Refractory dependence on opioid analgesics No abstract available

Itch sensitization? A systematic review of studies using quantitative sensory testing in patients with chronic itch As well established for patients with chronic pain, patients suffering from chronic itch also exhibit signs of peripheral and central sensitization. This has been linked to parallel neuroplastic sensitization processes. However, for chronic itch, sensitization has not yet been systematically assessed, studied, and hence validated. This review (Prospero CRD42016043002) summarizes and meta-analytically evaluates whether sensory aberrations including sensitization for itch occur in chronic itch. Databases PubMed, Embase, and Cochrane Library were searched for studies investigating somatosensory sensitivity assessment by quantitative sensory testing stimuli, including experimental cutaneous chemical pruritic provocations, in patients with chronic itch from skin/neurological conditions and compared with healthy controls. Outcomes were extracted for lesional and nonlesional skin, and risk of biases were assessed. Meta-analyses were performed when sufficient quantitative data were available. Of 4667 identified articles, 46 were included and 25 were eligible for meta-analyses. Patients (66% atopic dermatitis [AD]) were found more sensitive than the controls to histamine-evoked itch in lesional skin (standardized mean difference [SMD]: 0.66 confidence interval [CI]: 0.16-1.15), but not nonlesionally (SMD: −0.26 [CI: −0.58 to 0.06]). Cowhage did not evoke more itch in nonlesional skin of patients as compared to the controls (SMD: 0.38 [CI: −0.04 to 0.81]). For numerous other chemical provocations as well as for mechanical, thermal, and electrical stimulation paradigms, results were ambiguous or based on few studies. Patients with chronic itch are only robustly sensitized to various chemical pruritic stimuli when applied lesionally. More studies on somatosensory aberrations in chronic itch conditions other than AD are needed to establish whether sensitization is robustly present across chronic itch conditions.

Conditioned pain modulation as a biomarker of chronic pain: a systematic review of its concurrent validity Conditioned pain modulation (CPM) is a promising psychophysical biomarker of central pain mechanisms because it significantly discriminates patients with chronic pain from healthy controls. Nevertheless, it is unclear in what extent CPM assessed experimentally is correlated with clinical manifestations of pain. To assess the concurrent validity of CPM, we performed a systematic review of the literature reporting correlations between CPM responses and pain intensity, disability, duration, and area in patients with different chronic pain conditions. We included 32 studies that altogether encompassed data from 1958 patients and provided 62 correlations. The majority of the results (69%) reported nonsignificant correlations between CPM efficiency and clinical manifestations of pain, whereas the remaining results showed a correlation between CPM reduction and worse clinical symptoms of pain. The modality of stimulation, the type of pain, and the stimulation site appear to be critical variables that influenced the pattern of results. Given that most of the studies were conducted with highly heterogeneous methodologies and unclear risk of bias, the findings highlight the need for future studies using standardized measures of clinical and experimental pain before considering CPM as a valid biomarker of pain. We discuss some guidelines to overcome the constraints in this promising line of research.

A randomized pilot study to investigate the effect of opioids on immunomarkers using gene expression profiling during surgery Endogenous opioid peptides and exogenous opioids modulate immune function, and animal and human studies have shown that some have a depressant immunomodulatory effect. This is potentially of high clinical significance, eg, in cancer patients and surgery. The primary objective of this pilot study was to evaluate the effect of morphine and oxycodone on immune pathways associated with immunosuppression in gynecological laparotomy patients. Gene expression was analyzed in CD4+, CD8+, and natural killer (NK) cells using the 3′ Affymetrix microarray. Patients were randomized to receive morphine, oxycodone, or nonopioid “control” analgesia during and after surgery. Genes demonstrating differential expression were those with a ≥±2-fold difference and P-value ≤0.05 after analysis of variance. Cytometric bead array and NK cell degranulation assay were used to investigate changes in serum cytokine concentration and in NK cell cytotoxicity, respectively. Forty patients had satisfactory RNA which was hybridized to gene chips. Genes were identified (Partek Genomics Suite 6.6) at baseline, 2, 6, and 24 hours and were either ≥2-fold upregulated or downregulated from baseline. At 2 hours, a large number of genes were downregulated with morphine but not with control analgesia or oxycodone. Statistically significant increases in IL-6 concentrations were induced by morphine only; NK cell activity was suppressed with morphine, but maintained with oxycodone and epidural analgesia. Gene expression profiles suggest that at 2 hours, post incision morphine appeared to be immunosuppressive as compared to oxycodone and nonopioid control analgesia.

Epidermal expression of human TRPM8, but not of TRPA1 ion channels, is associated with sensory responses to local skin cooling Human cold perception and nociception play an important role in persisting pain. However, species differences in the target temperature of thermosensitive ion channels expressed in peripheral nerve endings have fueled discussions about the mechanism of cold nociception in humans. Most frequently implicated thermosensors are members of the transient receptor potential (TRP) ion channel family TRPM8 and TRPA1. Regularly observed, distinct cold pain phenotype groups suggested the existence of interindividually differing molecular bases. In 28 subjects displaying either high or medium sensitivity to local cooling of the skin, the density at epidermal nerve fibers of TRPM8, but not that of TRPA1 expression, correlated significantly with the cold pain threshold. Moreover, reproducible grouping of the subjects, based on high or medium sensitivity to cooling, was reflected in an analogous grouping based on high or low TRPM8 expression at epidermal nerve fibers. The distribution of TRPM8 expression in epidermal nerve fibers provided an explanation for the previously observed (bi)modal distribution of human cold pain thresholds which was reproduced in this study. In the light of current controversies on the role of human TRPA1 ion channels in cold pain perception, the present observations demonstrating a lack of association of TRPA1 channel expression with cold sensitivity–related measures reinforce doubts about involvement of this channel in cold pain in humans. Since TRP inhibitors targeting TRPM8 and TRPA1 are currently entering clinical phases of drug development, the existence of known species differences, in particular in the function of TRPA1, emphasizes the increasing importance of new methods to directly approach the roles of TRPs in humans.

Dermorphin [D-Arg2, Lys4] (1-4) amide inhibits below-level heat hypersensitivity in mice after contusive thoracic spinal cord injury Opioid use for chronic pain is limited by severe central adverse effects. We examined whether activating mu-opioid receptors (MORs) in the peripheral nervous system attenuates spinal cord injury (SCI) pain-like behavior in mice. We produced a contusive SCI at the T10 vertebral level and examined motor and sensory dysfunction for 6 weeks. At 6 weeks, we tested the effect of subcutaneous (s.c.) injection of dermorphin [D-Arg2, Lys4] (1-4) amide (DALDA), a peripherally acting MOR-preferring agonist, on mechanical and heat hypersensitivity. Basso mouse scale score was significantly decreased after SCI, and mice showed hypersensitivity to mechanical and heat stimulation at the hind paw beginning at 2 weeks, as indicated by increased paw withdrawal frequency to mechanical stimulation and decreased paw withdrawal latency to heat stimulation. In wild-type SCI mice, DALDA (1 mg/kg, s.c.) attenuated heat but not mechanical hypersensitivity. The effect was blocked by pretreatment with an intraperitoneal injection of methylnaltrexone (5 mg/kg), a peripherally restricted opioid receptor antagonist, and was also diminished in Pirt-MOR conditional knockout mice. DALDA did not adversely affect exploratory activity or induced preference to drug treatment in SCI mice. In vivo calcium imaging showed that DALDA (1, 10 mg/kg, s.c.) inhibited responses of small dorsal root ganglion neurons to noxious heat stimulation in Pirt-GCaMP6s mice after SCI. Western blot analysis showed upregulation of MOR in the lumbar spinal cord and sciatic nerves at 6 weeks after SCI. Our findings suggest that peripherally acting MOR agonist may inhibit heat hypersensitivity below the injury level with minimal adverse effects.

Fatty acid suppression of glial activation prevents central neuropathic pain after spinal cord injury About half of patients with spinal cord injury (SCI) develop debilitating central neuropathic pain (CNP), with no effective treatments. Thus, effective, safe, and novel therapies are needed urgently. Previously, docosahexaenoic acid (DHA) was reported to confer neuroprotection in preclinical SCI models. However, its therapeutic potential on SCI-CNP remains to be elucidated. Here, we demonstrated for the first time that intravenous DHA administrations with 3-day intervals (250 nmol/kg; starting 30 minutes after injury and maintained for 6 weeks) effectively prevented SCI-CNP development in a clinically relevant rat contusion model. SCI-CNP was assessed by a novel sensory profiling approach combining evoked pain measures and pain-related ethologically relevant rodent behaviours (burrowing, thigmotaxis, and place/escape avoidance) to mimic those for measuring human (sensory, affective, cognitive, and spontaneous) pain. Strikingly, already established SCI-CNP could be abolished partially by similar DHA administrations, starting from the beginning of week 4 after injury and maintained for 4 weeks. At spinal (epicenter and L5 dorsal horns) and supraspinal (anterior cingulate cortex) levels, both treatment regimens potently suppressed microglial and astrocyte activation, which underpins SCI-CNP pathogenesis. Spinal microgliosis, a known hallmark associated with neuropathic pain behaviours, was reduced by DHA treatments. Finally, we revealed novel potential roles of peroxisome proliferator–activated and retinoid X receptors and docosahexaenoyl ethanolamide (DHA's metabolite) in mediating DHA's effects on microglial activation. Our findings, coupled with the excellent long-term clinical safety of DHA even in surgical and critically ill patients, suggest that systemic DHA treatment is a translatable, effective, safe, and novel approach for preventing and managing SCI-CNP.

Motor simulation is disturbed when experiencing pain While the contribution of social processes to pain perception is well documented, surprisingly little is known about the influence of pain on social perception. In particular, an important question is how pain modulates the processing of other people's actions. To address this question, the current study tests, using automatic imitation, the hypothesis that pain interferes with motor simulation—that is, the processing of observed actions in the motor system. Participants in both experiments performed an automatic imitation task requiring them to abduct their index or little finger while they saw someone else performing either a congruent or incongruent action. Automatic imitation was measured in a pain-free context, a context where pain was coupled to the execution of a movement (experiment 1), and a context where pain occurred randomly (experiment 2). The results revealed that automatic imitation, indexed by slower responses on incongruent compared with congruent trials, was reduced when experiencing pain, both when pain was linked to movement execution and when it was not. Thus, the current study shows that pain leads to reduced motor processing of others' behavior and, as such, has important implications for understanding the social difficulties associated with pain.

Brain dysfunction in chronic pain patients assessed by resting-state electroencephalography Chronic pain is a common and severely disabling disease whose treatment is often unsatisfactory. Insights into the brain mechanisms of chronic pain promise to advance the understanding of the underlying pathophysiology and might help to develop disease markers and novel treatments. Here, we systematically exploited the potential of electroencephalography to determine abnormalities of brain function during the resting state in chronic pain. To this end, we performed state-of-the-art analyses of oscillatory brain activity, brain connectivity, and brain networks in 101 patients of either sex suffering from chronic pain. The results show that global and local measures of brain activity did not differ between chronic pain patients and a healthy control group. However, we observed significantly increased connectivity at theta (4-8 Hz) and gamma (>60 Hz) frequencies in frontal brain areas as well as global network reorganization at gamma frequencies in chronic pain patients. Furthermore, a machine learning algorithm could differentiate between patients and healthy controls with an above-chance accuracy of 57%, mostly based on frontal connectivity. These results suggest that increased theta and gamma synchrony in frontal brain areas are involved in the pathophysiology of chronic pain. Although substantial challenges concerning the reproducibility of the findings and the accuracy, specificity, and validity of potential electroencephalography-based disease markers remain to be overcome, our study indicates that abnormal frontal synchrony at theta and gamma frequencies might be promising targets for noninvasive brain stimulation and/or neurofeedback approaches.

Heme and sensory neuropathy: insights from novel mutations in the heme exporter feline leukemia virus subgroup C receptor 1 Hereditary sensory and autonomic neuropathies (HSANs) are a group of clinically and genetically heterogeneous disorders of the peripheral nervous system mainly characterized by impaired nociception and autonomic dysfunction. We previously identified heme metabolism as a novel pathway contributing to sensory neurons maintenance and nociception. Indeed, we reported mutations in the feline leukemia virus subgroup C receptor 1 (FLVCR1) gene in individuals affected by HSAN. FLVCR1 gene encodes for 2 heme export proteins, FLVCR1a (plasma membrane) and FLVCR1b (mitochondria), crucially involved in the regulation of cellular heme homeostasis. Here, we report on 2 additional patients carrying novel biallelic mutations in FLVCR1 translation initiation codon (c.2T>C; p.(Met1Thr) and c.3G>T; p.(Met1Ile)). We overexpressed the c.2T>C; p.(Met1Thr) mutant in human cell lines and we describe its impact on protein structure and function in comparison with other HSAN-related mutations. We found that the mutation interferes with translation in 2 different ways: by lowering levels of translation of wild-type protein and by inducing translation initiation from a downstream in-frame ATG, leading to the production of an N-terminal truncated protein that is retained in the endoplasmic reticulum. The impact of different kinds of mutations on FLVCR1a localization and structure was also described. The identification of novel FLVCR1 mutations in HSAN reinforces the crucial role of heme in sensory neuron maintenance and pain perception. Moreover, our in vitro findings demonstrate that heme export is not completely lost in HSAN patients, thus suggesting the possibility to improve FLVCR1 expression/activity for therapeutic purposes.