Examining what factors mediate treatment effect in chronic low back pain: a mediation analysis of a Cognitive Functional Therapy clinical trial

Abstract

Cognitive Functional Therapy (CFT) is a physiotherapist‐led individualised intervention for people with people with non‐specific chronic low back pain (CLBP), involving biopsychosocial pain education, graded movement exposure and lifestyle coaching. A multicentre randomised controlled trial (RCT), including 206 participants with CLBP in Ireland, supported CFT’s effectiveness for reducing disability, but not pain, compared to a group exercise and education intervention. In this study, causal mediation analysis was used to determine whether the effect of CFT on disability and the lack of effect on pain (relative to a group exercise and education intervention) is mediated by certain psychological and lifestyle factors. Hypothesised mediators measured were pain self‐efficacy, stress, fear of physical activity, coping, depression, anxiety, and sleep, at 6 months. The outcomes measured were functional disability and pain intensity at 12 months. This causal mediation study shows that the majority of benefit of CFT (relative to a group exercise and education intervention) for disability is due to increasing pain self‐efficacy. CFT did not improve the majority of the hypothesised mediators (stress, fear of physical activity, coping, depression, anxiety and sleep) and these mediators were not associated with either disability or pain. Unfortunately, the proportion of missing data in this study is substantial and these findings can only be considered hypothesis‐generating. Therefore, future research should examine replicating the results of this study to verify the role of self‐efficacy and other proposed mediators (e.g. stress, coping, sleep, fear) on clinical outcomes.

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An Initial Psychometric Evaluation of the Pain Concepts Questionnaire in a Low-SES Setting

This study is an initial evaluation of the psychometric properties of a new measure of chronic pain beliefs, the Pain Concepts Questionnaire (PCQ). The PCQ is literacy-adapted and was assessed within a low-SES population. Psychometric proprieties of this measure were promising and could be useful in pain assessment and interventions.

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Chronic Musculoskeletal Pain and Foot Reaction Time in Older Adults

Chronic musculoskeletal pain affects more than half of older people,31 and poses serious risks leading to mobility decline and falls in older adults.9,20,40,45 It has been reported that musculoskeletal pain and specifically multisite pain are associated with slower gait speed and increased gait variability.8,39 Although studies have examined cognitive factors contributing to falls and several have determined a relationship between pain and falls,16,45 little research has explored mechanisms underlying the relationship between chronic musculoskeletal pain and falls.

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Exposure to contact sports results in maintained performance during experimental pain

Athletes who play contact sports have a higher pain tolerance and report lower pain intensity than other athletes31,30,33. These reduced pain responses may result in contact athletes being able to cope better, and therefore perform better in pain than non-contact athletes34. Evidence suggests that performance in both complex and simple motor tasks tends to decline during painful stimulation in the general population5 (. It is clear that some athletes are able to maintain performance despite the pain inherent in high contact sports such as rugby, however the mechanisms underpinning this ability are not yet fully understood.

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Methadone in Pain Management: A Systematic Review

Pain is a significant contributor to a poor quality of life for many patients. Acute pain, typically lasting less than three months, is inadequately managed in over 40% of patients13,30. Chronic pain, which persists for greater than three months following the initial tissue damage, is estimated to have a prevalence over 60%30,51. Long-term use of pharmacologic agents in patients with chronic pain presents additional challenges, including opioid tolerance and treatment failure of anti-depressant medications31,64.

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Exercise-induced hypoalgesia in healthy individuals and people with chronic musculoskeletal pain: a systematic review and meta-analysis

Exercise-induced hypoalgesia (EIH) is a reduction in pain that occurs during or following a single bout of exercise. This phenomenon has been studied for almost 40 years with diverse methodology3,16. The magnitude of EIH appears to vary according to the modality, dose, and intensity of exercise performed23,24,32, the type of noxious stimulus used to evoke pain39, the method used to quantify pain (e.g. threshold, tolerance, rating)39, the site of pain assessment (e.g. over an exercised or non-exercised area and over bone or muscle)28,37,53, and the timing of pain assessment (e.g.

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[Clinical Picture] Myocarditis in a 16-year-old boy positive for SARS-CoV-2

A 16-year-old boy was admitted to our emergency department, in Lombardy, complaining of intense pain in his chest—radiating to his left arm—which had started 1 h earlier. The day before he had a fever of 38·3°C that decreased after 100 mg of nimesulide. He reported no other symptoms, no medical history, and no contact with anyone with confirmed COVID-19.

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Parent cognitive, behavioural, and affective factors and their relation to child pain and functioning in pediatric chronic pain: a systematic review and meta-analysis

Previous studies have demonstrated that parental cognitive, behavioral, and emotional factors are related to child functioning in children and adolescents with chronic pain. This is particularly important to understand how to potentially enhance the efficacy of psychological interventions for children by incorporating interventions targeting parents. We conducted a systematic review and meta-analysis to identify the specific parent factors that have been examined in the literature and to quantify the associations observed between parent factors and child pain and disability. A search of the electronic databases EMBASE, PsychINFO, Medline, and PubMed was conducted, using search terms related to chronic pain, pediatric population, and parents. Fifty-four studies met criteria and were included in the review. Parent pain catastrophizing and protective behavior were the most commonly assessed parental constructs in the literature. Meta-analyses were conducted for associations between parent pain catastrophizing, parent protective behaviors, parent anxiety and depression, and parent stress associated with parenting a child with chronic pain with child pain, disability, school functioning, and emotional functioning. Correlation coefficients were pooled using the random-effects model. A medium relationship was observed between higher protective behavior and poorer school functioning (r = −0.39), and small relationships were found between higher parent pain catastrophizing and increased child disability (r = 0.29); higher protective behaviors and increased child disability (r = 0.25); and increased parent depression and anxiety with increased child disability (r = 0.23 and r = 0.24, respectively). Future research is needed to investigate broader parent variables and overcome methodological weaknesses in this field.

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A highly cognitive demanding working memory task may prevent the development of nociceptive hypersensitivity

Whether, how, and which cognitive factors modulate the development of secondary hypersensitivity/hyperalgesia after central sensitization is not fully understood. Here, we tested, in 3 subsequent experiments, whether being engaged in non–pain-related cognitive demanding tasks: (1) lessens the amount of hypersensitivity developed after an experimental procedure sensitizing nociceptive pathways; and (2) modulates cortical responses to somatosensory stimuli (measured by electroencephalography, EEG). In the first experiment, we validated a novel model in humans using low-frequency stimulation of the skin and demonstrated that it was able to successfully induce hypersensitivity to mechanical pinprick stimuli in the area surrounding the sensitized site. In the second and third experiments, we engaged participants in tasks of increasing difficulty (the Eriksen Flanker Task in experiment 2, and a modified N-back task in experiment 3). We observed that hypersensitivity to mechanical stimuli still developed in experiment 2, that is, the pinprick stimuli applied on the sensitized arm were perceived as more intense after low-frequency stimulation. By contrast, no statistically significant enhancement of mechanical hypersensitivity was observed in experiment 3, indicating that, at the group level, being engaged in a difficult N-back task may interfere with the development of mechanical hypersensitivity. Contrary to previous studies, which have used different methods to induce sensitization, we did not observe any increase in the cortical response to somatosensory stimuli applied on the sensitized arm. We conclude that (1) the development of pinprick hypersensitivity is modulated by the concomitant execution of a difficult N-back task, and (2) the enhancement of cortical responses to somatosensory stimuli is related to the method used to induce central sensitization.

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Magnetic resonance imaging of neuroinflammation in chronic pain: a role for astrogliosis?

Noninvasive measures of neuroinflammatory processes in humans could substantially aid diagnosis and therapeutic development for many disorders, including chronic pain. Several proton magnetic resonance spectroscopy (1H-MRS) metabolites have been linked with glial activity (ie, choline and myo-inositol) and found to be altered in chronic pain patients, but their role in the neuroinflammatory cascade is not well known. Our multimodal study evaluated resting functional magnetic resonance imaging connectivity and 1H-MRS metabolite concentration in insula cortex in 43 patients suffering from fibromyalgia, a chronic centralized pain disorder previously demonstrated to include a neuroinflammatory component, and 16 healthy controls. Patients demonstrated elevated choline (but not myo-inositol) in anterior insula (aIns) (P = 0.03), with greater choline levels linked with worse pain interference (r = 0.41, P = 0.01). In addition, reduced resting functional connectivity between aIns and putamen was associated with both pain interference (whole brain analysis, pcorrected < 0.01) and elevated aIns choline (r = −0.37, P = 0.03). In fact, aIns/putamen connectivity statistically mediated the link between aIns choline and pain interference (P < 0.01), highlighting the pathway by which neuroinflammation can impact clinical pain dysfunction. To further elucidate the molecular substrates of the effects observed, we investigated how putative neuroinflammatory 1H-MRS metabolites are linked with ex vivo tissue inflammatory markers in a nonhuman primate model of neuroinflammation. Results demonstrated that cortical choline levels were correlated with glial fibrillary acidic protein, a known marker for astrogliosis (Spearman r = 0.49, P = 0.03). Choline, a putative neuroinflammatory 1H-MRS-assessed metabolite elevated in fibromyalgia and associated with pain interference, may be linked with astrogliosis in these patients.

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Pain-related behaviors associated with persistence of mechanical hyperalgesia after antigen-induced arthritis in rats

Upon transient musculoskeletal diseases, some patients develop persistent pain while others recover from pain. Here, we studied whether such heterogeneity also occurs in rats after recovery from unilateral antigen-induced arthritis (AIA) in the knee joint, and which pain phenotype may predict the course of pain. Typically, inflammatory swelling lasts about 3 weeks. Pain-related behaviors were monitored for 84 days after AIA induction. Unbiased cluster analysis of intragroup differences at day 84 of AIA revealed that about one-third of the rats (cluster 1) showed persistent mechanical hyperalgesia at the injected knee joint, whereas the other rats (cluster 2) had recovered from pain. Retrograde analysis of pain-related behaviors revealed that cluster 1 rats exhibited more severe mechanical hyperalgesia at the injected knee from day 3 of AIA and mechanical hyperalgesia at the contralateral knee. Cluster 1 and 2 rats did not show different inflammatory swelling, secondary mechanical and thermal hyperalgesia at the ipsilateral hindpaw, guarding score, and asymmetry of weight bearing during AIA. Thus, in particular, early severe mechanical hyperalgesia in the inflamed joint and segmental contralateral mechanical hyperalgesia seem to be a risk factor for the development of persistent mechanical hyperalgesia pointing to the importance of spinal mechanisms. However, none of the rats showed an expression of ATF3 in dorsal root ganglion neurons, nor morphological spinal microglia activation thus not suggesting development of neuropathic pain. Both clusters showed a persistent upregulation of pCREB in dorsal root ganglion neurons, inversely correlated with mechanical hyperalgesia at the knee. The role of pCREB needs to be further explored.

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Distribution of functional opioid receptors in human dorsal root ganglion neurons

Preclinical evidence has highlighted the importance of the μ-opioid peptide (MOP) receptor on primary afferents for both the analgesic actions of MOP receptor agonists, as well as the development of tolerance, if not opioid-induced hyperalgesia. There is also growing interest in targeting other opioid peptide receptor subtypes (δ-opioid peptide [DOP], κ-opioid peptide [KOP], and nociceptin/orphanin-FQ opioid peptide [NOP]) on primary afferents, as alternatives to MOP receptors, which may not be associated with as many deleterious side effects. Nevertheless, results from several recent studies of human sensory neurons indicate that although there are many similarities between rodent and human sensory neurons, there may also be important differences. Thus, the purpose of this study was to assess the distribution of opioid receptor subtypes among human sensory neurons. A combination of pharmacology, patch-clamp electrophysiology, Ca2+ imaging, and single-cell semiquantitative polymerase chain reaction was used. Our results suggest that functional MOP-like receptors are present in approximately 50% of human dorsal root ganglion neurons. δ-opioid peptide-like receptors were detected in a subpopulation largely overlapping that with MOP-like receptors. Furthermore, KOP-like and NOP-like receptors are detected in a large proportion (44% and 40%, respectively) of human dorsal root ganglion neurons with KOP receptors also overlapping with MOP receptors at a high rate (83%). Our data confirm that all 4 opioid receptor subtypes are present and functional in human sensory neurons, where the overlap of DOP, KOP, and NOP receptors with MOP receptors suggests that activation of these other opioid receptor subtypes may also have analgesic efficacy.

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PAC1 receptor blockade reduces central nociceptive activity: new approach for primary headache?

Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) may play an important role in primary headaches. Preclinical evidence suggests that PACAP38 modulates trigeminal nociceptive activity mainly through PAC1 receptors while clinical studies report that plasma concentrations of PACAP38 are elevated in spontaneous attacks of cluster headache and migraine and normalize after treatment with sumatriptan. Intravenous infusion of PACAP38 induces migraine-like attacks in migraineurs and cluster-like attacks in cluster headache patients. A rodent-specific PAC1 receptor antibody Ab181 was developed, and its effect on nociceptive neuronal activity in the trigeminocervical complex was investigated in vivo in an electrophysiological model relevant to primary headaches. Ab181 is potent and selective at the rat PAC1 receptor and provides near-maximum target coverage at 10 mg/kg for more than 48 hours. Without affecting spontaneous neuronal activity, Ab181 effectively inhibits stimulus-evoked activity in the trigeminocervical complex. Immunohistochemical analysis revealed its binding in the trigeminal ganglion and sphenopalatine ganglion but not within the central nervous system suggesting a peripheral site of action. The pharmacological approach using a specific PAC1 receptor antibody could provide a novel mechanism with a potential clinical efficacy in the treatment of primary headaches.

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Pain memory in patients with chronic pain versus asymptomatic individuals: A prospective cohort study

Abstract

Background

The main objective of this study was to assess painful memory as well as long‐term episodic memory, both in patients with chronic pain (CP) and in asymptomatic participants (AP).

Methods

A prospective cohort study design was used. Sixty‐eight participants were divided into two groups: CP (n = 34) and AP (n = 34). The protocol consisted of taking eight tests, four painful provocation tests and four distracting tests, and completing a memory test on the order of the tests at the end of the experiment and at 1‐month post‐experiment.

Results

Patients with CP showed acceptable concordance in the classification, in ascending order from lower to higher pain perception, both post‐experiment and 1‐month post‐experiment (κ = 0.41–0.60, p <.001). No differences were found regarding recall of the order of the tests, but differences were found in painful tests isolated only post‐experiment in the CP group with a moderate effect size (p < .05, d = 0.77).

Conclusions

Patients with CP had a more reliable memory than AP in relation to the memory of the pain caused experimentally until at least one month after the experiment. Interspersing distraction tests appeared to result in increased complexity and difficulty in coding and decoding information in patients with CP, leading to similar reliable long‐term memory consolidation in comparison with AP.

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Crying out in pain‐ a systematic review into the validity of vocalization as an indicator for pain

Abstract

Background

Vocalization is often used to assess pain, sometimes combined with other behaviors such as facial expressions. Contrary to facial expressions, however, for vocalization there is little evidence available on the association with pain. The aim of this systematic review was to critically analyze the association between vocalization and pain, to explore if vocalizations can be used as a ‘stand‐alone’ indicator for pain.

Methods

The search was performed according to the Prisma Guidelines for systematic reviews and meta‐analysis. The following terms were used: “Pain Measurement”, “Vocalization”, and “Verbalization”. The study population included verbal and non‐verbal individuals, including older people and children. The search was performed in three different databases: Pubmed, Embase, and Cinahl. A total of 35 studies were selected for detailed investigation. Quality assessments were made using two grading systems; Grading of Recommendations Assessment Development and Evaluation system and the Newcastle‐Ottawa scale.

Results

An association between vocalization and pain was found in most studies, particularly when different types of vocalizations were included in the investigation. Different types of vocalization, but also different types of pain shape this association. The association is observed within all groups of individuals, although age, amongst others, may have an influence on preferred type of vocalization.

Conclusions

There is an association between vocalization and pain. However, vocalization as a ‘stand‐alone’ indicator for pain indicates only a limited aspect of this multifactorial phenomenon. Using vocalization as an indicator for pain may be more reliable if other pain indicators are also taken into account.

Significance

Vocalizations are frequently used in pain scales, although not yet thoroughly investigated as a ‘single‐indicator’ for pain, like for example facial expression. This review confirms the role of vocalizations in pain scales, and stresses that vocalizations might be more reliable if used in combination with other pain indicators.

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Reduced pain and analgesic use after acoustic binaural beats therapy in chronic pain ‐ a double blind randomized control cross‐over trial

Abstract

Background

Binaural Beats (BB) consist of two artificial acoustic stimuli with different frequency, presented simultaneously but independently to each ear. The human brain perceives and synchronizes to this frequency difference (entrainment).

Methods

In a double blind, randomized, cross‐over trial, BB at 5Hz (theta rhythm) were applied for 30 minutes, under simultaneous electroencephalogram recordings, followed by liberal, on demand use by chronic pain patients for a week, compared to sham stimulation (SS). Pain as the main outcome (numeric scale, NRS), stress (STAI) and medication usage (defined daily doses, DDD) were assessed at baseline, 30 minutes and week's end.

Results

Perceived pain (NRS) was significantly reduced in BB intervention (5.6±2.3 to 3.4±2.6, p<0.001), compared to SS (5.2±2.1 to 4.8±2.3, p=0.78), during the first 30‐minute phase, as well as at the week's end (to 3.9±2.5 compared to 5.5±2.6 respectively, p<0.001). The mean EEG theta power at 5Hz was significantly increased only during BB application.

Stress was significantly reduced at 30 minutes in both interventions but remained reduced only in the BB group at the week's end.

Analgesic medication consumption (DDD, g) during the week was significantly less in the BB intervention (3.9±3.7 vs. 4.6±4.1, p<0.05), while reporting equal to SS mean levels of pain.

Conclusions

Acoustic BB reduced pain intensity, stress and analgesic use, compared to SS, in chronic pain patients.

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Inter-individual differences in the responses to pain neuroscience education in adults with chronic musculoskeletal pain: A systematic review and meta-analysis of randomised controlled trials

Pain neuroscience education (PNE) is an educational approach used in the management of chronic pain. PNE aims to reconceptualise an individuals’ understanding of their pain as less threatening to facilitate rehabilitation23. Since its inception PNE has become increasingly popular in clinical practice24. Our group recently published a mixed-methods systematic review and meta-analysis on the effectiveness of PNE for adults with chronic musculoskeletal pain (CMP)39. Quantitatively we found no evidence to indicate that PNE results in clinically important changes over control for pain or disability.

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Exercise interventions for persistent non-specific low back pain – does matching outcomes to treatment targets make a difference? A systematic review and meta-analysis

Exercise is a core recommended treatment for patients with persistent non-specific low back pain (NSLBP) in almost all international guidelines 49,62 with no evidence that one type of exercise is superior to another 41. NSLBP has the highest consultation prevalence among musculoskeletal conditions, and is most frequently managed in primary care 54. Despite the documented benefits of exercise more generally 5, 3, the standardised mean differences (SMDs) between exercise for NSLBP and non-exercise comparison/control interventions in randomised controlled trials (RCTs) are small to moderate 3,41, suggesting that they provide, at best, modest benefits over other treatments.

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Development and Psychometric Evaluation of the PROMIS® Pediatric Pain Intensity Measure in Children and Adolescents with Chronic Pain

Appropriate management of pediatric pain relies on accurate assessment of pain intensity. The gold standard for assessing pain intensity is by self-report: “pain is what the patient says it is, and occurs when he or she says it does”.27 A number of patient-reported pain intensity measures are widely used in pediatric populations, including visual analog scales (VAS 26), numeric rating scales (NRS 28,32), and faces pain scales (FPS-R 2,18); however the psychometric precision of these measures are limited.

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Systematic Review of Research Methods and Reporting Quality of Randomized Clinical Trials of Spinal Cord Stimulation for Pain

The use of spinal cord stimulation (SCS) for the treatment of chronic pain was first described in 1967.67 Its development was based on the gate-control theory of pain, introduced a few years earlier by Melzack and Wall, who hypothesized that a “gate” in the dorsal horn of the spinal cord dictated transmission of nociception within the central nervous system.49 The hypothetical gate could be closed when stimulation of large diameter myelinated fibers associated with touch, pressure, or vibration predominated over stimulation of thinner, unmyelinated pain fibers, in turn attenuating or eliminating noxious signaling to the brain.

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NMDA receptor modulates spinal iron accumulation via activating DMT1(-)IRE in remifentanil-induced hyperalgesia

Mounting data from animal and observational human studies are raising the concern that opioids, commonly used to supply sufficient analgesia in general anesthesia, may cause paradoxical pain amplification after their exposure which is called opioid-induced hyperalgesia (OIH).3,4,10,20,32 In particular, the phenomenon of hyperalgesia is responsible for weakening antinociception from sustained medication, thereby leading to irritable allodynia and supplemental drug consumption.3 The μ-opioid receptor agonist remifentanil is an important component in clinical anesthesia, while it is definitely inclined to induce hyperalgesia compared to other opioids.

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Comparing central pain processing in individuals with non-traumatic neck pain and healthy individuals: a systematic review and meta-analysis

Neck pain is prevalent40 and up to 80% of people with this problem experience long-term pain and disability.10 Globally, this problem ranked the fourth greatest cause of disability out of 291 conditions studied in the Global Burden of Disease 2010 Study39, with around 29 million disability-adjusted life-years reported in 2016.28 Neck pain is generally classified into traumatic (whiplash-associated disorders) and non-traumatic neck pain. Most people suffer from non-traumatic neck pain, which is defined as pain in the neck and/or shoulder regions (with or without referral of pain into the upper limb(s)) without trauma or specific diseases at the onset of pain development.

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The Relationship between Education and Pain among Adults Aged 30-49 in the United States

Pain is strongly influenced by social characteristics such as educational attainment.19 Indeed, education is one of the most powerful determinants of health in general.47 While an extensive literature has documented educational disparities for various health outcomes,9, 50, 66 research on the relationship between education and pain is surprisingly limited.

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Individualized augmented reality training reduces phantom pain and cortical reorganization in amputees: A proof of concept study

Phantom limb pain (PLP) may be relieved using a visual representation of an intact limb. However, patients with distorted (telescoped) phantoms seem unable to associate with visualizations of intact limbs. A virtual arm visualization was matched to the individual's phantom perception and controlled in an augmented reality (AR) intervention. Seven PLP participants with telescoped phantoms performed eight supervised home-based AR-training sessions (45 min each) within two weeks. The virtual arm was superimposed in AR onto their residual limb and controlled using electromyography from the residual limb.

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Preoperative Mental Health Component Scoring Is Related to Patient Reported Outcomes Following Lumbar Fusion

Study Design. Retrospective cohort review. Objective. The objective of this study was to identify depression using the Mental Component Score (MCS-12) of the Short Form-12 (SF-12) survey and to correlate with patient outcomes. Summary of Background Data. The impact of preexisting depressive symptoms on health-care related quality of life (HRQOL) outcomes following lumbar spine fusion is not well understood. Methods. Patients undergoing lumbar fusion between one to three levels at a single center, academic hospital were retrospectively identified. Patients under the age of 18 years and those undergoing surgery for infection, trauma, tumor, or revision, and less than 1-year follow-up were excluded. Patients with depressive symptoms were identified using an existing clinical diagnosis or a score of MCS-12 less than or equal to 45.6 on the preoperative SF-12 survey. Absolute HRQOL scores, the recovery ratio (RR) and the percent of patients achieving minimum clinically important difference (MCID) between groups were compared, and a multiple linear regression analysis was performed. Results. A total of 391 patients were included in the total cohort, with 123 (31.5%) patients reporting symptoms of depression based on MCS-12 and 268 (68.5%) without these symptoms. The low MCS-12 group was found to have significantly worse preoperative Oswestry disability index (ODI), visual analogue scale back pain (VAS Back) and visual analogue scale leg pain (VAS Leg) scores, and postoperative SF-12 physical component score (PCS-12), ODI, VAS Back, and VAS Leg pain scores (P <� 0.05) than the non-depressed group. Finally, multiple linear regression analysis revealed preoperative depression to be a significant predictor of worse outcomes after lumbar fusion. Conclusion. Patients with depressive symptoms, identified with an MCS-12 cutoff below 45.6, were found to have significantly greater disability in a variety of HRQOL domains at baseline and postoperative measurement, and demonstrated less improvement in all outcome domains included in the analysis compared with patients without depression. However, while the improvement was less, even the low MCS-12 cohort demonstrated statistically significant improvement in all HRQOL outcome measures after surgery. Level of Evidence: 3

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Systematic Review of Outcomes Following 10-Year Mark of Spine Patient Outcomes Research Trial (SPORT) for Degenerative Spondylolisthesis

Study Design. We performed a comprehensive search of PubMed, MEDLINE, and EMBASE for all English language studies of all levels of evidence pertaining to Spine Patient Outcomes Research Trial (SPORT), in accordance with Preferred Reported Items for Systematic Reviews and Meta-analyses guidelines. Objective. We aim to summarize the 10-year clinical outcomes of SPORT and its numerous follow-up studies for degenerative spondylolisthesis. Summary of Background Data. The SPORT was a landmark randomized control trial including approximately 2500 patients at 13 clinics across the country. SPORT compared surgical and nonoperative management of the three most common spinal pathologies. Methods. Keywords used in the literature search included SPORT, spine patient outcomes research trial, degenerative spondylolisthesis, and surgical outcomes. Results. The intent-to-treat analysis failed to show a significant difference between patients treated surgically as compared to those treated nonoperatively. However, as-treated analysis revealed statically greater improvements at 6 weeks, 2 years, and 4 years in patients treated surgically. Secondary outcomes such as low back pain, leg pain, stenosis bothersome scales, overall satisfaction with current symptoms, and self-rated progress were also significantly improved in surgical patients. Regardless of the initial grade of listhesis, disk height, or mobility, patients who had surgical treatment improved more in terms of Oswestry Disability Index, bodily pain, physical function, and low back pain bothersomeness scales. Risk of reoperation increased with age, having two or three moderate or severe stenotic levels, pain predominantly localized to the back, no physical therapy, the absence of neurogenic claudication, and greater leg pain scores. Risk of reoperation was not significantly affected by type of surgery performed, smoking, diabetes, obesity, longer duration of symptoms, or workman's compensation. Conclusion. Although intent-to-treat analysis failed to show significant differences in patients treated surgically, results of the as-treated analysis determined statically greater improvements in those patients with spondylolisthesis who were treated surgically as compared to those treated nonoperatively. Level of Evidence: 2

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Systematic Review of Outcomes Following 10-Year Mark of Spine Patient Outcomes Research Trial for Intervertebral Disc Herniation

Mini We summarized the 10-year outcomes of Spine Patient Outcomes Research Trial for intervertebral disc herniation through a systematic review. The observational cohort 2-year analysis and the as-treated analysis of the randomized control trial at 4 and 8 years showed statistically greater improvements in those patients who were treated surgically. Study Design. We performed a comprehensive search of Pubmed, MEDLINE, and EMBASE for English-language studies of all levels of evidence pertaining to SPORT, in accordance with Preferred Reported Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Objective. We aim to summarize the 10-year clinical outcomes of SPORT and its numerous follow-up studies for intervertebral disc herniation. Summary of Background Data. The Spine Patient Outcomes Research Trial (SPORT) was a landmark study. SPORT compared surgical and nonoperative management of the three most common spinal pathologies. Methods. Keywords utilized included: SPORT, spine patient outcomes research trial, disc herniation, and surgical outcomes. Results. The observational cohort analysis revealed statically greater improvement in primary outcomes at 3 months and 2 years in patients who had surgery, while analysis of the randomized control trial cohort failed to show a significant difference based on the intent-to-treat principle due to significant patient crossover. However, 4 year and 8 year as-treated analysis showed statistically greater improvements in those patients who were treated surgically. SPORT's subgroup analysis evaluated important factors when considering the treatment of IDH, including patient characteristics, level of herniation, duration of symptoms, recurrence of pain, presence of retrolistheiss, patient functional status, effects of previous treatment with epidural steroid injections and opioid medication, outcomes after incidental durotomy, MRI reader reliability, reoperation rates, and risk factors for reoperation. The clinical impact of SPORT was also investigated and included comparison of SPORT patients to NSQIP patients to determine generalizability, outcome differences in SPORT's surgical center sites, patient preferences, patient expectations, level of education, and effects of watching an evidence-based video. Conclusion. Ten years after its inception, SPORT has made strides in standardization and optimization of treatment for spinal pathologies. SPORT has provided clinicians with insight about outcomes of surgical and nonoperative treatment of IDH. Results showed significantly greater improvements in patients treated surgically. Level of Evidence: 3

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Systematic Review of Outcomes Following 10-year Mark of Spine Patient Outcomes Research Trial (SPORT) for Spinal Stenosis

Study Design. We performed a comprehensive search of Pubmed, MEDLINE, and EMBASE for all English-language studies of all levels of evidence pertaining to SPORT, in accordance with Preferred Reported Items for Systematic Reviews and Meta-analayses (PRISMA) guidelines. Objective. We aim to summarize the 10-year clinical outcomes of SPORT and its numerous follow-up studies for spinal stenosis. Summary of Background Data. The Spine Patient Outcomes Research Trial (SPORT) was a landmark randomized control trial including approximately 2,500 patients at 13 clinics across the country. SPORT compared surgical and nonoperative management of the three most common spinal pathologies. Methods. Keywords utilized in the literature search included: SPORT, spine patient outcomes research trial, spinal stenosis, and surgical outcomes. Results. Surgical intervention showed significantly greater improvement in pain and physical function scales from 6 weeks through 4 years. However, between 4 and 8 years, the difference between the two groups diminished, and the benefits in both groups stabilized. Secondary factors investigated showed that smoking was a confounding variable for treatment benefits and a positive sedimentation sign correlated with a greater surgical treatment effect. Obese patients were found to have higher rates of infection and reoperation and less improvement from baseline function. Risk factors for reoperation included duration of pretreatment symptoms for longer than 12 months, increased age, multiple levels of stenosis, predominant back pain, no physical therapy, greater leg pain, the use of antidepressants and no neurogenic claudication upon enrollment. Conclusion. Ten years after its inception, SPORT has made strides in standardization and optimization of treatment for spinal pathologies. SPORT has provided clinicians with insight about outcomes of surgical and nonoperative treatment of spinal stenosis. Results showed significantly greater improvement through 4 year follow up in those patients that received surgical treatment, however the difference between the surgical and nonsurgical groups diminished at 8 year follow up. Level of Evidence: 3

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Chronic Opioid Use Is Associated With Surgical Site Infection After Lumbar Fusion

Study Design. Retrospective, database review. Objective. The purpose of this study was to explore the association between preoperative opioid use and postoperative infection requiring operative wound washout in elective lumbar fusion patients. Summary of Background Data. Numerous peer-reviewed publications have conducted multivariate analyses of risk factors for surgical site infection. However, few have explored preoperative opioid use. Opioids have been widely prescribed preoperatively for pain management, but their effect on postsurgical infection is currently inconclusive. Methods. We retrospectively queried the PearlDiver national insurance claims database and included patients from 2007 to 2017 with a history of lumbar fusion. Any interbody fusion history designated exclusion. We stratified patients by single or multilevel procedures and conducted univariate analyses of previously documented infection risk factors, as well as our variable of interest, chronic preoperative opioid use. Variables associated (P <� 0.100) with the outcome measure of 90-day postoperative infection treated with operative irrigation and wound debridement were included in a multivariate analysis. Results. A total of 12,519 patients matched our inclusion criteria. Among the single-level cohort, only diabetes was observed to be associated with infection requiring operative wound washout and thus no subsequent regression was performed. For the cohort of patients who underwent multilevel fusion, chronic opioid use, diabetes, congestive heart failure, chronic obstructive pulmonary disease, and hypertension trended toward significance in the univariate analysis and were included in a logistic regression model. In the multivariate analysis, chronic opioid use (odds ratio [OR] = 1.435, P = 0.025), diabetes (OR = 1.591 P = 0.003), and congestive heart failure (OR = 1.929, P = 0.003) were identified as independent risk factors for infection requiring operative wound washout. Conclusion. In this analysis, preoperative opioid use was significantly associated with infection requiring operative wound washout in multilevel lumbar fusion patients. Limiting opioid consumption may have the benefit of reducing the risk of infection following spine surgery. Level of Evidence: 3

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A Secondary Analysis from a Randomized Trial on the Effect of Plasma Tetrahydrocannabinol Levels on Pain Reduction in Painful Diabetic Peripheral Neuropathy

Preclinical studies note that a major cannabinoid receptor, CB1, is expressed in pain modulating regions, suggesting that cannabinoids binding to the CB1 receptor may modulate nociceptive transmission.13 The majority of work in this area has focused on the partial CB1 agonist delta-9-tetrahydrocannabinol (THC). Indeed, there is recent evidence showing nociceptive benefits of inhaled cannabis containing THC as low as 1.3% [26, but other work suggests analgesia occurs only with higher potencies (eg, 9.4%;21).

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Orofacial quantitative sensory testing: Current evidence and future perspectives

Abstract

Background and objective

Orofacial quantitative sensory testing (QST) is an increasingly valuable psychophysical tool for evaluating neurosensory disorders of the orofacial region. Here, we aimed to evaluate the current evidence regarding this testing method and to discuss its future clinical potential.

Data treatment

We conducted a literature search in Medline, Embase and Scopus for English‐language articles published between 1990 and 2019. The utilized search terms included QST, quantitative, sensory testing and neurosensory, which were combined using the AND operator with the terms facial, orofacial, trigeminal, intraoral and oral.

Results

Our findings highlighted many methods for conducting QST—including method of levels, method of limits and mapping. Potential stimuli also vary, and can include mechanical or thermal stimulation, vibration or pinprick stimuli. Orofacial QST may be helpful in revealing disease pathways and can be used for patient stratification to validate the use of neurosensory profile‐specific treatment options. QST is reportedly reliable in longitudinal studies and is thus a candidate for measuring changes over time. One disadvantage of QST is the substantial time required; however, further methodological refinements and the combination of partial aspects of the full QST battery with other tests and imaging methods should result in improvement.

Conclusions

Overall, orofacial QST is a reliable testing method for diagnosing pathological neurosensory conditions and assessing normal neurosensory function. Despite the remaining challenges that hinder the use of QST for everyday clinical decisions and clinical trials, we expect that future improvements will allow its implementation in routine practice.

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Generalizability of harm and pain expectations after exposure in chronic low back pain patients

Abstract

Background

Exposure treatments are shown to be effective in reducing pain‐related fear and the perceived harmfulness of physical activities. However, due to the fragility of extinction its stability is questionable. We investigated the generalizability of exposure effects in chronic low back pain (CLBP) patients by integrating a behavioral test in the context of an intervention study.

Methods

The study is an additional analysis of a randomized controlled trial investigating the efficacy of exposure in vivo. A total of 67 CLBP patients were randomly assigned to one of the three groups: Exposure‐short (EXP‐S); exposure‐long (EXP‐L) and cognitive behavioral therapy (CBT). Participants rated the expected harmfulness of daily activities (Photograph Series of Daily Activities) before and after therapy. Post‐treatment participants were confronted with an individually tailored, threatening movement in a new context. Harm and pain expectations before the exposure were compared to the actual experience after exposure.

Results

We found that EXP leads to more strongly reduced harm expectations (F (2,50) = 11.37, p  < .001, η² = 0.31) compared to CBT, regardless of the duration of EXP. After therapy, patients expected less harm (F (2,50) = 3.61, p =  .034, η² = 0.13) but not less pain (F (2,50) = 3.61, p =  .034, η² = 0.13) when confronted with a novel movement.

Conclusions

Exposure successfully reduced harm but not pain expectations in patients with CLBP. Further, preliminary results showed that these specific exposure effects were generalized to a novel activity in a different context outside therapy.

Significance

This study investigats the generalizability and stability of exposure effects in patients with CLBP by combining a behavioral test with an intervention study. We found strong and stable effects on harm expectations but not on pain expectations. Results show promising preliminary evidence that reduced harm expectations can be generalized to a novel threatening activity in a new context. Clinical implications of our findings suggest that exposure treatment would benefit from a clear focus on harm expectations.

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The N2pc component as a neural index of early attention allocation among adults with chronic musculoskeletal pain

Abstract

Recent evidence from event‐related potentials (ERPs) has identified N2 posterior contralateral (pc) amplitudes as a neural marker of early attention allocation. The N2pc has been used to evaluate attention biases (ABs) in samples with anxiety‐based problems, but its utility has yet to be considered among persons with chronic pain, another group theorized to display ABs that perpetuate their difficulties. To address this gap, we assessed N2pc responses of adults with chronic pain (N  = 70) and pain‐free controls (N  = 70) during a dot‐probe task comprising painful‐neutral and happy‐neutral facial expression image pairs. Analyses indicated that (1) larger N2pc amplitudes were elicited by both painful and happy expressions compared to complementary neutral expressions in each sample, (2) the chronic pain sample displayed larger N2pc amplitudes during exposure to both painful and happy expressions than controls did and (3) no group differences were evident for N2pc latencies. Overall N2pc results reflected general biases in early allocation of attention towards affectively valenced expressions rather than pain‐specific ABs among chronic pain cohorts.

Significance

Although numerous researchers have examined pain‐related attention biases, these data are based exclusively upon behavioural measures of attention such as reaction times and eye movements. Drawing from relevant event‐related potentials research, this study is the first to evaluate and identify differences in orienting of attention between adults with chronic pain and pain‐free controls based on N2 posterior contralateral (pc) amplitudes which provide a neural index of early attention allocation.

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Disentangling trait versus state characteristics of the Pain Catastrophizing Scale and the PHQ‐8 Depression Scale

Abstract

Research on the role of trait versus state characteristics of a variety of measures among persons experiencing pain has been a focus for the past few decades. Studying the trait versus state nature of the Pain Catastrophizing Scale (PCS) and the Patient Health Questionnaire (PHQ‐8) depression scale would be highly informative given both are commonly measured in pain populations and neither scale has been studied for trait/state contributions..

The PHQ‐8 and PCS were obtained on persons undergoing knee arthroplasty at baseline, 2‐, 6‐, and 12‐months post‐surgery (N=402). The multitrait generalization of the latent trait‐state model was used to partition trait and state variability in PCS and PHQ‐8 item responses simultaneously. A set of variables were used to predict trait catastrophizing and trait depression.

For total scores, the latent traits and latent states explain 63.2% (trait=43.2%; state=20.0%) and 50.2% (trait=29.4%; state=20.8%) of the variability in PCS and PHQ‐8, respectively. Patients with a high number of bodily pain sites, high levels of anxiety, young patients, and African American patients had high levels of trait catastrophizing and trait depression. The PCS and the PHQ‐8 consist of both enduring trait and dynamic state characteristics, with trait characteristics dominating for both measures.

Clinicians and researchers using these scales should not assume the obtained measurements solely reflect either trait or state‐based characteristics.

Clinicians and researchers using the PCS or PHQ‐8 scales are measuring both state and trait characteristics and not just trait or state‐based characteristics.

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The roles of race, sex and cognitions in response to experimental pain

Abstract

Background

This study reports a multivariate test of sex and race differences in experimental pain, and the degree to which these differences could be uniquely attributable to three levels of cognition: primary appraisals (threat, challenge), secondary appraisals (pain catastrophizing) and/or cognitive processes (mindful observing, non‐reactivity). Both the predictive and mediator role of the cognitive variables was of interest.

Methods

The study employed a cross‐sectional experimental design, with the cold pressor task employed as the pain stimulus. The total sample included N  = 355 healthy adults (67% female, 33% male; 70% Caucasian, 30% Asian).

Results

Significant sex and race differences on pain tolerance were found, with females and racial minorities reporting less pain tolerance (p s < 0.001). Males reported significantly higher challenge appraisals and non‐reactivity, and lower pain catastrophizing than females; Asians reported significantly higher threat appraisals and pain catastrophizing than Caucasians. In multivariate analyses, challenge appraisals and non‐reactivity emerged as the strongest predictors of pain tolerance. Furthermore, challenge appraisals mediated the sex‐pain tolerance association (p  = .017).

Conclusions

This study showed that race and sex differences, at least in part, may be accounted for by differences in pain‐related cognitions.

Significance

The three levels of cognition investigated in this research represent changeable, important processes for potentially mitigating the impact of pain in vulnerable groups.

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Identifying pain perceptual biases related to fear of pain and threat in a pain‐free sample

Abstract

Background

The association between fear of pain (FOP) and pain intensity has remained unclear. This study aimed to examine whether highly pain‐fearful participants showed pain perceptual biases to general painful stimulus or to specific threatening painful stimulus.

Methods

Fifty‐nine undergraduates were recruited into low (n  = 30) and high (n  = 29) FOP groups and completed a threatening pain perception task with two tasks. Task 1 assessed pain perceptual biases by calculating the percentage of near‐threshold pain stimulus judged as painful and assessing the average pain intensity ratings to those painful stimuli. Task 2 assessed pain perceptual biases by measuring pain ratings to each single threshold (low intensity) and twice‐threshold (high intensity) pain stimulus.

Results

Results from task 1 indicated that higher FOP levels were associated with higher pain sensitivity when pain was appraised as a threat, reflected as high FOP group reporting higher pain intensity to those stimuli judged as painful in high threat condition than in low threat condition. Consistently, results from task 2 observed that when noxious stimulus intensity increased to threshold pain and twice threshold pain levels, high FOP group also generally reported higher pain intensity in high threat condition than in low threat condition. However, for both tasks, no such threat level differences were observed in low FOP group.

Conclusions

The current research emphasized that participants with higher FOP level showed pain perceptual biases to specific threatening painful stimulus. Threat appraisal of pain played a key role in the positive association between pain‐related fear and pain perceptual biases.

Significance

The findings highlight the modulatory influence of threat appraisal of pain in the positive association between pain‐related fear and pain perceptual biases.

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GABAergic modulation of secondary hyperalgesia: A randomized controlled 4‐way crossover trial with the α2‐subunit preferring GABA positive allosteric modulator, N‐desmethyl‐clobazam in healthy volunteers

Abstract

The antihyperalgesic and sedative effects of the α2‐subunit preferring GABA_A positive allosteric modulator (GAM), N ‐desmethyl‐clobazam (NDMC), 20 and 60 mg, were assessed in a randomized, placebo and active‐controlled (clonazepam 1,5 mg), 4‐way crossover study, in healthy volunteers, using the ultraviolet B‐induced experimental pain model. Single (20, 40, 60 mg) and repeated doses (20 mg over 15 days) of NDMC pharmacokinetics were evaluated. Thirty‐two subjects participated in the study. Primary outcome parameter was maximal change in the area of cutaneous UVB irradiation‐induced secondary hyperalgesia (ASH). ASH decreased under all treatments. Mean (SD ) relative change was 79 (22)%, 83 (24)%, 77 (30)% and 92 (16)% for placebo, NDMC20, NDMC60 and clonazepam, respectively. Neither absolute change nor relative change in ASH was significantly different between NDMC60 and placebo (mean difference = 2.3 cm² [95% CI 4.0–8.5], p  = .462 and 0.4% [−11.9 to 12.6], p  = .952, respectively). An overall treatment effect was found on level of sedation. Compared to placebo, sedation was higher under clonazepam (mean difference = 39 mm [30–49] on a visual analogue scale, p  < .001) while NDMC was free of sedative effect. NDMC pharmacokinetics after single doses showed poor absorption, but was linear. Steady‐state plasma concentrations of NDMC20 were attained within 14 days, with low between‐subjects variability. Mean steady‐state concentration (C _S‐S, SD ) reached 209 (22) ng/ml. NDMC absence of sedative effect and its overall well‐characterized safety coming from years of utilization as a metabolite from clobazam, raise the prospect of dose escalating trials in patients to quantify its clinical utility.

Significance

This article, presenting the Phase I data of the new antihyperalgesic compound, α2‐subunit GABA_A positive allosteric modulator, N ‐desmethyl‐clobazam (NDMC) is exploring the modulation of a new target in the treatment of neuropathic pain. Based on these results and on its preclinical properties NDMC would qualify as a good tool compound to seek confirmation of the clinical utility of selective GABA allosteric modulators in neuropathic pain patients.

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Pain modulation by illusory body rotation: A new way to disclose the interaction between the vestibular system and pain processing

Abstract

Background

Clinical and experimental evidence advocates a structural and functional link between the vestibular and other sensory systems. For instance, visuo‐vestibular and vestibular–somatosensory interactions have been widely reported. However, whether visual inputs carrying vestibular information can modulate pain is not yet clear. Recent evidence using natural vestibular stimulation or moving visual stimuli, points at an unspecific effect of distraction.

Methods

By using immersive virtual reality (VR), we created a new way to prompt the vestibular system through the vision of static visual cues, studying the possible interaction with pain. Twenty‐four healthy participants were visually immersed in a virtual room which could appear with five different degrees of rotation in the sagittal axis, either towards the right, left or with no rotation. Participants' heat pain thresholds and subjective reports of perceived body rotation, sense of presence and attention were measured.

Results

‘Being’ in a tilted room induced the sensation of body rotation in our participants, even though they were always in an upright position. We also found that rotating the visual scenario can modulate the participants' pain thresholds, determining a significant increase when a left tilt is displayed. In addition, a positive correlation between the perceived body midline rotation and pain threshold was found when the virtual room was titled 15 degrees toward the left. Importantly, all VR conditions were found to be equally distractive.

Conclusions

Vestibular information present in static visual cues can modulate experimentally‐induced acute pain according to a side‐dependent manner and bypassing supramodal attentional mechanisms. These findings may help refining pain management approaches based on multimodal stimulation.

Significance

This study explored how the visualization of static environments in immersive virtual reality can lead to pain threshold modulation through the activation of the vestibular system. Immersion into rotated virtual environments led to the illusory sensation of body rotation, and this sensation was found to be related with a modulation of pain perception. Possible analgesic effects due to distraction could be ruled out. These results expand our current knowledge about how the visual, vestibular and somatosensory (pain) systems interact. These findings may influence future pain treatment strategies based on multisensory stimulation.

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Anodal transcranial direct current stimulation over the primary motor cortex attenuates capsaicin‐induced dynamic mechanical allodynia and mechanical pain sensitivity in humans

Abstract

Background

Anodal transcranial direct current stimulation over the primary cortex has been shown to activate regions of the brain involved in the descending modulation of pain sensitivity. However, more research is required to dissect the spinal cord analgesic mechanisms associated with the development of central sensitization.

Methods

In this randomized, double blind, crossover study 12 healthy participants had baseline mechanical stimulus response (S/R) functions measured before and after the development of capsaicin‐induced ongoing pain sensitivity. The effects of 20 min of either real or sham transcranial direct current stimulation (tDCS, 2 mA) over the primary motor cortex on dynamic mechanical allodynia (DMA) and mechanical pain sensitivity (MPS) were then investigated.

Results

Topical application of capsaicin resulted in an increase in area under the pain ratings curve for both DMA (p  < .01) and MPS (p  < .01). The effects of tDCS on the area under the curve ratio (i.e. post‐/pre‐treatment) revealed significant analgesic effects over DMA (p  < .05) and MPS (p  < .05) when compared with sham.

Conclusions

This study demonstrates that anodal tDCS over the primary motor cortex can reduce both dynamic and static forms of mechanical pain sensitivity associated with the development of DMA and MPS, respectively. The use of tDCS may provide a novel mechanism‐driven therapy in chronic pain patients with altered mechanical S/R functions.

Significance

This research shows new evidence that anodal tDCS over the primary motor cortex can reduce dynamic and static forms of mechanical pain sensitivity in the capsaicin model of ongoing pain. By using this approach, it may be possible to provide mechanism‐driven analgesia in chronic pain patients who have dynamic mechanical allodynia and/or secondary mechanical hyperalgesia.

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Minocycline reduces experimental muscle hyperalgesia induced by repeated nerve growth factor injections in humans: A placebo‐controlled double‐blind drug‐crossover study

Abstract

Background

Hyperalgesia is a heightened pain response to a noxious stimulus and is a hallmark of many common neuropathic and chronic pain conditions. In a double‐blind placebo‐controlled drug‐crossover trial, the effects of concomitant and delayed minocycline treatment on the initiation and resolution of muscle hyperalgesia were tested.

Methods

An initial cohort (n  = 10) received repeated injections (5 µg: days 0, 2 and 4) of nerve growth factor (NGF) in the flexor carpi ulnaris muscle of the forearm and pressure pain thresholds were collected at day 0 (control), day 7 (peak) and day 14 (recovery). A second cohort (n  = 18) underwent an identical procedure, however, half received a placebo between days 0 and 7 before switching to minocycline from days 7 to 14 (P1/M2), while the remaining subjects received minocycline (day 0: 200mg then 100mg b.i.d. for 7 days) before switching to placebo (M1/P2).

Results

The initial cohort exhibited a diffuse muscular pain hypersensitivity with a decrease in pressure pain thresholds at day 7 before a partial return to normalcy at day 14. The P1/M2 treatment group exhibited an identical peak in hypersensitivity at day 7, however, after switching to minocycline in week 2 showed a significant reduction in muscle hyperalgesia compared with the initial cohort at day 14. The M1/P2 treatment group had significantly less (~43%) hyperalgesia at day 7 compared with the other groups.

Conclusions

The study indicates that the administration of minocycline can reduce experimentally induced muscle pain regardless of the time of administration.

Significance

In a double‐blind placebo‐controlled drug‐crossover study, the common antibiotic minocycline was found to reduce the muscle hyperalgesia induced by intramuscular injection of nerve growth factor. The results of the study showed that both concomitant (pre‐emptive) and delayed administration of minocycline can ameliorate the onset and facilitate the resolution of experimentally induced muscle hyperalgesia.

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Strong opioid consumption and its correlation with pain intensity and inpatient complexity. A 6‐year analysis in a tertiary hospital

Abstract

Background

An increasing trend in opioid consumption has been observed worldwide in last decades. However, data related to opioid utilization in hospital settings are scarce. The aim of this study was to determine the evolution of use of strong opioids and pain intensity in a tertiary hospital during 6 years.

Methods

Consumption of strong opioid analgesics used at the hospital at any time between 2012 and 2017 was collected. Data were expressed on oral morphine equivalents (OMEs) per 100 bed‐days. Pain intensity was measured by the numerical rating scale (NRS) and the percentage of patients who experienced a NRS value ≥3 and ≥7 were calculated. Case mix index (CMI) was also collected. Data were quantified in medical and surgical area separately.

Results

Consumption of opioids varied from 812.4 to 1,038.8 OMEs/100 bed‐days and from 967.3 to 1,023.7 in medical and surgical area. The percentage of patients that experienced a value of NRS ≥ 3 and ≥7 in medical area increased from 24.2% and 5.5% to 31.7% and 7.5%, (p  = .038, p  = .040). It was observed a correlation between the percentage of patients that experienced a NRS ≥ 7 in two consecutive determinations and opioid prescription in medical area (p  = .039).The CMI increased from 1.05 and 0.91 to 1.18 and 1.04 in medical and surgical area (p  = .020, p  = .004).

Conclusions

Consumption of strong opioids has remained stable, both in medical and surgical area, during last years. A correlation between prescription of opioids and pain intensity is observed in case of repeated and severe pain in medical departments.

Significance

This study shows a stable consumption of strong opioid analgesics in a hospital setting in contrast to what appears to be the extrahospitalary trend during last years. The association between consumption of opioids and pain intensity seems to indicate a good control of pain in the clinical setting, showing a significant correlation between the consumption of opioids and repeated and severe pain in medical departments.

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Lack of relationship between epidermal denervation by capsaicin and incisional pain behaviours: A laser scanning confocal microscopy study in rats

Abstract

Background

Spontaneous pain after surgical incision is a significant problem for most post‐operative patients. Pain management that relies on opioids is hindered by numerous side effects, fuelling interest in non‐opioid alternatives and multimodal approaches. Subcutaneous capsaicin infiltration has shown potential for reducing post‐operative pain, but there are unanswered questions about safety and possible side effects. In adult rats, we characterized the analgesic effects of pre‐operative capsaicin infiltration into the skin prior to plantar incision and assessed wound healing and epidermal innervation.

Methods

The surgical site on the plantar surface of the rat hind paw was infiltrated with 1% capsaicin or vehicle 30 min or 1 week prior to surgical incision. Spontaneous and evoked pain behaviours were assessed. Digital images of incised hind paws were used to quantify the surface area of the wound after suture removal. Epidermal nerve fibre quantification was performed on peri‐incisional tissue biopsies.

Results

Intraplantar administration of capsaicin 30 min before surgical incision attenuated spontaneous pain behaviours, heat hyperalgesia, epidermal innervation, but it did not alter the rate of wound healing. Incisional pain hypersensitivity returned to baseline 2 weeks post‐incision, at a time when no recovery of epidermal innervation is observed.

Conclusions

Subcutaneous infiltration of capsaicin prior to surgical incision attenuated incision‐induced pain behaviours and reduced epidermal innervation around the incision site. The long‐lasting epidermal denervation by capsaicin had no impact in the rate of wound healing and recovery from pain behaviours.

Significance

Pre‐operative capsaicin infiltration attenuated spontaneous pain‐like behaviour and prevented the development of heat hyperalgesia following plantar skin incision. While capsaicin caused long‐lasting and widespread loss of epidermal and dermal nerve fibres, there was no measurable impact on the rate of wound healing. Pre‐ or intra‐operative infiltration of capsaicin into surgical sites could act as a safe prophylactic for post‐operative pain and reduce the need for opioids during recovery.

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Pain thresholds and intensities of CRPS type I and neuropathic pain in respect to sex

Abstract

Background and Aims

Healthy women have generally been found to have increased experimental pain perception and chronic pain has a higher prevalence in female as compared to male patients. However, no study has investigated whether pain intensity and pain perception thresholds are distinct or similar between sexes within various chronic pain entities. We investigated whether average pain intensities and pain thresholds assessed using quantitative sensory testing (QST) differed between women and men suffering from three distinct chronic pain conditions: Complex Regional Pain Syndrome (CRPS type I), peripheral nerve injury (PNI) or polyneuropathy (PNP), as compared to paired healthy volunteers.

Methods

QST data of 1,252 patients (669 female, 583 male) with PNI (n  = 342), PNP (n  = 571) or CRPS (n  = 339), and average pain intensity reports from previously published studies were included. Absolute and z ‐values (adjusted for age and body region) of cold, heat, pressure (PPT) and pinprick pain thresholds were compared in generalized linear models with aetiology, duration of underlying pain disease and average pain intensity as fixed effects.

Results

Average pain intensity during the past four weeks did not differ between women and men, in both mean and range. In women absolute pain thresholds for cold, heat and pinprick were lower than in males across all diagnoses (p  < .05). However, after z ‐transformation these differences disappeared except for PPT in CRPS (p  = .001).

Discussion

Pain thresholds in patients show only minor sex differences. However, these differences mimic those observed in healthy subjects and do not seem to be linked to specific pathophysiological processes.

Significance

Female healthy participants and female patients with neuropathic pain conditions or CRPS I report lower pain thresholds compared to males, but pain intensity is similar and there is no sex difference in the extent to which the thresholds are altered in neuropathic pain or CRPS. Thus, the sex differences observed in various chronic pain conditions mimic those obtained in healthy participants, indicating that these differences are not linked to specific pathophysiological processes and are of minor clinical relevance.

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Acute pain measured with the modified Bernese Pain Scale for Neonates is influenced by individual contextual factors

Abstract

Background

Individual contextual factors like gestational age (GA) or previous painful experiences have an influence on neonates’ pain responses and may lead to inaccurate pain assessment when not appropriately considered.

Objectives

We set out to determine the influence of individual contextual factors on variability in pain response in neonates, measured with the modified Bernese Pain Scale for Neonates (BPSN), and, if necessary, to incorporate relevant individual factors into a revised version of the BPSN.

Methods

We videotaped 154 full‐term and preterm neonates of different GAs during 1–5 capillary heel sticks in their first 14 days of life. For each heel stick, we produced three video sequences: baseline, heel stick, and recovery. The randomized sequences were rated on the BPSN by five blinded nurses. Individual contextual factors were retrospectively extracted from patient charts and from the video recordings. We analysed the data in single and multiple linear mixed models.

Results

Premature birth (b  = −0.721), caffeine (b  = −0.302), and the behavioural states quiet and awake (b  = −0.283), active and asleep (b  = −0.158), and quiet and asleep (b  = −0.498) were associated with changes in behavioural pain scores. Premature birth (b  = −0.232), mechanical ventilation (b  = −0.196), and duration of the heel stick procedure (b  = 0.0004) were associated with changes in physiological pain scores. Premature birth (b  = −0.907), Caffeine (b  = −0.402), the behavioural states quiet and awake (b  = −0.274), and quiet and asleep (b  = −0.459), and duration of the heel stick procedure (b  = 0.001) were associated with changes in the modified BPSN total scores.

Conclusions

Postmenstrual age, behavioural state, caffeine, and ventilation status have an influence on neonates’ pain response and should be incorporated in the revised BPSN to enhance clinical pain assessment in neonates with different GAs.

Significance

We identified individual contextual factors associated with dampened pain response in neonates and will incorporate them into a revised version of the Bernese Pain Scale for Neonates to provide clinicians with a tool they can use to more accurately assess and manage pain in this vulnerable population.

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Small fibre pathology in chronic whiplash‐associated disorder: A cross‐sectional study

Abstract

Background

Mechanisms underpinning ongoing symptoms in chronic whiplash associated‐disorder (WAD) are not well understood. People with chronic WAD can exhibit sensory dysfunction consistent with small nerve fibre pathology, including thermal hypoaesthesia and hyperalgesia. This study investigated small fibre structure and function in chronic WAD.

Methods

Twenty‐four people with chronic WAD (median [IQR] age 49 [15] years, 16 females) and 24 pain‐free controls (50 [17] years, 16 females) were recruited. Intraepidermal nerve fibre density (IENFD) and dermal innervation were assessed by skin biopsy. This was performed at (a) the lateral index finger on the primary side of pain and (b) superior to the lateral malleolus on the contralateral side. Quantitative sensory testing was performed over the hand.

Results

The WAD group exhibited lower IENFD at the finger (WAD: median [IQR] 4.5 [4.9] fibres/mm; control 7.3 [3.9]; p  = .010), but not the ankle (WAD: mean [SD ] 7.3 [3.7] fibres/mm; control 9.3 [3.8]; p  = .09). Dermal innervation was lower in the WAD group at the finger (WAD: median [IQR] 3.7 [2.8] nerve bundles/mm²; controls: 4.9 [2.1]; p  = .017) but not the ankle (WAD: median [IQR] 2.1 [1.9] nerve bundles/mm²; controls: 1.8 [1.8]; p  = .70). In the WAD group, hand thermal and light touch detection were impaired, and heat pain thresholds were lowered (p  ≤ .037).

Conclusions

Findings suggest small fibre structural and functional deficits in chronic WAD, implicating potential involvement of small fibre pathology.

Significance

Our study found decreased intraepidermal nerve fibre density, reduced dermal innervation, thermal hypoaesthesia and hypersensitivity in people with chronic WAD, suggestive of small fibre pathology. This observation of peripheral nervous system pathology in chronic whiplash provides novel insights on mechanisms underpinning symptoms and challenges commonly held beliefs regarding this condition.

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Appropriate referral and selection of patients with chronic pain for spinal cord stimulation: European consensus recommendations and e‐health tool

Abstract

Background

Spinal cord stimulation (SCS) is an established treatment for chronic neuropathic, neuropathic‐like and ischaemic pain. However, the heterogeneity of patients in daily clinical practice makes it often challenging to determine which patients are eligible for this treatment, resulting in undesirable practice variations. This study aimed to establish patient‐specific recommendations for referral and selection of SCS in chronic pain.

Methods

A multidisciplinary European panel used the RAND/UCLA Appropriateness Method (RUAM) to assess the appropriateness of (referral for) SCS for 386 clinical scenarios in four pain areas: chronic low back pain and/or leg pain, complex regional pain syndrome, neuropathic pain syndromes and ischaemic pain syndromes. In addition, the panel identified a set of psychosocial factors that are relevant to the decision for SCS treatment.

Results

Appropriateness of SCS was strongly determined by the neuropathic or neuropathic‐like pain component, location and spread of pain, anatomic abnormalities and previous response to therapies targeting pain processing (e.g. nerve block). Psychosocial factors considered relevant for SCS selection were as follows: lack of engagement, dysfunctional coping, unrealistic expectations, inadequate daily activity level, problematic social support, secondary gain, psychological distress and unwillingness to reduce high‐dose opioids. An educational e‐health tool was developed that combines clinical and psychosocial factors into an advice on referral/selection for SCS.

Conclusions

The RUAM was useful to establish a consensus on patient‐specific criteria for referral/selection for SCS in chronic pain. The e‐health tool may help physicians learn to apply an integrated approach of clinical and psychosocial factors.

Significance

Determining the eligibility of SCS in patients with chronic pain requires careful consideration of a variety of clinical and psychosocial factors. Using a systematic approach to combine evidence from clinical studies and expert opinion, a multidisciplinary European expert panel developed detailed recommendations to support appropriate referral and selection for SCS in chronic pain. These recommendations are available as an educational e‐health tool (https://www.scstool.org/).

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Psychological and pain profiles in persons with patellofemoral pain as the primary symptom

Abstract

Background

Patellofemoral pain (PFP) is defined biomechanically, but is characterized by features that fit poorly within nociceptive pain. Mechanisms associated with central sensitization may explain why, for some, symptoms appear nociplastic. This study compares psychological and somatosensory characteristics between those with persistent PFP and controls.

Methods

A total of 150 adults with PFP were compared to 61 controls. All participants completed a survey evaluating participant characteristics, PFP‐related constructs and psychological factors: anxiety, depression, pain catastrophizing, kinesiophobia, pain self‐efficacy. Participants also attended a session of somatosensory testing, which included knee and elbow thermal and mechanical detection and pain thresholds, conditioned pain modulation (CPM), and temporal summation of pain (TSP). Differences were evaluated using analysis of covariance (sex as covariate). Multivariate backward stepwise linear regression examined how psychological and somatosensory variables relate to PFP (knee injury and osteoarthritis outcome score‐patellofemoral [KOOS‐PF]).

Results

The PFP group had multimodal reduced pain thresholds at the knee and elbow (standardized mean difference [SMD], p : 0.86–1.2, <.001), reduced mechanical detection at the elbow (0.43, .01) and higher TSP (0.41, .01). CPM was not different. Psychological features demonstrated small effects (0.47–0.59, 0.01–0.04). The PFP group had a 55% (95% CI: 0.47–0.62) risk of kinesiophobia and an 11% (0.06–0.15) reduced pain self‐efficacy risk. Kinesiophobia, knee pressure pain threshold, pain self‐efficacy and pain catastrophizing explained 40% of KOOS‐PF variance (p  = <.001).

Conclusions

Widespread hyperalgesia and evidence of symptom amplification may reflect nociplastic pain. Clinicians should be aware that kinesiophobia and the nociplastic pain may characterize the condition.

Significance

(a) Individuals with PFP have widespread reduced pain thresholds to pressure and thermal stimuli. (b) Mechanically induced pain is likely amplified in those with PFP. (c) Pain‐related fear is highly prevalent and helps explain PFP‐related disability.

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Necessary components of psychological treatment in pain management programs: A Delphi study

Abstract

Background

There are various approaches to the psychological management of chronic pain and it is difficult to know which components of psychological therapies are necessary or desirable for the effective management of chronic pain.

Methods

We conducted a Delphi study to develop a consensus on the necessary and desirable psychological intervention strategies for chronic pain management. First, we identified 49 components of treatments that had been used in a treatment evaluated in a randomized controlled trial (RCT) through a systematic review. In the first round of the Delphi process, 23 (32% of 72) authors who had completed RCTs in chronic pain took part. In round 2, these experts plus clinicians working at pain management programs around Australia were invited to take part, and 44 experts completed the study.

Results

The panel agreed that it was necessary to include psycho‐education, particularly about pain mechanisms and the role of thoughts in maintaining pain. Cognitive approaches were deemed necessary, although the panel did not specify one particular strategy. Finally, approaches to increase activity were deemed necessary, including the strategies of pacing, goal setting and graded exposure. Relaxation training and relapse prevention were also deemed necessary.

Conclusions

There was a consensus that there were many desirable strategies to include in psychological chronic pain management approaches, but that treatments should include psycho‐education, approaches to increase activity and cognitive approaches as a first line of intervention. Where patients fail to benefit from these approaches, experts identified other desirable strategies that could be utilized.

Significance

The expert consensus indicated that psycho‐education, strategies to increase activity and cognitive therapy strategies were necessary for effective psychological treatment of patients with chronic pain. While other strategies were deemed desirable, psychological treatments should include at least those three components.

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Commentary on “Effectiveness of motor imagery and action observation training on musculoskeletal pain intensity: A systematic review and meta‐analysis” by Suso‐Martí et al.

European Journal of Pain, Volume 24, Issue 6, Page 1003-1004, July 2020.

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Breakthrough pain is not a fixed fraction of constant cancer pain

European Journal of Pain, Volume 24, Issue 6, Page 999-1000, July 2020.

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Necessary components of psychological treatment for chronic pain: More packages for groups or process‐based therapy for individuals?

European Journal of Pain, Volume 24, Issue 6, Page 1001-1002, July 2020.

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Psychosocial predictors of acute and chronic pain in adolescents undergoing major musculoskeletal surgery

Acute and chronic pain are common experiences after major surgery. Compared to younger children, adolescents are at elevated risk for both acute and chronic pain following surgery.22,46 Negative consequences include delayed recovery and impaired health-related quality of life (HRQOL),45,47,49 making effective pain management a high priority. Despite high prevalence of acute pain (>50%)37,45 and chronic pain (20%),19,26,38,47,53 risk factors for postsurgical pain in youth remain largely unknown.51 Given the influence of a large range of biopsychosocial factors on development of chronic pain,14 it is possible that a different set of risk factors may predict acute versus chronic pain.

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Once an avoider always an avoider? Return of pain-related avoidance after extinction with response prevention

Contemporary theories emphasize the pivotal role of avoidance behaviour in the development and chronification of pain-related disability.24,43,44 Avoiding pain-related stimuli (e.g. movements) is adaptive when pain is acute, but persisting avoidance leads to functional disability through the disengagement from daily-life activities.43,44 Further, it prevents the disconfirmation of erroneous catastrophic beliefs21 and, paradoxically, maintains pain-related fear by conveying the message that a threat really exists.

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The impact of chronic pain on patients and spouses: Consequences on occupational status, distribution of household chores and caregiving burden

Abstract

Background

Informal caregiving by spouses has become frequent in chronic pain settings. However, the impact of pain on occupational, functional, and health outcomes in spouses has not been systematically investigated.

Aims

The goal of the present study was to examine the impact of pain on both patient and spousal outcomes. Methods

In the present study, the impact of chronic pain on 114 heterosexual dyads was explored (patients: 59% females, average age = 57.81 years, SD = 11.85; spouses: 41% females, average age = 57.32 years, SD = 12.15).

Results

Overall, both patients and spouses reported important consequences of pain on outcomes, including occupational status distribution of household chores and marital satisfaction). Almost 52% of spouses indicated a high‐to‐severe burden. A multivariate model with spouse and patient factors accounted for 37.8% of the variance of this burden. In the model, patient disability (β = 0.36, p = .002), spouses’ change in occupational status (β = 0.26, p = .002), and spousal perception of marital adjustment (β = ‐0.36, p < .001) were uniquely associated with burden.

Conclusions

The results indicate that the impact of chronic pain should be evaluated both for patients and spouses and point to patient and spouse factors that might contribute to spousal burden, which might help guide family interventions in a more effective manner.

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Conditional expression of HIV‐1 Tat in the mouse alters the onset and progression of tonic, inflammatory, and neuropathic hypersensitivity in a sex‐dependent manner

Abstract

At least one third of HIV‐1‐afflicted individuals experience peripheral neuropathy. Although the underlying mechanisms are not known, they may involve neurotoxic HIV‐1 proteins. We assessed the influence of the neurotoxic HIV‐1 regulatory protein, Tat, on inflammatory and neuropathic nociceptive behaviors using transgenic male and female transgenic mice that conditionally expressed (or did not express) HIV‐1 Tat_1‐86 in glial fibrillary acidic protein‐expressing glia in the central and peripheral nervous systems. Tat induction significantly attenuated the time spent paw‐licking following formalin injection (2.5%, i.pl.) in both male and female mice. However, significant sex differences were observed in the onset and magnitude of inflammation and sensory sensitivity following complete Freund’s adjuvant (CFA) injection (10%, i.pl.) after Tat activation. Unlike female mice, males showed a significant attenuation of paw swelling and an absence of mechanical/thermal hypersensitivity in response to CFA after Tat induction. Male Tat(+) mice also showed accelerated recovery from chronic constrictive nerve injury (CCI)‐induced neuropathic mechanical and thermal hypersensitivity compared to female Tat(+) mice. Morphine (3.2 mg/kg) fully reversed CCI‐induced mechanical hypersensitivity in female Tat(−) mice, but not in Tat(+) females. The ability of Tat to decrease edema, paw swelling, and limit allodynia suggest a sequela of events in which Tat‐induced functional deficits precede the onset of mechanical hypersensitivity. Moreover, HIV‐1 Tat attenuated responses to inflammatory and neuropathic insults in a sex‐dependent manner. HIV‐1 Tat appears to directly contribute to HIV sensory neuropathy and reveals sex differences in HIV responsiveness and/or the underlying peripheral neuroinflammatory and nociceptive mechanisms.

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Sifting the wheat from the chaff? Evidence for the existence of an asymmetric fibromyalgia phenotype

Abstract

Background

The different phenotypic presentations of fibromyalgia (FM) have been infrequently studied and may have diagnostic and therapeutic implications. The aim of this study was to explore differences between FM patients with classical symmetric (s‐FM) presentation and FM patients with marked asymmetric (a‐FM) pain.

Methods

We performed two consecutive cross‐sectional studies on FM patients and matched healthy volunteers (HV). FM patients were divided into a‐FM (and s‐FM groups according to their score of pain intensity on each body side; patients with a difference of ≥ 40mm in VAS between left and right sides were classified as a‐FM, otherwise classified as s‐FM. Participants (FM=32; HV=31) were assessed for clinical, cortical excitability (CE), quantitative sensory testing (QST) (study 1), and intraepidermal nerve fiber density (IENFD) determinations (study 2).

Results

While pain intensity did not significantly differ between s‐FM and a‐FM patients, pain interference in daily activities was significantly higher in the a‐FM as compared to the s‐FM group (54.7±8.9 and 37.6±13.5; p<0.0001). PPT was significantly lower in the more painful side of a‐FM as compared to the HV (27.7±7.9 and 49.9±13.0; p<0.0001), while PPT in the less painful side of a‐FM was significantly higher than PPT values in the s‐FM (35.8±8.3 and 27.7±5.5; p=0.031). S‐FM and a‐FM had significantly abnormal intracortical inhibition values on CE measurements compared to HV. There were no significant differences in IENFD between groups.

Conclusions

Within the current FM criteria, there exist different phenotypes with clinical, psychophysics, and neurophysiological findings that are not related to peripheral IENFD abnormalities.

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The response‐time relationship and covariate effects of acupuncture for chronic pain: a systematic review and model‐based longitudinal meta‐analysis

Abstract

Background And Objective

Critical clinical questions regarding how soon and how long the analgesic effect will be achieved by acupuncture, as well as who will responsive to acupuncture, need further address. This study is aim to investigate response‐time relationship and covariate effects of acupuncture.

Databases And Data Treatment

PubMed and EMBASE were searched up to December 2018 for randomised controlled trials that involved sham acupuncture, true acupuncture and conventional therapy. We used model‐based meta‐analysis to characterize the response‐time profile of these treatments.

Results

Seventy‐seven randomized clinical trials involved chronic shoulder, neck, knee and low back pain were included. The response‐time analysis suggested that the treatment duration of acupuncture will be 5 weeks or more to achieve 80% of maximum analgesic effect. Moreover, a lower baseline pain intensity and the location of low back pain resulted in a lower pain relief of acupuncture intervention. The absolute maximum analgesic effects of sham acupuncture and conventional therapy were 22.6 and 15.8 points at a 0‐100 NRS scale. The absolute effect of true acupuncture was 26.1 points for low back pain (relative effect of 3.5 and 9.4 points to sham and conventional therapy), 34.9 points for other pain body locations (relative effect of 12.3 and 19.1 points to sham and conventional therapy), in patients with a baseline pain intensity of 60 points.

Conclusion

The treatment duration of acupuncture will not be less than 5 weeks. Higher analgesic effect was related to higher baseline pain intensity and pain location of neck, shoulder and knee.

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Reconnecting the Brain with the Rest of the Body in Musculoskeletal Pain Research

Over the past few decades, pain research has greatly strengthened our view of chronic pain as a “disease of the brain.” However, as our knowledge about the role of the nervous system in chronic pain continues to expand, some disconnects are emerging between this knowledge and our understanding of peripheral tissue pathology, particularly for chronic musculoskeletal pain. This article will outline some important gaps that stand in the way of understanding chronic musculoskeletal pain, as well as areas where substantial knowledge exists but is “siloed” in different fields of medicine that need better integration.

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Time course of attention interruption after transient pain stimulation

Human brains perceive an enormous amount of information in any given moment. It is crucial for survival that individuals can allocate more attentional resources to relevant information. In particular, threatening stimuli can capture attentional resources at the expense of other, neutral, stimuli.2 The abilities to detect and respond to bodily threats rapidly are undoubtedly adaptive to survival. While attention is useful in protecting the pursuit of current goals and ongoing behavior from less important demands, in an unpredictable and potentially dangerous environment, it may be necessary to interrupt ongoing behavior to address an emerging threat.

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Avoiding based on shades of grey: Generalization of pain-related avoidance behavior to novel contexts

Pain-related fear and avoidance are known contributors to the transition from acute to chronic pain.6,24,25 Catastrophic misinterpretations of pain may generate pain-related fear, which in turn prompts avoidance behavior to protect the body from further damage. When avoidance behavior serves to reduce/eliminate genuine bodily threat, it is highly adaptive. However, in chronic pain, and in the absence of actual threat, avoidance behavior ceases to be protective, and may initiate a pathway towards disability.

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Increased CSF levels of apolipoproteins and complement factors in trigeminal neuralgia patients – in depth proteomic analysis using mass spectrometry

Trigeminal neuralgia (TN) is an extremely painful neurological disorder, characterized by short-lasting stabbing facial pain within the distribution of one or more branches of the trigeminal nerve 29. It affects females more than men (ratio 1:1.5) and the prevalence varies between 0.07 – 0.3% 24, 27. Neuroimaging- and cadaver studies imply that the disease is mainly caused by a neurovascular conflict (NVC) at the root entry zone (REZ) of the trigeminal nerve, however, this does not seem to be the only etiology 48.

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“What Should I Do First?” The Effect of Manipulated Goal Conflict on Affect, Motivation, and Helping Behavior in Chronic Pain Couples

Social support, especially from romantic partners, is an important resource for individuals with chronic pain (ICPs)4. Providing sufficient and high-quality help may, however, be a challenge for partners17,36. Research has shown that some helping behaviors (e.g., solicitous behaviors) may have unfavorable effects on patient outcomes4,8,26,36,37 and that partners may appraise their helping role as stressful, which depletes their ability to provide effective support3,23,56.

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