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Many studies have shown a global efficacy of laparoscopic surgery for patients with endometriosis in reducing painful symptoms and improving quality of life (QoL) in the short and long-term. The aim of this study was to analyze the different trajectories of long-term evolution in QoL and symptoms following surgical treatment for endometriosis, and to identify corresponding patient profiles. This prospective and multicenter cohort study concerned 962 patients who underwent laparoscopic treatment for endometriosis. QoL was evaluated using the Short Form (SF)-36 questionnaire and intensity of pain was reported using a visual analog scale prior to surgery and at 6, 12, 18, 24 and 36 months after surgery. Distinctive trajectories of pain and QoL evolution were identified using group-based trajectory modeling, an approach which gathers individuals into meaningful subgroups with statistically similar trajectories. Pelvic symptom trajectories (models of the evolution of dysmenorrhea, dyspareunia and chronic pelvic pain intensity over years) correspond to (1) patients with no pain or pain no longer after surgery, (2) patients with the biggest improvement in pain and (3) patients with continued severe pain after surgery. Our study reveals clear trajectories for the progression of symptoms and QoL after surgery that correspond to clusters of patients. This information may serve to complete information obtained from epidemiological methods currently used in selecting patients eligible for surgery.
Learn More >Fibromyalgia syndrome (FMS) is a chronic condition of widespread pain. In 2010, the American College of Rheumatology (ACR) proposed new diagnostic criteria for FMS based on two scales: the Widespread Pain Index (WPI) and Symptoms Severity (SS) scale. This study evaluated the reliability, factor structure and predictive validity of WPI and SS. In total, 102 women with FMS and 68 women with rheumatoid arthritis (RA) completed the WPI, SS, McGill Pain Questionnaire, Trait Anxiety Inventory, Fatigue Severity Scale, Oviedo Quality of Sleep Questionnaire, and Beck Depression Inventory. Pain threshold and tolerance and a measure of central sensitization to pain were obtained by pressure algometry. Values on WPI and SS showed negative-skewed frequency distributions in FMS patients, with most of the observations concentrated at the upper end of the scale. Factor analysis did not reveal single-factor models for either scale; instead, the WPI was composed of nine pain-localization factors and the SS of four factors. The Cronbach's α (i.e., Internal consistency) was 0.34 for the WPI,0.83 for the SS and 0.82 for the combination of WPI and SS. Scores on both scales correlated positively with measures of clinical pain, fatigue, insomnia, depression, and anxiety but were unrelated to pain threshold and tolerance or central pain sensitization. The 2010 ACR criteria showed 100% sensitivity and 81% specificity in the discrimination between FMS and RA patients, where discrimination was better for WPI than SS. In conclusion, despite their limited reliability, both scales allow for highly accurate identification and differentiation of FMS patients. The inclusion of more painful areas in the WPI and of additional symptoms in the SS may reduce ceiling effects and improve the discrimination between patients differing in disease severity. In addition, the use of higher cut-off values on both scales may increase the diagnostic specificity in Spanish samples.
Learn More >The prefrontal ventrolateral orbital cortex (VLO) is involved in antinociception. It has been found that dopamine receptors, adrenoceptors, serotonin receptors and μ-opioid receptors are involved in this effect through direct/indirect activation of the VLO output neurons. However, the effect of CB1 receptors on the VLO modulation of pain has not been studied. In this study, we investigated whether activation of CB1 receptors in the VLO modulates nociception. A common peroneal nerve (CPN) ligation model was used to induce neuropathic pain in male mice. On day 13 after CPN ligation, spontaneous firing of the VLO pyramidal neurons was recorded and CB1 receptor level in the VLO was detected. Mechanical allodynia was measured after HU210 was microinjected into the VLO. Relative contribution of CB1 receptors on GABAergic neurons and glutamatergic neurons was determined by CB1 receptor knockdown using a viral strategy. Our data indicated that on day 13 after nerve injury, spontaneous firing of the VLO pyramidal neurons reduced significantly but was enhanced by intraperitoneal injection of HU210 (20 μg/kg), a potent CB1 receptor agonist. Expression of CB1 receptor in the VLO was up-regulated. Microinjection of HU210 into the VLO attenuated allodynia, and this effect was blocked by pre-microinjection of specific CB1 receptor antagonist AM281. Deletion of CB1 receptors on GABAergic neurons in the VLO can completely block HU210-induced analgesia. Thus, it can be concluded that activation of CB1 receptors on GABAergic interneurons in the VLO may be involved in analgesia effect of cannabinoids.
Learn More >Pain produced by bone cancer is often severe and difficult to treat. Here we examined effects of Resolvin D1 (RvD1) or E1 (RvE1), antinociceptive products of ω-3 polyunsaturated fatty acids, on cancer-induced mechanical allodynia and heat hyperalgesia. Experiments were performed using a mouse model of bone cancer produced by implantation of osteolytic ficrosarcoma into and around the calcaneus bone. Mechanical allodynia and heat hyperalgesia in the tumor-bearing paw were assessed by measuring withdrawal responses to a von Frey monofilament and to radiant heat applied on the plantar hind paw. RvD1, RvE1, and cannabinoid receptor antagonists were injected intrathecally. Spinal content of endocannabinoids was evaluated using UPLC-MS/MS analysis. RvD1 and RvE1 had similar antinociceptive potencies. ED for RvD1 and RvE1 in reducing mechanical allodynia were 0.2 pg (0.53 fmol) and 0.6 pg (1.71 fmol), respectively, and were 0.3 pg (0.8 fmol) and 0.2 pg (0.57 fmol) for reducing heat hyperalgesia. Comparisons of dose-response relationships showed equal efficacy for reducing mechanical allodynia, however, efficacy for reducing heat hyperalgesia was greater for of RvD1. Using UPLC-MS/MS we determined that RvD1, but not RvE1, increased levels of the endocannabinoids Anandamide and 2-Arachidonoylglycerol in the spinal cord. Importantly, Resolvins did not alter acute nociception or motor function in naïve mice. Our data indicate, that RvD1 and RvE1 produce potent antiallodynia and antihyperalgesia in a model of bone cancer pain. RvD1 also triggers spinal upregulation of endocannabinoids that produce additional antinociception predominantly through CB2 receptors.
Learn More >This study aims to explore whether orexin 1 receptors (Orx1R) in the ventrolateral periaqueductal gray matter (vlPAG) play a role in the modulation of migraine headaches in adult male Wistar rats. To model chronic migraine-associated pain, nitroglycerin (NTG) (5 mg/kg/IP) was administered to test subjects every second day for 9 days. After the last NTG injection, rats were randomly separated into the following groups (n = 6): orexin-A (OrxA) groups that received intra-vlPAG OrxA (25, 50, and 100 pM), an Orx1R antagonist group, a SB-334867 (20 μM) group; and a SB-334867 (20 μM) + OrxA (100 pM) group. After 10 min, migraine-associated behavioral symptoms were recorded in all animals for up to 90 min. Light-dark chamber and hot plate tests were used for assessing light aversion and thermal hyperalgesia, respectively. Calcitonin gene-related peptide (CGRP)-positive cells were detected in the trigeminal nucleus caudalis (Vc) by immunofluorescence microscopy. NTG caused significant freezing behavior, which was prevented by all OrxA doses. Moreover, OrxA (100 pM) could obstruct NTG-induced increases in facial rubbing and decreases in climbing and body grooming. Furthermore, NTG-induced light aversion and thermal hyperalgesia were attenuated by OrxA at doses of 50 and 100 pM. The effects of OrxA were significantly blocked by SB-334867 (20 μM). Besides, OrxA (100 pM) decreased NTG-induced CGRP upregulation. The data revealed that the activation of Orx1Rs in the vlPAG is effective in relieving NTG-induced migraine symptoms mainly by the downregulation of CGRP in the Vc of rats.
Learn More >Chronic pain is one of the most challenging and debilitating symptoms to manage after traumatic brain injury (TBI), yet the underlying mechanisms remain elusive. The disruption of normal endogenous pain control mechanisms has been linked to several forms of chronic pain and may play a role in pain after TBI. We hypothesized therefore that dysfunctional descending noradrenergic and serotonergic pain control circuits may contribute to the loss of diffuse noxious inhibitory control (DNIC), a critical endogenous pain control mechanism, weeks to months after TBI. For these studies, the rat lateral fluid percussion model of mild TBI was used along with a DNIC paradigm involving a capsaicin-conditioning stimulus. We observed sustained failure of the DNIC response up to 180-days post injury. We confirmed, that descending α adrenoceptor-mediated noradrenergic signaling was critical for endogenous pain inhibition in uninjured rats. However, augmenting descending noradrenergic signaling using reboxetine, a selective noradrenaline reuptake inhibitor, failed to restore DNIC after TBI. Furthermore, blocking serotonin-mediated descending signaling using selective spinal serotonergic fiber depletion with 5, 7-dihydroxytryptamine was also unsuccessful at restoring endogenous pain modulation after TBI. Unexpectedly, increasing descending serotonergic signaling using the selective serotonin reuptake inhibitor escitalopram and the serotonin-norepinephrine reuptake inhibitor duloxetine restored the DNIC response in TBI rats at both 49- and 180- days post injury. Consistent with these observations, spinal serotonergic fiber depletion with 5, 7-dihydroxytryptamine eliminated the effects of escitalopram. Intact α adrenoceptor signaling, however, was not required for the serotonin-mediated restoration of DNIC after TBI. These results suggest that TBI causes maladaptation of descending nociceptive signaling mechanisms and changes in the function of both adrenergic and serotonergic circuits. Such changes could predispose those with TBI to chronic pain.
Learn More >Recent years have seen a dramatic escalation of off-label prescribing for gabapentin and pregabalin (gabapentinoids) owing in part to generic versions of each being released over the past two decades, but also in part as a response to increasing calls for multimodal and non-opioid pain management strategies. In this context, several recent articles have been published alleging widespread misuse, with speculations on the unappreciated addictive potential of the gabapentinoid class of drugs. Reports of a 1% population-level abuse prevalence stem from a single internet survey in the UK, and the vanishingly small adverse event outcomes data do not support such frequency. In this targeted narrative review, we aim to disabuse pain physicians and other clinicians, pharmacists, and policymakers of both the positive and negative myths concerning gabapentinoid medications.
Learn More >Deprescribing, the process of reducing or discontinuing unnecessary or harmful medicines is an essential part of clinical practice.
Learn More >The engineered multifunctional protein C2C was tested for control of sensory neuron activity by targeted G-actin modification. C2C consists of the heptameric oligomer, C2II-CI, and the monomeric ribosylase, C2I. C2C treatment of sensory neurons and SH-SY5Y cells in vitro remodeled actin and reduced calcium influx in a reversible manner. C2C prepared using fluorescently labeled C2I showed selective in vitro C2I delivery to primary sensory neurons but not motor neurons. Delivery was dependent on presence of both C2C subunits and blocked by receptor competition. Immunohistochemistry of mice treated subcutaneously with C2C showed colocalization of subunit C2I with CGRP-positive sensory neurons and fibers but not with ChAT-positive motor neurons and fibers. The significance of sensory neuron targeting was pursued subsequently by testing C2C activity in the formalin inflammatory mouse pain model. Subcutaneous C2C administration reduced pain-like behaviors by 90% relative to untreated controls 6 h post treatment and similarly to the opioid buprenorphene. C2C effects were dose dependent, equally potent in female and male animals and did not change gross motor function. One dose was effective in 2 h and lasted 1 week. Administration of C2I without C2II-CI did not reduce pain-like behavior indicating its intracellular delivery was required for behavioral effect.
Learn More >Cognitive models of chronic pain emphasize the critical role of pain catastrophizing in attentional bias to pain-related stimuli. The aim of this study was (a) to investigate the relationship between pain catastrophizing and the ability to inhibit selective attention to pain-related faces (attentional bias); and (b) to determine whether attentional control moderated this relationship. One hundred and ten pain-free participants completed the anti-saccade task with dynamic facial expressions, specifically painful, angry, happy, and neutral facial expressions and questionnaires including a measure of pain catastrophizing. As predicted, participants with high pain catastrophizing had significantly higher error rates for antisaccade trials with pain faces relative to other facial expressions, indicating a difficulty disinhibiting attention towards painful faces. In moderation analyses, data showed that attentional control moderated the relationship between attentional bias to pain faces and pain catastrophizing. Post-hoc analyses demonstrated that it was shifting attention (not focusing) that accounted for this effect. Only for those with high self-reported ability to shift attention was there a significant relationship between catastrophizing and attentional bias to pain. These findings confirm that attentional control is necessary for an association between attentional bias and catastrophizing to be observed, which may explain the lack of relationships between attentional bias and individual characteristics, such as catastrophizing, in prior research.
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