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Sickle cell disease (SCD) is a common hereditary hematologic disorder. SCD patients suffer from acute vaso-occlusive episodes (VOEs), chronic organ damage, and premature death, with few therapeutic options. Although severe pain is a major clinical manifestation of SCD, it remains unknown whether nociception plays a role in SCD pathogenesis. To address this question, we generated nociceptor-deficient SCD mice and found, unexpectedly, that the absence of nociception led to more severe and more lethal VOE, indicating that somatosensory nerves protect SCD mice from VOE. Mechanistically, the beneficial effects of sensory nerves were induced by the neuropeptide calcitonin gene-related peptide (CGRP), which acted on hematopoietic cells. Additionally, oral capsaicin consumption, which can activate somatosensory nerves by binding to TRPV1, dramatically alleviated acute VOE and significantly prevented chronic liver and kidney damage in SCD mice. Thus, the manipulation of nociception may provide a promising approach to treat SCD.
Learn More >Touch and itch sensations are crucial for evoking defensive and emotional responses, and light tactile touch may induce unpleasant itch sensations (mechanical itch or alloknesis). The neural substrate for touch-to-itch conversion in the spinal cord remains elusive. We report that spinal interneurons expressing Tachykinin 2-Cre (Tac2) receive direct Aβ low threshold mechanoreceptor (LTMR) input and form monosynaptic connections with GRPR neurons. Ablation or inhibition markedly reduces mechanical but not acute chemical itch nor noxious touch information. Chemogenetic inhibition of Tac2 neurons also displays pronounced deficit in chronic dry skin itch, a type of chemical itch in mice. Consistently, ablation of gastrin-releasing peptide receptor (GRPR) neurons, which are essential for transmitting chemical itch, also abolishes mechanical itch. Together, these results suggest that innocuous touch and chemical itch information converge on GRPR neurons and thus map an exquisite spinal circuitry hard-wired for converting innocuous touch to irritating itch.
Learn More >Irritable bowel syndrome is a functional gastrointestinal disorder with symptoms including abdominal pain associated with a change in stool form or frequency. The condition affects between 5% and 10% of otherwise healthy individuals at any one point in time and, in most people, runs a relapsing and remitting course. The best described risk factor is acute enteric infection, but irritable bowel syndrome is also more common in people with psychological comorbidity and in young adult women than in the rest of the general population. The pathophysiology of irritable bowel syndrome is incompletely understood, but it is well established that there is disordered communication between the gut and the brain, leading to motility disturbances, visceral hypersensitivity, and altered CNS processing. Other less reproducible mechanisms might include genetic associations, alterations in gastrointestinal microbiota, and disturbances in mucosal and immune function. In most people, diagnosis can be made on the basis of clinical history with limited and judicious use of investigations, unless alarm symptoms such as weight loss or rectal bleeding are present, or there is a family history of inflammatory bowel disease or coeliac disease. Once the diagnosis is made, an empathetic approach is key and can improve quality of life and symptoms, and reduce health-care expenditure. The mainstays of treatment include patient education about the condition, dietary changes, soluble fibre, and antispasmodic drugs. Other treatments tend to be reserved for people with severe symptoms and include central neuromodulators, intestinal secretagogues, drugs acting on opioid or 5-HT receptors, or minimally absorbed antibiotics (all of which are selected according to predominant bowel habit), as well as psychological therapies. Increased understanding of the pathophysiology of irritable bowel syndrome in the past 10 years has led to a healthy pipeline of novel drugs in development.
Learn More >Visceral pain is a prevalent symptom of inflammatory bowel disease (IBD) that can be difficult to treat. Pain and hypersensitivity are mediated by extrinsic primary afferent neurons (ExPANs) that innervate the colon. Recent studies indicate that the colon epithelium contributes to initiating ExPAN firing and nociceptive responses. Based on these findings we hypothesized that the epithelium contributes to inflammation-induced hypersensitivity. A key prediction of this hypothesis is that inhibition of the epithelium would attenuate nociceptive signaling and inflammatory hypersensitivity. To test this hypothesis, the inhibitory yellow light activated protein archaerhodopsin was targeted to the intestinal epithelium (villin-Arch) or the ExPANs (TRPV1-Arch) that innervate the colon. Visceral sensitivity was assessed by measuring the visceromotor response (VMR) to colorectal distension (CRD), with and without yellow light illumination of the colon lumen. Inhibition of the colon epithelium in healthy villin-Arch mice significantly diminished the CRD-induced VMR. Direct inhibition of ExPANs during CRD using TRPV1-Arch mice showed that ExPAN and epithelial inhibition were similarly effective in reducing the VMR to CRD. We then investigated the effect of epithelial and ExPAN inhibition in the dextran sulfate sodium (DSS) model of inflammatory bowel disease (IBD). Inhibition of the colon epithelium significantly decreased DSS-induced hypersensitivity and was comparable to inhibition of ExPANS. Together these results reveal the potential of targeting the colon epithelium for treatment of pain.
Learn More >Neonatal tissue damage can have long-lasting effects on nociceptive processing in the central nervous system, which may reflect persistent injury-evoked alterations to the normal balance between synaptic inhibition and excitation in the spinal dorsal horn. Spinal dynorphin-lineage (pDyn) neurons are part of an inhibitory circuit which limits the flow of nociceptive input to the brain and is disrupted by neonatal tissue damage. To identify the potential molecular underpinnings of this disruption, an unbiased single-nucleus RNAseq analysis of adult mouse spinal pDyn cells characterized this population in depth and then identified changes in gene expression evoked by neonatal hindpaw incision. The analysis revealed 11 transcriptionally distinct subpopulations (ie, clusters) of dynorphin-lineage cells, including both inhibitory and excitatory neurons. Investigation of injury-evoked differential gene expression identified 15 genes that were significantly upregulated or downregulated in adult pDyn neurons from neonatally incised mice compared with naive littermate controls, with both cluster-specific and pan-neuronal transcriptional changes observed. Several of the identified genes, such as Oxr1 and Fth1 (encoding ferritin), were related to the cellular stress response. However, the relatively low number of injury-evoked differentially expressed genes also suggests that posttranscriptional regulation within pDyn neurons may play a key role in the priming of developing nociceptive circuits by early-life injury. Overall, the findings reveal novel insights into the molecular heterogeneity of a key population of dorsal horn interneurons that has previously been implicated in the suppression of mechanical pain and itch.
Learn More >Men and women can exhibit different pain sensitivities and many chronic pain conditions are more prevalent in one sex. Although there is evidence of sex differences in the brain, it is not known whether there are sex differences in the organization of large-scale functional brain networks in chronic pain. Here, we used graph theory with modular analysis and machine-learning of resting-state (RS)-fMRI data from 220 participants; 155 healthy controls and 65 individuals with chronic low back pain due to ankylosing spondylitis (AS), a form of arthritis.We found an extensive overlap in the graph partitions with the major brain intrinsic systems (i.e., default mode, central, visual and sensorimotor modules), but also sex-specific network topological characteristics in healthy people and those with chronic pain. People with chronic pain exhibited higher cross-network connectivity, and sex-specific nodal graph properties changes (i.e., Hubs disruption), some of which were associated with the severity of the chronic pain condition. Females exhibited atypically higher functional segregation in the mid- and subgenual cingulate cortex and lower connectivity in the network with the default mode and fronto-parietal modules; whereas males exhibited stronger connectivity with the sensorimotor module. Classification models on nodal graph metrics could classify an individuals' sex and whether they have chronic pain with high accuracies (77-92%). These findings highlight the organizational abnormalities of RS-brain networks in people with chronic pain and provide a framework to consider sex-specific pain therapeutics.
Learn More >Pain is a common non-motor symptom in patients with Parkinson's disease (PD) but the correct diagnosis of the respective cause remains difficult because suitable tools are lacking, so far. We developed a framework to differentiate PD- from non-PD-related pain and classify PD-related pain into three groups based on validated mechanistic pain descriptors (nociceptive, neuropathic, or nociplastic), which encompass all the previously described PD pain types. Severity of PD-related pain syndromes was scored by ratings of intensity, frequency, and interference with daily living activities. The PD-Pain Classification System (PD-PCS) was compared with classic pain measures (ie, brief pain inventory (BPI) and McGill pain questionnaire (MPQ), PDQ-8 quality of life score, MDS-UPDRS scores, and non-motor symptoms). 159 non-demented PD patients (disease duration 10.2±7.6 years) and 37 healthy controls were recruited in four centers. PD-related pain was present in 122 patients (77%), with 24 (15%) suffering one or more syndromes at the same time. PD-related nociceptive, neuropathic, or nociplastic pain was diagnosed in 87 (55%), 25 (16%), or 35 (22%), respectively. Pain unrelated to PD was present in 35 (22%) patients. Overall, PD-PCS severity score significantly correlated with pain's BPI and MPQ ratings, presence of dyskinesia and motor fluctuations, PDQ-8 scores, depression and anxiety measures. Moderate intra- and inter-rater reliability was observed. The PD-PCS is a valid and reliable tool for differentiating PD-related pain from PD-unrelated pain. It detects and scores mechanistic pain subtypes in a pragmatic and treatment-oriented approach, unifying previous classifications of PD-pain.
Learn More >Nitrous oxide (N2O) is an odorless and colorless gas routinely used as an adjuvant of anesthesia and for short duration analgesia in various clinical settings mostly in the form of a N2O/O2 50%-50% equimolar mixture (EMONO). Experimental studies have suggested that EMONO could also induce long lasting analgesic effects related to the blockade of NMDA receptors. We designed the first international multicenter proof of concept randomized, placebo-controlled study to assess the efficacy and safety of a one hour administration of EMONO or placebo (medical air) on three consecutive days up to one month after the last administration in patients with chronic peripheral neuropathic pain. A total of 240 patients were recruited in 22 centers in France and Germany and randomly assigned to one study group (120 per group). Average pain intensity (primary outcome), neuropathic pain characteristics (NPSI), patient global impression of change (PGIC), anxiety, depression and quality of life were systematically assessed before and after treatment. The changes in average pain intensity between baseline and seven days after the last administration were not significantly different between the two groups. However, evoked pain intensity (predefined secondary endpoint) and PGIC (exploratory endpoint), were significantly improved in the EMONO group and these effects were maintained up to four weeks after the last treatment administration. Mostly transient side effects were reported during the treatment administration. These encouraging results provide a basis for further investigation of the long term analgesic effects of EMONO in neuropathic pain patients.
Learn More >It currently remains unclear, why some patients with entrapment neuropathies develop neuropathic pain (neuP) whereas others have non-neuP, presumably of nociceptive character. Studying patients with carpal tunnel syndrome (CTS), this cross-sectional cohort study investigated changes in somatosensory structure and function as well as emotional wellbeing specific to the presence and severity of neuP.Patients with CTS (n=108) were subgrouped by the DN4 questionnaire into those without and with neuP. The latter group was further subdivided into mild and moderate/severe neuP using a pain visual analogue scale. N=32 participants served as healthy controls. All participants underwent a clinical examination, quantitative sensory testing (QST), electrodiagnostic testing (EDT) and skin biopsy to determine structural integrity of dermal and intraepidermal nerve fibres. Patients also completed questionnaires evaluating symptom severity and functional deficits, pain distribution, sleep quality and emotional wellbeing. The overall prevalence of neuP in patients with CTS was 80%, of which 63% had mild neuP. Symptom severity and functional deficits as well as somatosensory dysfunction were more pronounced with the presence and increasing severity of neuP. No difference was identified among patient groups for EDT and nerve fibre integrity on biopsies. The severity of neuP was accompanied by more pronounced deficits in emotional wellbeing and sleep quality. Intriguingly, extraterritorial spread of symptoms was more prevalent in patients with moderate/severe neuP, indicating the presence of central mechanisms. NeuP is common in patients with CTS and its severity is related to the extent of somatosensory dysfunction and a compromise of emotional wellbeing.
Learn More >Improving the ability to predict persistent pain after spine surgery would allow identification of patients at risk and guide treatment decisions. Quantitative sensory tests (QST) are measures of altered pain processes, but in our previous study, preoperative QST did not predict pain and disability at single time-points. Trajectory analysis accounts for time-dependent patterns. We hypothesized that QST predict trajectories of pain and disability during 1 year after low back surgery. We performed a trajectory analysis on the cohort of our previous study (n = 141). Baseline QST included electrical, pressure, heat, and cold stimulation of the low back and lower extremity, temporal summation, and conditioned pain modulation. Pain intensity and Oswestry Disability Index were measured before, and 2, 6, and 12 months after surgery. Bivariate trajectories for pain and disability were computed using group-based trajectory models. Multivariable regressions were used to identify QST as predictors of trajectory groups, with sociodemographic, psychological, and clinical characteristics as covariates. Cold pain hypersensitivity at the leg, not being married, and long pain duration independently predicted worse recovery (complete-to-incomplete, incomplete-to-no recovery). Cold pain hypersensitivity increased the odds for worse recovery by 3.8 (95% confidence intervals 1.8-8.0, P < 0.001) and 3.0 (1.3-7.0, P = 0.012) in the univariable and multivariable analyses, respectively. Trajectory analysis, but not analysis at single time-points, identified cold pain hypersensitivity as strong predictor of worse recovery, supporting altered pain processes as predisposing factor for persisting pain and disability, and a broader use of trajectory analysis. Assessment of cold pain sensitivity may be a clinically applicable, prognostic test.
Learn More >To define the melanopsin and cone luminance retinogeniculate pathway contributions to photophobia in healthy controls and migraineurs.
Learn More >Chronic pain following musculoskeletal trauma is common, which may partially be attributed to the early presence of central sensitisation (CS). Multiple measures are suggested to assess clinical features of CS, yet no systematic review has evaluated the measurement properties of these measures in a musculoskeletal trauma population.
Learn More >Neuropathic pain is associated with poor health-related quality of life (HRQL) in pain conditions other than sickle cell disease (SCD); this relationship in SCD is unknown. We investigated this relationship and hypothesized neuropathic pain is associated with poor HRQL in adolescents with SCD.
Learn More >Acupuncture for chronic cancer-related pain: a systematic review and network meta-analysis protocol.
Chronic cancer-related pain is one of the most common excruciating symptom that can be caused by the cancer (by the primary tumour or by metastases) or by its treatment (surgery, chemotherapy and radiotherapy). Although multiple clinical trials and systematic reviews have suggested that acupuncture could be effective in treating chronic cancer-related pain, the comparative efficacy and safety of these acupuncture methods remains unclear. We, therefore, performed this study to evaluate and rank the efficacy and safety of different acupuncture methods for chronic cancer-related pain.
Learn More >This study discovered a novel neuro-epidermal BNP-TRPV3-Serpin E1-mediated pathway in severe atopic dermatitis (AD). Serpin E1 was identified as a new itch-inducer. We propose this pathway represents an important target for the treatment of AD.
Learn More >A successful acute inflammatory response results in the elimination of infectious agents by neutrophils and monocytes, followed by resolution and repair through tissue-resident and recruited macrophages. Resolvins (D-series and E-series) are pro-resolving lipid mediators involved in resolution and tissue repair, whose intracellular signaling remains of interest. Here, we report that D-series resolvins (RvD1- RvD5) activate phospholipase D (PLD), a ubiquitously expressed membrane lipase enzyme activity in modulating phagocyte functions. The mechanism for PLD-mediated actions of Resolvin-D5 (RvD5) in polarizing macrophages (M1-like toward M2-like) was found to be two-pronged: (a) RvD5 inhibits post-transcriptional modifications, by miRs and 3'exonucleases that process PLD2 mRNA, thus increasing PLD2 expression and activity; and (b) RvD5 enhances PLD2-S6Kinase signaling required for membrane expansion and efferocytosis. In an in vivo model of second organ reflow injury, we found that RvD5 did not reduce lung neutrophil myeloperoxidase levels in PLD2 mice compared to WT and PLD1 mice, confirming a novel role of PLD2 as the isoform in RvD5-mediated resolution processes. These results demonstrate that RvD5-PLD2 are attractive targets for therapeutic interventions in vascular inflammation such as ischemia-reperfusion injury and cardiovascular diseases.
Learn More >The mainstay of atopic dermatitis treatment has been largely unchanged over the last few decades. With improved understanding of the immunologic pathways underlying atopic dermatitis in recent years, targeted biologic therapies are being developed. Discuss efficacy and safety profiles of emerging biologics in phase 2 and 3 clinical trials.: A systemic literature review was conducted to identify results of randomized, placebo-controlled trials of monoclonal antibodies up to March 1, 2020 for the treatment of atopic dermatitis. Targeted biologics appear to have acceptable safety profiles. Dupilumab, lebrikizumab, and nemolizumab demonstrate efficacy as agents producing improvement in clinical severity and pruritus. The growing class of biologics shows promise in meeting the needs of treatment-resistant atopic dermatitis. The use of validated core measurements is necessary for future trials in order to adequately compare agents and progress evidence-based medicine.
Learn More >A consistent line of investigation proposes fibromyalgia as a dysautonomia-associated neuropathic pain syndrome. Comorbid anxiety or depression amplifies fibromyalgia symptoms. The recent recognition of small fiber neuropathy in fibromyalgia patients supports the neuropathic nature of the illness. Corneal confocal microscopy accurately identifies small nerve fiber pathology. The newly developed Small-Fiber Symptom Survey captures the spectrum of small fiber neuropathy symptoms. We aimed to correlate corneal nerve density with different fibromyalgia disease severity questionnaires including the Small-Fiber Symptom Survey. We defined the possible confounding role of comorbid anxiety or depression severity in the clinical-pathological association.
Learn More >To compare the long-term effectiveness of an integrated rehabilitation programme with an existing rehabilitation programme, in terms of back-specific disability, in patients with chronic low back pain.
Learn More >This journal recently published a paper by Vowles et al., entitled "Initial Evaluation of the Chronic Pain Acceptance Questionnaire – 2. The authors discuss the development of a two-item measure to assess chronic pain acceptance. Items for this tool were derived from the Chronic Pain Acceptance Questionnaire (CPAQ) 20, and aim to map two key features of acceptance: (1) Activity Engagement, which entails participating in important or meaningful activities with continued pain and (2) Pain Willingness, which entails a willingness to experience pain without the need to reduce, avoid, or otherwise change it.
Learn More >Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is known to reduce motor symptoms of Parkinson's disease (PD). The effects of DBS on various nonmotor symptoms often differ from patient to patient. The factors that determine whether or not a patient will respond to treatment have not been elucidated. Here, the authors evaluated sex differences in pain relief after DBS for PD.
Learn More >Not all factors that predict persistent pain and disability following whiplash injury are known. In particular, few physical factors, such as changes in movement and muscle behaviour, have been investigated. The aim of this study is to identify predictive factors that are associated with the development of persistent pain and disability following a whiplash injury by combining contemporary measures of physical function together with established psychological and pain-related predictive factors.
Learn More >Prostaglandin E2 (PGE2) is a lipid mediator which plays a role in the generation of inflammatory and neuropathic pain. In the peripheral nervous system, PGE2 sensitizes nociceptive afferent neurons through E-prostanoid (EP) receptors. In the central nervous system, PGE2 modulates pain sensitivity and contributes to the development of neuropathic pain. However, the distribution of PGE2 and EP receptors in the spinal cord remains unclear. In the present study, we examined the expression of PGE2 synthases (microsomal PGE synthase [mPGES]-1, mPGES-2, and cytosolic PGE synthase [cPGES]) and EP receptors (EP1-4) in a rat model of neuropathic pain. We identified that mPGES-1 mRNA was upregulated in spinal endothelial cells after nerve injury and exhibited co-localization with cyclooxygenase-2 (COX-2). We detected that mPGES-2 mRNA and cPGES mRNA were expressed in spinal neurons and noted that their expression level was not affected by nerve injury. With respect to EP receptors, EP2 mRNA and EP4 mRNA were expressed in spinal neurons in the dorsal horn. EP3 mRNA was expressed in motor neurons, whereas EP1 mRNA was not detected in the spinal cord. Intrathecal injection of tumor necrosis factor alpha (TNFα) upregulated mPGES-1 mRNA in blood vessels in the spinal cord. Intrathecal injection of a TNFα-neutralizing antibody partially inhibited the upregulation of mPGES-1 mRNA after nerve injury. These results indicate that PGE2 is synthesized by COX-2/mPGES-1 in spinal endothelial cells after nerve injury. These results suggest that in neuropathic pain condition, endothelial cell-derived PGE2 may act on EP2 and EP4 receptors on spinal neurons and modulate pain sensitivity.
Learn More >Chronic pain from temporomandibular disorders remains an undertreated condition with debate regarding the most effective treatment modalities.
Learn More >Nonspecific neck pain is associated with chronic pain, disability, reduced cervical mobility, postural control disorders and impaired proprioceptive control.
Learn More >To summarize for the trainee audience the possible mechanisms of headache in patients with COVID-19 as well as to outline the impact of the pandemic on patients with headache disorders and headache medicine in clinical practice.
Learn More >Evaluate the safety and efficacy of a single injection of STRO-3+ adult allogeneic mesenchymal precursor cells (MPCs) combined with hyaluronic acid (HA) in subjects with chronic low back pain (CLBP) associated with degenerative disc disease (DDD) through 36 months follow-up.
Learn More >Intractable or recurrent chronic itch greatly reduces the patients' quality of life and impairs their daily activities. In this study, we investigated whether there are certain key signaling molecules downstream of the recently identified peptides mediating itch in the spinal cord. RNA sequencing analysis of mouse spinal cord in chronic itch models induced by squaric acid dibutylester and imiquimod showed that extracellular signal-regulated kinase 1/2 (ERK1/2) cascade is the most significantly up-regulated gene cluster in both models. In four different mouse models of chronic itch, sustained ERK phosphorylation was detected mainly in spinal neurons, and MEK inhibitors significantly inhibited chronic itch in these models. Phosphorylated ERK (pERK) was observed in interneurons expressing receptors of different neuropeptides for itch, including GRPR, NPRA, NMBR or sst. Blocking GRPR and NPRA by genetic approaches or toxins in mice significantly attenuated or ablated spinal pERK. When HEK293T cells transfected with these receptors were exposed to their respective agonists, ERK was the most significantly activated intracellular signaling molecule. Together, our work showed that pERK is a unique marker for itch signal transmission in the spinal cord and an attractive target for the treatment of chronic itch.
Learn More >Transient receptor potential melastatin member 8 (TRPM8), a Ca -permeable nonselective cation channel activated by cold and cooling agents, mediates allodynia. Dysfunction or abnormal expression of TRPM8 has been found in several human cancers. The role of ubiquitination in the regulation of TRPM8 function remains poorly understood. Here, we identified the ubiquitin (Ub)-ligase E3, tripartite motif-containing 4 (TRIM4), as a novel interaction partner of TRPM8 and confirmed that the TRIM4-TRPM8 interaction was mediated through the SPRY domain of TRIM4. Patch-clamp assays showed that TRIM4 negatively regulates TRPM8-mediated currents in HEK293 cells. Moreover, TRIM4 reduced the expression of TRPM8 on the cell surface by promoting the K63-linked ubiquitination of TRPM8. Further analyses revealed that the TRPM8 N-terminal lysine residue at 423 was the major ubiquitination site that mediates its functional regulation by TRIM4. A Ub-activating enzyme E1, Ub-like modifier-activating enzyme 1 (UBA1), was also found to interact with TRPM8, thereby regulating its channel function and ubiquitination. In addition, knockdown of UBA1 impaired the regulation of TRPM8 ubiquitination and function by TRIM4. Thus, this study demonstrates that TRIM4 downregulates TRPM8 via K423-mediated TRPM8 ubiquitination and requires UBA1 to regulate TRPM8.
Learn More >Opioids are the "gold standard" treatment for postoperative pain, but these drugs also have limiting adverse effects. Thus, adjuvant drugs might be useful in opioid therapy for postoperative pain. The aim of the present study was to evaluate the effect of Phα1β, a dual blocker of Cav2 and TRPA1 channels, on antinociceptive and adverse actions of morphine in a model of postoperative pain. Phα1β (100-300 pmol/site) or morphine (3-10 mg/kg), alone, largely reduced postoperative nociception. However, Phα1β (100 pmol/site) or morphine (10 mg/kg) also produced motor impairment. Lower doses of Phα1β (30 pmol/site) or morphine (1 mg/kg), that did not have an effect alone, showed antinociceptive effect when concomitantly administrated. Moreover, co-administration of Phα1β (30 pmol/site) with morphine (1 or 10 mg/kg) was unable to cause motor impairment. Preoperative repeated treatment with morphine increased the expression of Cav2 and TRPA1 channels in spinal cord, and caused tolerance and withdrawal syndrome, which were reversed with a single injection of Phα1β (30 pmol/site). When injected postoperatively, escalating doses of morphine worsened postoperative hyperalgesia, induced tolerance, and withdrawal syndrome. Similarly, Phα1β (30 pmol/site) reversed these adverse effects. Single or repeated morphine caused constipation, which was not altered by Phα1β. Thus, a low dose of Phα1β potentiated the analgesia, and reversed some adverse effects of morphine on operated mice, indicating the potential use of this agent as an adjuvant drug in opioid therapy for postoperative pain.
Learn More >Traditional pain management after total knee arthroplasty (TKA) relies heavily on opioids. Although there is evidence that in-hospital multimodal pain management (MMPM) is more effective than opioid-only (OO) analgesia, there has been little focus on postdischarge pain management. The hypothesis of this study was that MMPM after TKA would reduce pain scores and opioid consumption in the 30-day period after hospital discharge.
Learn More >The white matter state in migraine has been investigated using diffusion tensor imaging (DTI) measures, but results using this technique are conflicting. To overcome DTI measures, we employed ensemble average diffusion propagator measures obtained with apparent measures using reduced acquisitions (AMURA). The AMURA measures were return-to-axis (RTAP), return-to-origin (RTOP) and return-to-plane probabilities (RTPP). Tract-based spatial statistics was used to compare fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity from DTI, and RTAP, RTOP and RTPP, between healthy controls, episodic migraine and chronic migraine patients. Fifty healthy controls, 54 patients with episodic migraine and 56 with chronic migraine were assessed. Significant differences were found between both types of migraine, with lower axial diffusivity values in 38 white matter regions and higher RTOP values in the middle cerebellar peduncle in patients with a chronic migraine ( < 0.05 family-wise error corrected). Significantly lower RTPP values were found in episodic migraine patients compared to healthy controls in 24 white matter regions ( < 0.05 family-wise error corrected), finding no significant differences using DTI measures. The white matter microstructure is altered in a migraine, and in chronic compared to episodic migraine. AMURA can provide additional results with respect to DTI to uncover white matter alterations in migraine.
Learn More >Menthol, which acts as an agonist for transient receptor potential melastatin 8 (TRPM8), has complex effects on nociceptive transmission, including pain relief and hyperalgesia. Here, we addressed the effects of menthol on spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs, respectively) in medullary dorsal horn neurons, using a whole-cell patch-clamp technique. Menthol significantly increased sEPSC frequency, in a concentration-dependent manner, without affecting current amplitudes. The menthol-induced increase in sEPSC frequency could be completely blocked by AMTB, a TRPM8 antagonist, but was not blocked by HC-030031, a transient receptor potential ankyrin 1 (TRPA1) antagonist. Menthol still increased sEPSC frequency in the presence of Cd, a general voltage-gated Ca channel blocker, suggesting that voltage-gated Ca channels are not involved in the menthol-induced increase in sEPSC frequency. However, menthol failed to increase sEPSC frequency in the absence of extracellular Ca, suggesting that TRPM8 on primary afferent terminals is Ca permeable. On the other hand, menthol also increased sIPSC frequency, without affecting current amplitudes. The menthol-induced increase in sIPSC frequency could be completely blocked by either AMTB or CNQX, an AMPA/KA receptor antagonist, suggesting that the indirect increase in excitability of inhibitory interneurons may lead to the facilitation of spontaneous GABA and/or glycine release. The present results suggested that menthol exerts analgesic effects, via the enhancement of inhibitory synaptic transmission, through central feed-forward neural circuits within the medullary dorsal horn region.
Learn More >Objectives Physical activity is essential for long-term chronic pain management, yet individuals struggle to participate. Exercise professionals, including fitness instructors, and personal trainers, are preferred delivery agents for education and instruction on chronic pain, physical activity, and strategies to use adherence-promoting behavioral skills. However, exercise professionals receive no relevant training during certification or continuing education opportunities to effectively support their participants living with chronic pain. Based on the ORBIT model for early pre-efficacy phases of development and testing of new behavioral treatments, the present Phase IIa proof-of-concept study was conducted. The purpose was to examine the impacts of a newly developed chronic pain and physical activity training workshop on psychosocial outcomes among exercise professionals. Outcomes included knowledge and attitudes regarding chronic pain, attitudes and beliefs about the relationship between pain and impairment, and self-efficacy to educate and instruct participants with chronic pain. Methods Forty-eight exercise professionals (Mage=44.4±11.0 years) participated in a three-hour, in-person workshop that was offered at one of four different locations. Participants completed pre- and post-workshop outcome assessment surveys. Results Mixed MANOVA results comparing time (pre- versus post-workshop) by workshop location (sites 1 to 4) illustrated a significant within-subjects time effect (p<0.001). All outcomes significantly improved from pre- to post-workshop (p's<0.001), demonstrating large effect sizes (partial eta-squared values ranging from 0.45 to 0.59). Conclusions Findings offer early phase preliminary support for the effectiveness of the chronic pain and physical activity training workshop for exercise professionals. Based on ORBIT model recommendations, findings warrant future phased testing via a pilot randomized clinical trial as well as testing for impacts that trained professionals have on activity adherence among their clients living with chronic pain. Eventual workshop adoption by exercise professional certification organizations would ensure widespread and sustainable access to qualified exercise professionals to help individuals engage in physical activity. By increasing the capacity of available exercise professionals to deliver effective support, active individuals could better manage their chronic pain and live well.
Learn More >To assess the relative safety of oral tapentadol PR and other opioid analgesics for moderate or severe chronic pain in adults, we conducted a systematic review and network meta-analysis (NMA). A systematic review was conducted to identify randomized controlled trials (RCTs) and randomised withdrawal trials of tapentadol with other WHO stage II and III opioid analgesics in patients with moderate or severe chronic pain. Searches were conducted in MEDLINE, EMBASE, PubMed, Cochrane databases and trial registries. Feasibility assessment evaluated the trials' suitability for NMA. Outcomes assessed were overall AEs, overall serious adverse events, constipation, nausea, dizziness, somnolence, headache, and discontinuation due to AEs. Randomized withdrawal trials were analysed separately to other RCTs. Searches conducted in April 2019 identified 16,604 records. Following screening and feasibility assessment, 29 RCTs and 19 randomized withdrawal trials were identified and included in the NMA.Consistent with existing research, evidence from RCTs suggested that tapentadol is associated with relatively lower odds of adverse events occurring than most active comparators. The withdrawal trial data were less clear, with higher uncertainty around the results, and results that appear to contradict the RCT evidence. There are a number of trial design factors that may be affecting these results. RCT evidence suggests that tapentadol can be a useful treatment option for patients suffering from chronic pain and in need of an opioid analgesic. Opioids should be prescribed by a qualified physician only after other analgesics have been considered, taking side effects and misuse risk into account.
Learn More >Chronic pain is a global health problem, affecting around 1 in 5 individuals in the general population. The understanding of the key role of functional brain alterations in the generation of chronic pain has led researchers to focus on pain treatments that target brain activity. Electroencephalographic neurofeedback attempts to modulate the power of maladaptive electroencephalography frequency powers to decrease chronic pain. Although several studies have provided promising evidence, the effect of electroencephalographic neurofeedback on chronic pain is uncertain.
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