediating role of expectancies on the relations between pain catastrophizing and return to work, and fear of movement and return to work following whiplash injury. The study sample consisted of 154 individuals with whiplash injury who were enrolled in a multidisciplinary pain rehabilitation program.

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From the Serotonin Model of Suicide to a Mental Pain Model of Suicide

Psychother Psychosom 2015;84:323-329

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A systematic review and meta-analysis of the ability of analgesic drugs to reduce metastasis in experimental cancer models

Abstract: Analgesics are commonly used to manage pain in cancer patients. It has been suggested that there might be a relation between analgesics and the outgrowth of metastases. Opioids might increase and non-steroidal anti-inflammatory drugs decrease the risk of metastasis. Robust analysis of all preclinical evidence, however, has so far been lacking. Therefore, we conducted a systematic review and meta-analysis on the effect of treatment with analgesics on metastasis in experimental animal models. One hundred forty-seven studies met the inclusion criteria. Study characteristics, outcome data on the number, and incidence of metastases were extracted, and methodological quality was assessed. In the meta-analysis, we included 215 (±4000 animals) and 137 (±3000 animals) comparisons between analgesic vs control treatment, respectively, on the number and incidence of metastases. Overall, treatment with analgesics significantly decreases the number and risk of metastasis. This effect appears mainly to be the consequence of the efficacy of NSAIDs. Other factors that modify the efficacy are species, type of NSAIDs administered, timing, and duration of treatment. There is no evidence indicating that treatment with any analgesics increases the occurrence of metastases. Our findings appear robust for the various animal models and designs included in this review, which increases our confidence in the result and translatability to the clinical situation.

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Behavioral and neurochemical analysis of ongoing bone cancer pain in rats

Abstract: Cancer-induced bone pain is described as dull, aching ongoing pain. Ongoing bone cancer pain was characterized after intratibial injection of breast cancer cells in rats. Cancer produced time-dependent bone remodeling and tactile hypersensitivity but no spontaneous flinching. Conditioned place preference (CPP) and enhanced dopamine (DA) release in the nucleus accumbens (NAc) shell was observed after peripheral nerve block (PNB) selectively in tumor-bearing rats revealing nociceptive-driven ongoing pain. Oral diclofenac reversed tumor-induced tactile hypersensitivity but did not block PNB-induced CPP or NAc DA release. Tumor-induced tactile hypersensitivity, and PNB-induced CPP and NAc DA release, was blocked by prior subcutaneous implantation of a morphine pellet. In sham rats, morphine produced a modest but sustained increase in NAc DA release. In contrast, morphine produced a transient 5-fold higher NAc DA release in tumor bearing rats compared with sham morphine rats. The possibility that this increased NAc DA release reflected the reward of pain relief was tested by irreversible blockade of rostral anterior cingulate cortex (rACC) μ-opioid receptors (MORs). The rACC MOR blockade prevented the morphine-induced transient increased NAc DA release in tumor bearing rats but did not affect morphine-induced effects in sham-operated animals. Consistent with clinical experience, ongoing cancer pain was controlled by morphine but not by a dose of diclofenac that reversed evoked hypersensitivity. Additionally, the intrinsic reward of morphine can be dissociated from the reward of relief of cancer pain by blockade of rACC MOR. This approach allows mechanistic and therapeutic assessment of ongoing cancer pain with likely translation relevance.

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Neonatal vaginal irritation results in long-term visceral and somatic hypersensitivity and increased hypothalamic–pituitary–adrenal axis output in female mice

Abstract: Experiencing early life stress or injury increases a woman's likelihood of developing vulvodynia and concomitant dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. To investigate the outcome of neonatal vaginal irritation (NVI), female mouse pups were administered intravaginal zymosan on postnatal days 8 and 10 and were assessed as adults for vaginal hypersensitivity by measuring the visceromotor response to vaginal balloon distension (VBD). Western blotting and calcium imaging were performed to measure transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) in the vagina and innervating primary sensory neurons. Serum corticosterone (CORT), mast cell degranulation, and corticotropin-releasing factor receptor 1 (CRF1) expression were measured as indicators of peripheral HPA axis activation. Colorectal and hind paw sensitivity were measured to determine cross-sensitization resulting from NVI. Adult NVI mice had significantly larger visceromotor response during VBD than naive mice. TRPA1 protein expression was significantly elevated in the vagina, and calcium transients evoked by mustard oil (TRPA1 ligand) or capsaicin (TRPV1 ligand) were significantly decreased in dorsal root ganglion from NVI mice, despite displaying increased depolarization-evoked calcium transients. Serum CORT, vaginal mast cell degranulation, and CRF1 protein expression were all significantly increased in NVI mice, as were colorectal and hind paw mechanical and thermal sensitivity. Neonatal treatment with a CRF1 antagonist, NBI 35965, immediately before zymosan administration largely attenuated many of the effects of NVI. These results suggest that NVI produces chronic hypersensitivity of the vagina, as well as of adjacent visceral and distant somatic structures, driven in part by increased HPA axis activation.

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Neuropathic pain as part of chronic widespread pain: environmental and genetic influences

Abstract: Chronic widespread pain (CWP) has complex aetiology and forms part of the fibromyalgia syndrome. Recent evidence suggests a higher frequency of neuropathic pain features in those with CWP than previously thought. The aim of this study was to determine the prevalence of neuropathic pain features in individuals with CWP and to estimate the influence of genetic and environmental factors on neuropathic pain in CWP. Validated questionnaires (the London Fibromyalgia Screening Study questionnaire and PainDETECT questionnaire) were used to classify twins as having CWP and neuropathic pain, respectively. The prevalence of CWP was 14.7% (n = 4324), and of the 1357 twins invited to complete neuropathic pain screening, 15.9% of those having CWP demonstrated features of neuropathic pain. Neuropathic pain was found to be heritable (A = 37%; 95% confidence interval [CI]: 23%-50%) with unique environmental factors accounting for 63% (95% CI: 49%-79%) of the variance. Heritability of neuropathic pain and CWP were found to be correlated, 0.54 (95% CI: 0.42-0.65). Increasing age, raised body mass index, female gender, and smoking were all risk factors for neuropathic pain (P < 0.05), and CWP (P < 0.05). High socioeconomic status showed negative correlation with neuropathic pain (P = 0.003) and CWP (P = 0.001). Bivariate analysis of the 2 pain traits revealed that genetic predisposition to neuropathic pain is shared with that for CWP. This is the first study to provide formal heritability estimates for neuropathic pain in CWP. The findings suggest that at least some of the genetic factors underlying the development of neuropathic pain and CWP are the same.

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Life threatening complication of intramuscular injections for musculoskeletal back pain

A fit and well 27 year old woman presented to the emergency department with dyspnoea after bilateral intramuscular injections for musculoskeletal back pain. A chest radiograph demonstrated bilateral...

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Preventive Analgesia with Pregabalin in Neuropathic Pain from “Failed Back Surgery Syndrome”: Assessment of Sleep Quality and Disability

Abstract

Objective

Pregabalin group (PGB) is an antiepileptic used to treat neuropathic pain. We evaluated analgesic efficacy and safety for postoperative/chronic pain, disability, and sleep quality in patients who underwent spine surgery administered with PGB, or not, during the presurgical and postsurgical periods.

Design

Retrospective cohort study of 60 patients (two groups with 30 patients) with full information on 50 (29 with PGB and 21 without PGB). Ten patients were dismissed as information was lacking. The PGB group (P) (29 patients) received 75 mg/12 hours before surgery, 150 mg 10 hours after surgery, and 150 mg/12 hours 3 days after surgery. The control group (C; 21 patients) took no PGB.

Methods

Neuropathic pain was assessed before surgery, and 2 and 6 months later using visual analog scales (VAS), DN4, disability (Oswestry), and sleep quality. No serious adverse events occurred with PGB.

Results

The median VAS pain score at rest was lower in the PGB group at 2 months postsurgery (1 vs 2, P = 0.032), as was the median DN4 score (0 vs 3, P = 0.032) and the median Oswestry disability index (ODI: 12 vs 18, P = 0.001). At 6 months postsurgery, pain scores were also lower in the PGB group for VAS (0 vs 4, P = 0.001), DN4 score (0 vs 4, P = 0.001) and the ODI (10 vs 24, P = 0.001). Improvement in the functionality and sleep quality of the PGB group was noteworthy (P = 0.018).

Conclusions

PGB has analgesic/antihyperalgesic effects on postoperative neuropathic pain after surgery for lumbar disc hernia. Our findings show that this benefit increases with time.

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Profiles of Urine Drug Test in Clinical Pain Patients vs Pain Research Study Subjects

Abstract

Objective

To examine similarities and differences in urine drug test (UDT) results in clinical pain patients and pain subjects participating in pain research studies.

Design

An observational study with retrospective chart review and data analysis.

Methods

We analyzed 1,874 UDT results obtained from 1) clinical pain patients (Clinical Group; n = 1,529) and 2) pain subjects consented to participate in pain research studies (Research Group; n = 345). Since several medications such as opioids used in pain management are drugs of abuse (DOA) and can result in a positive UDT, we specifically identified those cases of positive UDT due to nonprescribed DOA and designated these cases as positive UDT with DOA (PUD).

Results

We found that 1) there was a higher rate of PUD in clinical pain patients (41.3%) than in pain research study subjects (14.8%); 2) although subjects in the Research Group were informed ahead of time that UDT will be conducted as a screening test, a substantial number (14.8%) of pain research study subjects still showed PUD; 3) there were different types of DOA between clinical pain patients (cannabinoids as the top DOA) and research study subjects (cocaine as the top DOA); and 4) a common factor associated with PUD was opioid therapy in both Clinical Group and Research Group.

Conclusion

These results support previous findings that PUD is a common finding in clinical pain patients, particularly in those prescribed opioid therapy, and we suggest that UDT be used as routine screening testing in pain research studies.

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Reply to: Is it not Important that we ask the Right Question, the Right Way, on an Appropriate Sample of Patients?

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Gabapentin in Headache Disorders: What Is the Evidence?

Abstract

Objective

Gabapentin (GBP), originally an antiepileptic drug, is more commonly used in the treatment of pain, including headache disorders. Off-label GBP is used in headache disorders with some success, some failure, and much debate. Due to this ambiguity, a clinical evidence literature review was performed investigating GBP's efficacy in headache disorders.

Methods

Bibliographic reference searches for GBP use in headache disorders were performed in PUBMED and OVID Medline search engines from January 1, 1983 to August 31, 2014. Based on abstracts read by two reviewers, references were excluded if: GBP was not a study compound or headache symptoms were not studied. The resulting references were then read, reviewed, and analyzed.

Results

Fifty-six articles pertinent to GBP use in headache disorders were retained. Eight headache clinical trials were quality of evidence Class 2 or higher based on American Academy of Neurology criteria. Seven of the eight clinical trials showed statistically significant clinical benefit from GBP in various headache syndromes (though modest affects at times). One study, Mathew et al., had concerns about intention-treat analysis breaches and primary outcomes.

Conclusion

Despite the conflicting evidence surrounding select studies, a significant amount of evidence shows that GBP has benefit for a majority of primary headache syndromes, including chronic daily headaches. GBP has some efficacy in migraine headache, but not sufficient evidence to suggest primary therapy. When primary headache treatments fail, a GBP trial may be considered in the individual patient.

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Progress of Perioperative Pain Management, but Still Far from Perfect

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Erratum

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Electrical Intramuscular Stimulation in Osteoarthritis Enhances the Inhibitory Systems in Pain Processing at Cortical and Cortical Spinal System

Abstract

Objective

To determine if in knee osteoarthritis (KOA), one session of active electrical intramuscular stimulation (a-EIMS) compared with sham causes an effect on the motor cortex excitability parameters [motor evoked potential (MEP; the primary outcome), short intracortical inhibition (SICI), intracortical facilitation (ICF) and cortical silent period (CSP)] and pain measurements [pain pressure threshold (PPT); visual analog scale (VAS) and change in numerical pain scale (NPS_0-10) during the conditioned pain modulation (CPM)-task]. This study also set out to determine if serum brain-derived neurotrophic factor (BDNF) mediates the effect of treatment on the cortical spinal system as assessed by MEP and PPT.

Design

Randomized clinical trial.

Subjects and methods

Women with KOA, 50–75-years old received a 30-min session of either sham (n = 13) or a-EIMS (n = 13) with 2 Hz. The pain measures and excitability parameters were measured before and immediately after a-EIMS or sham.

Results

The a-EIMS group compared with sham decreased the MEP by 31,67% [confidence interval (CI) 95%, 2.34–60.98]. For the secondary outcomes, the a-EIMS reduced the ICF and increased the CSP but not changed the SICI. The a-EIMS improved the pain reported on VAS, the PPT, and the score of the NPS (0–10) during the CPM-task The BDNF was negatively correlated with the PPT (r = −0.56).

Conclusions

The serum BDNF revealed an inverse relationship with PPT independent of the treatment group. These results suggest that a-EIMS enhanced the corticospinal inhibitory systems in cortical and infracortical pain processing sites most likely by bottom-up regulation mechanisms.

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Ising Model of the Chronification of Acute Pain: Editorial

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The Ising model applied on chronification of pain

This is a hypothesis-article suggesting an entirely new framework for understanding and treating longstanding pain. Most medical and psychological models are described with boxes and arrows. Such models are of little clinical and explanatory use when describing the phenomenon of chronification of pain due to unknown causes. To date no models that have been provided - and tested in a scientific satisfactory way - lays out a plan for specific assessment due to a specific causal explanation, and in the end serves the clinicians, patients and researcher with tools on how to address the specific pain condition to every individual pain patient's condition. By applying the Ising model (from physics) on the phenomenon of chronification of pain, one is able to detangle all these factors, and thus have a model that both suggests an explanation of the condition and outlines how one might target the treatment of chronic pain patients with the use of network science.

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Hip pain after a fall

A 60 year old woman was seen in the emergency department after she fell while playing badminton. She was unable to get up from the floor owing to pain in her right groin and was unable to weight bear...

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Oxycodone for Cancer Pain in Adult Patients

This Clinical Evidence Synopsis summarizes a Cochrane review of trials comparing oxycodone with placebo and other opioids for treating cancer pain in adults.

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The effects of catastrophizing on central motor activity

Abstract

Background

Pain catastrophizing significantly affects an individual's experience of pain. High pain catastrophizing is associated with increased fear avoidance behaviours, pain intensity and disability. The aim of this investigation was to determine the effect of pain catastrophizing on ongoing brain activity and movement-evoked brain activity during acute orofacial muscle pain.

Methods

Thirty-four healthy, pain-free subjects were recruited. In 17 subjects, the effect of catastrophizing on regional brain activity was determined. In 19 subjects, functional magnetic resonance imaging was used to determine the effects of pain catastrophizing on brain activation patterns during jaw movements in the presence of ongoing pain.

Results

We found that in the presence of pain, catastrophizing was significantly correlated with activity in multi-sensory integrative brain regions, including the dorsolateral and medial prefrontal cortices. Importantly, this relationship did not exist when subjects were not experiencing pain. In addition, during repetitive open–close jaw movements in the presence of pain, activity in the primary motor cortex, cerebellar cortex and the trigeminal motor nucleus was positively correlated with pain catastrophizing scores. In contrast, in the dorsolateral prefrontal cortex, as pain catastrophizing scores increased, the magnitude of signal intensity change during jaw movements decreased. Again, no such relationships occurred when the individual was not in pain.

Conclusions

These data show that during pain, catastrophic thinking has a significant impact on activity in motor and sensory integrative regions. Reducing negative coping strategies may be an effective means in reducing fear avoidance behaviours and the intensity of ongoing pain.

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A monoclonal antibody against the receptor for advanced glycation end products attenuates inflammatory and neuropathic pain in the mouse

Abstract

Background

The receptor for advanced glycation end products (RAGE) is a multi-ligand receptor in the immunoglobulin superfamily. RAGE is localized throughout ascending sensory pathways (skin, peripheral nerve, dorsal root ganglion, spinal cord), and in cell types interacting with sensory neurons (endothelial cells, smooth muscle cells, monocytes and macrophages). Neuronal RAGE expression increases in pathological pain states in humans and rodents, and soluble RAGE attenuates thermal hypoalgesia in diabetic mice. The objective of the present study was to investigate whether pharmacological modulation of RAGE could attenuate mechanical allodynia in rodent pain models.

Methods

We developed an anti-RAGE monoclonal antibody (11E6) that binds to the C₂ immunoglobulin domain of human RAGE, binds to mouse RAGE, and presumably to the same domain in mouse RAGE. The antinociceptive activity of 11E6 was investigated in mouse models of inflammatory (complete Freund's adjuvant) and neuropathic (chronic constriction injury of the sciatic nerve) pain. Mice were dosed intraperitoneally with 11E6 or IgG (negative control).

Results

Increased mechanical thresholds were observed following a single dose of 11E6 in both inflammatory and neuropathic pain models. Similar treatment with IgG did not alter nociceptive sensitivity. Repeated dosing with 11E6 significantly attenuated established mechanical hypersensitivity in a neuropathic pain model in a dose-related fashion.

Conclusions

These data demonstrate that specific modulation of RAGE effectively attenuates nociceptive sensitivity associated with chronic inflammatory and neuropathic pain states.

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BMJ paper wins Ig Nobel award for speed bump diagnosis of appendicitis

The 2015 Ig Nobel award for Diagnostic Medicine, for a study showing that pain while travelling over speed bumps is a sign of acute appendicitis, was presented to Helen Ashdown and her UK team on 17...

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