Peripheral cannabinoid receptor activation attenuates frostbite-induced chronic pain via modulation of TRP channels, neuroinflammation, and autophagy.

Development and validation of clinically Mimicable model of frostbite injury-induced chronic pain

Cold injury or frostbite is a common medical condition that causes serious clinical complications including sensory abnormalities and chronic pain ultimately affecting overall well-being. Opioids are the first-choice drug for the treatment of frostbite-induced chronic pain; however, their notable side effects, including sedation, motor incoordination, respiratory depression, and drug addiction, present substantial obstacle to their clinical utility. To address this challenge, we have exploited peripheral mu-opioid receptors as potential target for the treatment of frostbite-induced chronic pain. In this study, we investigated the effect of dermorphin [D-Arg2, Lys4] (1-4) amide (DALDA), a peripheral mu-opioid receptor agonist, on frostbite injury and hypersensitivity induced by deep freeze magnet exposure in rats. Animals with frostbite injury displayed significant hypersensitivity to mechanical, thermal, and cold stimuli which was significant ameliorated on treatment with different doses of DALDA (1, 3, and 10 mg/kg) and ibuprofen (100 mg/kg). Further, molecular biology investigations unveiled heightened oxido-nitrosative stress, coupled with a notable upregulation in the expression of TRP channels (TRPA1, TRPV1, and TRPM8), glial cell activation, and neuroinflammation (TNF-α, IL-1β) in the sciatic nerve, dorsal root ganglion (DRG), and spinal cord of frostbite-injured rats. Treatment with DALDA leads to substantial reduction in TRP channels, microglial activation, and suppression of the inflammatory cascade in the ipsilateral L4-L5 DRG and spinal cord of rats. Overall, findings from the present study suggest that activation of peripheral mu-opioid receptors mitigates chronic pain in rats by modulating the expression of TRP channels and suppressing glial cell activation and neuroinflammation.

BackgroundAn epidemiological survey conducted in Japan in fiscal year 2010 revealed a high prevalence of chronic musculoskeletal pain, low patient satisfaction with treatment, a high incidence of protracted treatment lasting a year or more, and reduced quality of life. To improve the current system for treating chronic musculoskeletal pain, it is important to identify risk factors, including patient characteristics, for developing chronic pain. Thus, we sought to determine the incidence of new chronic pain in the Japanese population, as well as the persistence rate, associated factors, and current state of treatment of chronic pain, by repeating a postal survey in a nationwide representative sample group first surveyed in 2010. MethodsAmong 11,507 participants in the 2010 epidemiological survey, 1,717 reported chronic pain and 6,283 reported no chronic pain. A repeat questionnaire, mailed to subjects in these 2 groups in fiscal year 2011, received replies from 85% of those who reported pain and 76% of those without pain in 2010. ResultsThe incidence of new chronic pain was 11.1%. Risk factors for developing chronic pain included working in a professional, managerial, or clerical/specialist occupation, being female, having a BMI ≥25; currently using alcohol or cigarettes; and having completed an education level of vocational school or higher. Persistent chronic pain was reported by 45.2% of respondents. Those with severe (VAS score ≥7) and constant lower-back pain lasting more than 5 years had the highest risk of the pain persisting. More than 80% respondents with persistent chronic pain had a history of treatment, and while about 30% were still receiving treatment at the time of the survey, the other 50% had discontinued treatment despite the persistence of pain because of a low degree of satisfaction with treatment. DiscussionWe identified risk factors related to the development of new chronic pain and the persistence of chronic pain. Countermeasures to prevent chronic pain could be especially important for the high-risk populations for understanding the pathology of chronic pain.

Peripheral Pain-Sensing Neurons: from Molecular Diversity to Functional Specialization

Recently published systematic reviews came to different conclusions with respect to the efficacy, tolerability and safety of cannabinoids for treatment of chronic neuropathic pain. A systematic search of the literature was carried out in MEDLINE, the Cochrane central register of controlled trials (CENTRAL) and clinicaltrials.gov up until November 2015. We included double-blind randomized placebo-controlled studies (RCT) of at least 2 weeks duration and with at least 9 patients per treatment arm comparing medicinal cannabis, plant-based or synthetic cannabinoids with placebo or any other active drug treatment in patients with chronic neuropathic pain. Clinical endpoints of the analyses were efficacy (more than 30 % or 50 % reduction of pain, average pain intensity, global improvement and health-related quality of life), tolerability (drop-out rate due to side effects, central nervous system and psychiatric side effects) and safety (severe side effects). Using a random effects model absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables. The methodological quality of RCTs was rated by the Cochrane risk of bias tool. We included 15 RCTs with 1619 participants. Study duration ranged between 2 and 15 weeks. Of the studies 10 used a plant-derived oromucosal spray with tetrahydrocannabinol/cannabidiol, 3 studies used a synthetic cannabinoid (2 with nabilone and 1 with dronabinol) and 2 studies used medicinal cannabis. The 13 studies with parallel or cross-over design yielded the following results with 95 % confidence intervals (CI): cannabinoids were superior to placebo in the reduction of mean pain intensity with SMD - 0.10 (95 % CI - 0.20- - 0.00, p = 0.05, 13 studies with 1565 participants), in the frequency of at least a 30 % reduction in pain with an RD of 0.10 [95 % CI 0.03-0.16, p = 0.004, 9 studies with 1346 participants, number needed to treat for additional benefit (NNTB) 14, 95 % CI 8-45] and in the frequency of a large or very large global improvement with an RD of 0.09 (95 % CI 0.01-0.17, p = 0.009, 7 studies with 1092 participants). There were no statistically significant differences between cannabinoids and placebo in the frequency of at least a 50 % reduction in pain, in improvement of health-related quality of life and in the frequency of serious adverse events. Patients treated with cannabinoids dropped out more frequently due to adverse events with an RD of 0.04 [95 % CI 0.01-0.07, p = 0.009, 11 studies with 1572 participants, number needed to treat for additional harm (NNTH) 19, 95 % CI 13-37], reported central nervous system side effects more frequently with an RD of 0.38 (95 % CI 0.18-0.58, p = 0.0003, 9 studies with 1304 participants, NNTH 3, 95 % CI 2-4) and psychiatric side effects with an RD of 0.11 (95 % CI 0.06-0.16, p < 0.0001, 9 studies with 1304 participants, NNTH 8, 95 % CI 7-12). Cannabinoids were marginally superior to placebo in terms of efficacy and inferior in terms of tolerability. Cannabinoids and placebo did not differ in terms of safety during the study period. Short-term and intermediate-term therapy with cannabinoids can be considered in selected patients with chronic neuropathic pain after failure of first-line and second-line therapies.

Comorbidities and the complexities of chronic pain.

Trifluoro-icaritin alleviates chronic inflammatory pain through α7nAChR-mediated suppression of HMGB1/NF-κB signaling in the spinal cord of rats

Background/Aims: Brachial plexus avulsion (BPA) generally causes a chronic persistent pain that lacks efficacious treatment. Curcumin has been found to possess anti-inflammatory abilities. However, little is known about the mechanisms and effects of curcumin in an animal model of BPA. Methods: Mechanical withdrawal thresholds (MWT) were examined by von Frey filaments. Cold allodynia was tested by the acetone spray test. The levels of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 in rat spinal cords were analyzed by the enzyme-linked immunosorbent assay, and the expression levels of c-Fos and nerve growth factor (NGF) were measured by Western blot. The expression level of glial fibrillary acidic protein (GFAP) was observed by immunofluorescence and Western blot. Results: After curcumin treatment, the MWT showed a significant increase when compared to the BPA group on both hind paws. A remarkable decrease of paw-withdrawal response frequency was observed compared with the BPA group. In addition, curcumin treatment significantly decreased the levels of TNF-α and IL-6 in rat spinal cords that were exceedingly upregulated in the BPA group. The protein levels of c-Fos and NGF were decreased by treatment with curcumin compared with the corresponding protein levels in the BPA group. Besides, curcumin reduced the number of GFAP positive cells and GFAP expression. Conclusions: Our findings suggest that curcumin significantly extenuates the BPA-induced pain and inflammation by reducing the expression level of proinflammatory cytokines and pain-associated proteins and inhibiting the activity of astrocytes.

Temporomandibular disorders

Differential effects of NMDA and group I mGluR antagonists on both nociception and spinal cord protein kinase C translocation in the formalin test and a model of neuropathic pain in rats

To determine the persistence of chronic pain among community-dwelling older persons and to identify factors related to persistent chronic pain. In this prospective longitudinal study, a random sample of Finnish community-dwelling people aged 76 years and older (n=256) were interviewed annually by a trained nurse at 3 time points. Data on prevalence, duration, location, and intensity of musculoskeletal pain, analgesic use, demographics, and health characteristics were collected during the interviews. Chronic pain was reported by 48.9% of the participants at baseline, with 74.4% of them experiencing persistent chronic pain, that is, they reported chronic pain at all 3 study points. Persistent chronic pain was associated with poor self-rated health (adjusted odds ratio [AOR]=2.26, 95% confidence interval [95% CI] 1.03-4.98), mobility difficulties (AOR=2.80, 95% CI, 1.22-6.43), and arthrosis or rheumatoid arthritis (AOR=3.07, 95% CI, 1.47-6.42) when compared with persons without chronic pain. However, only 15% of the persons with persistent chronic pain were using analgesics on a regular basis, and one out of every 5 was not taking any analgesics. Chronic musculoskeletal pain is a highly persistent condition among community-dwelling older persons and it is related to poor health and mobility difficulties. In addition, the use of daily analgesic is low despite the continuous nature of chronic pain.

Association of diurnal cortisol rhythm with chronic pain: Evidence from a prospective cohort study in community-dwelling adults.

ObjectivesChronic Pain in children is an undertreated and increasing cause of morbidity, with an estimated prevalence of between 8 and 88% depending on the type of pain.1 2 Biopsychosocial factors...

To determine the impact of pain, stress, and negative emotions like anger, sadness, fear and regret in the persistence or development of chronic pain four months after admission to the emergency department (ED). Data from 641 ED patients in the SOFTER IV clinical trial were analyzed. Pain, stress, and negative emotions were assessed at discharge, then dichotomized as non-severe or severe. Patients with chronic pain history were included in the analysis. Chronic pain at four months was evaluated using a binary yes/no question, and its predictors were identified using multivariable logistic regression with variable selection based on statistical significance. At four months post-ED admission, 35.1% of patients reported chronic pain. As expected, a prior history of chronic pain was a strong predictor. Among patients with no history of chronic pain, those who reported severe anger at discharge were at nearly three times the risk of developing chronic pain (OR=2.8, 95% CI: 1.4-5.6). In addition, patients admitted for traumatic injuries and female patients also showed elevated risk, with odds ratios of 1.7 (95% CI: 1.2-2.4) and 1.4 (95% CI: 1.0-2.0), respectively. Anger may affect the development or persistence of chronic pain after an emergency department admission.

Chronic pain after breast reconstruction is an ill-defined process which can generate significant patient morbidity and disability. The purpose of this study was to examine chronic, persistent pain in a prospective study of free flap breast reconstruction patients, in an effort to identify possible points of intervention and counseling. We performed a prospective study evaluating function, quality of life, and satisfaction in patients undergoing abdominally based autologous reconstruction between 2006 and 2010. Using the short form 36, we examined the presence of chronic body pain (>4 months) as well as overall mental and physical health. Patients with debilitating pain were compared to those without in a post hoc analysis. Overall, 399 women underwent reconstruction during the study period, with 149 enrolling and having long-term follow-up in this portion of the prospective study. Twenty-six (17%) of 149 patients experienced chronic body pain that was moderately debilitating after autologous reconstruction, making it one of the most common complications experienced in this cohort. No differences were noted in demographics, medical history, procedure type, history of axillary surgery, radiation treatment, surgical outcomes, or follow-up time between the cohorts. However, patients with chronic pain were found to have higher preoperative pain scores (P < 0.0001) and lower physical, mental, and overall health scores across time points. All scores significantly worsened with time in comparison to the cohort without pain, who, in contrast showed score improvement across all areas. Although pain issues trended toward being noted in postoperative visits more frequently in the chronic pain cohort (37% vs 19%, P = 0.051), only 1 (4.2%) patient was referred for pain service consultation. Additionally, satisfaction with reconstruction was significantly lower in patients who demonstrated chronic pain (P = 0.03). Factors contributing to chronic pain continue to be elusive and understudied. Our data demonstrate the importance of screening for chronic pain, as we determined that preoperative pain is linked to increased, moderately debilitating postoperative chronic pain. Persistent chronic pain, in turn, is associated with significant morbidity, disability, and dissatisfaction. Such patients with pain issues may benefit from additional preoperative counseling and early involvement of the pain service.