Luke Parkitny

Cortical changes in chronic low back pain: Current state of the art and implications for clinical practice

There is increasing evidence that chronic pain problems are characterised by alterations in brain structure and function. Chronic back pain is no exception. There is a growing sentiment, with accompanying theory, that these brain changes contribute to chronic back pain, although empirical support is lacking. This paper reviews the structural and functional changes of the brain that have been observed in people with chronic back pain. We cast light on the clinical implications of these changes and the possibilities for new treatments but we also advise caution against concluding their efficacy in the absence of solid evidence to this effect.

Inflammation in complex regional pain syndrome A systematic review and meta-analysis

ABSTRACT Objectives: We conducted a systematic review of the literature with meta-analysis to determine whether complex regional pain syndrome (CRPS) is associated with a specific inflammatory profile and whether this is dependent on the duration of the condition. Methods: Comprehensive searches of the literature using MEDLINE, Embase, Scopus, Web of Science, and reference lists from published reviews identified articles that measured inflammatory factors in CRPS. Two independent investigators screened titles and abstracts, and performed data extraction and risk of bias assessments. Studies were subgrouped by medium (blood, blister fluid, and CSF) and duration (acute and chronic CRPS). Where possible, meta-analyses of inflammatory factor concentrations were performed and pooled effect sizes were calculated using random-effects models. Results: Twenty-two studies were included in the systematic review and 15 in the meta-analysis. In acute CRPS, the concentrations of interleukin (IL)-8 and soluble tumor necrosis factor receptors I (sTNF-RI) and II (sTNF-RII) were significantly increased in blood. In chronic CRPS, significant increases were found in 1) TNFα, bradykinin, sIL-1RI, IL-1Ra, IL-2, sIL-2Ra, IL-4, IL-7, interferon-γ, monocyte chemoattractant protein-1 (MCP-1), and sRAGE (soluble receptor for advanced glycation end products) in blood; 2) IL-1Ra, MCP-1, MIP-1β, and IL-6 in blister fluid; and 3) IL-1β and IL-6 in CSF. Chronic CRPS was also associated with significantly decreased 1) substance P, sE-selectin, sL-selectin, sP-selectin, and sGP130 in blood; and 2) soluble intercellular adhesion molecule-1 (sICAM-1) in CSF. Most studies failed to meet 3 or more of our quality criteria. Conclusion: CRPS is associated with the presence of a proinflammatory state in the blood, blister fluid, and CSF. Different inflammatory profiles were found for acute and chronic cases.

Primary Somatosensory Cortex Function in Complex Regional Pain Syndrome: A Systematic Review and Meta-Analysis

UNLABELLED That complex regional pain syndrome (CRPS) is associated with functional reorganization in the primary somatosensory cortex (S1) is widely accepted and seldom questioned. Despite more than a decade of research, there has been no systematic review of the CRPS literature concerning the changes in S1 function, and therefore the extent of these changes is unclear. Here we conduct a systematic review and meta-analysis to quantify the spatial and temporal aspects of S1 function in CRPS. A comprehensive search strategy identified functional neuroimaging studies of S1 in CRPS. We adhered to a rigorous systematic review protocol when extracting data and appraising risk of bias. Outcomes were grouped into spatial representation; activation levels, including disinhibition; peak latency of activation; and glucose metabolism. Meta-analysis was conducted where possible. Fifteen studies were included, all investigating upper-extremity CRPS. In patients with CRPS, the S1 spatial representation of the affected hand is smaller than that of the unaffected hand and that of non-CRPS controls; however, this evidence comes from only a few studies. There is no difference in activation, disinhibition, or latency of peripherally evoked S1 responses in CRPS. The risk of bias was high across studies, mainly from unclear sampling methods and unblinded analysis of outcomes. PERSPECTIVE The evidence for a difference in function of the primary somatosensory cortex in CRPS compared with controls is clouded by high risk of bias and conflicting results, but reduced representation size seems consistent.

The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain

Low-dose naltrexone (LDN) has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, Crohn’s disease, multiple sclerosis, and complex regional pain syndrome. We review the evidence that LDN may operate as a novel anti-inflammatory agent in the central nervous system, via action on microglial cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone’s better-known activity on opioid receptors. As a daily oral therapy, LDN is inexpensive and well-tolerated. Despite initial promise of efficacy, the use of LDN for chronic disorders is still highly experimental. Published trials have low sample sizes, and few replications have been performed. We cover the typical usage of LDN in clinical trials, caveats to using the medication, and recommendations for future research and clinical work. LDN may represent one of the first glial cell modulators to be used for the management of chronic pain disorders.

Rasch Analysis Supports the Use of the Pain Self-Efficacy Questionnaire

Background The Pain Self-Efficacy Questionnaire (PSEQ) is used by physical therapists in clinical practice and in research. However, current understanding of the PSEQs measurement properties is incomplete, and investigators cannot be confident that it provides unbiased information on patient self-efficacy. Objective The aims of this study were: (1) to investigate the scale properties of the PSEQ using Rasch analysis and (2) to determine whether age, sex, pain intensity, pain duration, and pain-related disability bias function of the PSEQ. Design This was a retrospective study; data were obtained from 3 existing studies. Methods Data were combined from more than 600 patients with low back pain of varying duration. Rasch analysis was used to evaluate targeting, category ordering, unidimensionality, person fit, internal consistency, and item bias. Results There was evidence of adequate category ordering, unidimensionality, and internal consistency of the PSEQ. Importantly, there was no evidence of item bias. Limitations The PSEQ did not adequately target the sample; instead, it targeted people with lower self-efficacy than this population. Item 7 was hardest for participants to endorse, showing excessive positive misfit to the Rasch model. Response strings of misfitting persons revealed older participants and those reporting high levels of disability. Conclusions The individual items of the PSEQ can be validly summed to provide a score of self-efficacy that is robust to age, sex, pain intensity, pain duration, and disability. Although item 7 is the most problematic, it may provide important clinical information and requires further investigation before its exclusion. Although the PSEQ is commonly used with people with low back pain, of whom the sample in this study was representative, the results suggest it targets patients with lower self-efficacy than that observed in the current sample.

Multiplex cytokine concentration measurement: how much do the medium and handling matter?

Cytokine concentrations are thought to be affected by methods of sampling and processing and by storage conditions. In this study we compared 17 cytokine concentrations obtained from plasma and serum at baseline and after a controlled thaw condition. We found that absolute agreement was poor between concentrations of cytokines in plasma and serum, except for MIP1β. A thaw condition significantly changed the concentrations of most cytokines, but serum appeared less affected by this than plasma was. Closer examination using Bland-Altman analyses revealed that for each comparison, agreement was moderately good for many cytokine concentrations. This is important because measures of agreement must be interpreted based on the required precision, which may differ between clinical and research demands. We also identified that for some cytokines, the relationship between serum and plasma is affected by concentration, thus advocating for the use of appropriate methods when performing such comparisons in studies such as systematic reviews and meta-analyses.

The Depression Anxiety Stress Scale (DASS)

Instructions to client and scoring: A respondent indicates on a 4-point scale the extent to which each of 42 statements applied over the past week. A printed overlay is used to obtain total scores for each subscale. Higher scores on each subscale indicate increasing severity of depression, anxiety, or stress. Completion takes 10 to 20 minutes. A shorter, 21-item version of the DASS (DASS-21), which takes 5 to 10 minutes to complete, is also available. Subscale scores from the shorter questionnaire are converted to the DASS normative data by multiplying the total scores by 2.

Psychological Distress Mediates the Relationship Between Pain and Disability in Hand or Wrist Fractures.

Upper limb fracture is a common musculoskeletal injury and can lead to marked pain-related disability. Unlike other common painful musculoskeletal conditions, such as low back pain, little consideration has been given to the role that psychological variables may play in explaining the relationship between pain and disability during early fracture recovery. This cross-sectional study aimed to determine if psychological distress (symptoms of depression, anxiety, and/or stress) mediate the relationship between pain and disability in acute hand/wrist fractures. Self-reported data from a consecutive sample of 594 patients with acute hand/wrist fracture were used. Mediation analyses were conducted to determine the role of depression, anxiety, and stress in the relationship between pain and disability, controlling for relevant demographic and fracture-related variables. Depression and stress, but not anxiety, significantly mediated the relationship between pain and disability. That is, although each psychological distress variable was associated with pain (P < .001), only depression (b1 = 0.27, P = .03) and stress (b3 = .23, P = .02) were significantly associated with disability and fulfilled recommended criteria for establishing a mediating variable. Increased depression and stress, but not anxiety, explain the relationship between pain and disability and may be novel targets for interventions designed to reduce pain-related disability after upper limb fracture. Perspective: This study presents the mediating effect of psychological distress on the relationship between pain and disability in acute upper limb fracture. These factors may be novel targets for interventions designed to reduce pain-related disability after acute fracture.

Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Naltrexone for Fibromyalgia

Fibromyalgia (FM) is a complex, multi-symptom condition that predominantly affects women. The majority of those affected are unlikely to gain significant symptomatic control from the few treatments that are approved for FM. In this 10-week, single-blind, crossover trial we tested the immune effects of eight weeks of oral administration of low-dose naltrexone (LDN). We enrolled eight women with an average age of 46 years, symptom severity of 62 out of 100, and symptom duration of 14 years. We found that LDN was associated with reduced plasma concentrations of interleukin (IL)-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, IL-17A, IL-27, interferon (IFN)-α, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, and granulocyte-colony stimulating factor (G-CSF). We also found a 15% reduction of FM-associated pain and an 18% reduction in overall symptoms. The findings of this pilot trial suggest that LDN treatment in fibromyalgia is associated with a reduction of several key pro-inflammatory cytokines and symptoms. The potential role of LDN as an atypical anti-inflammatory medication should be explored further.

Depression may contribute to the sensory changes in whiplash patients? Re: Chien, A, Sterling, M. Sensory hypoaesthesia is a feature of chronic whiplash but not chronic idiopathic neck pain. Manual therapy 2010;15:48-53.

We read with great interest the recent paper by Chien and Sterling contrasting the sensory impairments of patients with chronic whiplash and chronic idiopathic neck pain (Chien and Sterling, 2010). Work from this group has previously provided invaluable insight into the problem of whiplash and this paper is no exception. In this study, chronic whiplash patients demonstrated sensory hypoaesthesia whereas idiopathic neck pain patients did not, and while both patient groups had lowered pressure pain thresholds, only the whiplash group demonstrated lowered cold pain thresholds. We were struck by the similarity between the findings demonstrated in this study and prior research involving quantitative sensory testing in depressed patients. Adler and Gattaz (1993) have demonstrated increased sensory thresholds to electrical stimulation in depressed patients. Bar et al. (2003) found some evidence for elevated warmth detection thresholds in depression, though this was dependent on medication status. This group also demonstrated that hyperalgesia is modality specific; depressed patients were shown to be more sensitive to ischemic pain yet less sensitive to thermal and electrical pain (Bar et al., 2005). Furthermore, Klauenberg et al. (2008) recently reported decreased cold pain thresholds but normal mechanical pain thresholds in a group of pain free depressed subjects. While the somatosensory abnormalities apparent in depression are still not fully described (Dickens et al., 2003) hypoaesthesia and modality specific hyperalgesia seem to be consistent features. In the Chien and Sterling paper whiplash patients demonstrated elevated depression scores when compared to the idiopathic neck pain patients and it may be worth considering that the intriguing set of sensory impairments found could in part be attributable to depressed mood and its associated central changes. While the authors controlled for psychological distress in their analyses, the depression scores contributed only a small part to this overall score so minimising the efficiency of the analyses to control for depression. Given the apparent importance of depression in the development of ongoing pain and disability following whiplash