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The incidence of chronic postoperative pain after total knee replacement (TKR) is approx. 20%, and hence preoperative risk factors are important to identify. Recent studies have indicated that preoperative inflammatory markers might hold prognostic information for the development of chronic postoperative pain. Long non-coding RNA (lncRNA) regulates the expression of genes related to e.g. inflammatory processes. The current study aimed to investigate the preoperative lncRNA signature as possible preoperative predictive markers for chronic postoperative pain following TKR.
Learn More >Human NaV1.9 (hNaV1.9), encoded by SCN11A, is preferentially expressed in nociceptors, and its mutations have been linked to pain disorders. NaV1.9 could be a promising drug target for pain relief. However, the modulation of NaV1.9 activity has remained elusive. Here, we identified a new candidate NaV1.9-interacting partner, protein arginine methyltransferase 7 (PRMT7). Whole-cell voltage clamp recordings showed that coelectroporation of human SCN11A and PRMT7 in dorsal root ganglia (DRG) neurons of Scn11a-/- mice increased the hNaV1.9 current density. In contrast, a Prmt7 inhibitor (DS-437) reduced mNaV1.9 currents in Scn11a+/+ mice. Using the reporter molecule CD4, we observed an increased distribution of hLoop1 on the cell surface of PRMT7-overexpressing HKE293T cells. Furthermore, we found that PRMT7 mainly binds to residues 563-566 within the first intracellular loop of hNaV1.9 (hLoop1) and methylates hLoop1 at arginine residue 519. Moreover, overexpression of Prmt7 increased the number of action potential fired in DRG neurons of Scn11a+/+ mice but not Scn11a-/- mice. However, DS-437 significantly inhibited the action potential frequency of DRG neurons and relieved pain hypersensitivity in Scn11aA796G/A796G mice. In summary, our observations revealed that PRMT7 modulates neuronal excitability by regulating NaV1.9 currents, which may provide a potential method for pain treatment.
Learn More >The existence of a trigeminocervical complex (TCC) has been suggested based on animal data, but only indirect evidence exists in humans. We investigated the functional relationship between the trigeminal and the occipital region by stimulating one region and measuring electrical pain thresholds (EPTs) of the corresponding opposite region. This study consists of two single-blinded, randomized protocols. 40 healthy participants were recruited in the propaedeutic Protocol I. EPTs were measured on the V1 and the greater occipital nerve (GON) dermatome bilaterally as well as on the left forearm longitudinally before and after application of topical capsaicin. Protocol II was then online pre-registered and, additionally, the ipsilateral trigeminal dermatomes V2 and V3 were tested. GON stimulation increased the EPT ipsilateral at V1 after 20 minutes (p=0.006) compared to baseline, whereas trigeminal stimulation increased the EPT at the ipsilateral (p=0.023) as well as the contralateral GON (p=0.001) following capsaicin application. Protocol II confirmed these results and additionally showed that GON stimulation with capsaicin increased EPTs ipsilateral at all three trigeminal dermatomes and that trigeminal stimulation on V1 led to an ipsilateral increase of EPTs at GON, V2 and V3. Our data suggest a strong functional interplay between the trigeminal and occipital system in humans. The fact that stimulation of one of these dermatomes increases the electrical pain threshold of the respective other nerve could be explained by segmental inhibition on brainstem level.
Learn More >Reports have emerged of abrupt tapering among recipients of long-term prescription opioids to conform to new prescribing guidelines. We conducted a population-based, repeated cross-sectional time-series study among very high-dose (≥200 MME) opioid recipients in Ontario, Canada, to examine changes in the monthly prevalence of rapid tapering from 2014 to 2018, defined as recipients experiencing either a ≥50% reduction in daily doses or abrupt discontinuation sustained for 30 days. Interventional autoregressive integrated moving average (ARIMA) models were used to test for significant changes following key guidelines, and drug policies and programs. A sensitivity analysis examined rapid tapering sustained for 90 days. The monthly prevalence of rapid tapering events was stable from January 2014 to September 2016 (average monthly prevalence: 1.4%), but increased from 1.4% in October 2016 to 1.8% in April 2017 (p=0.001), coincident with Ontario's Fentanyl Patch-for-Patch Return Program implementation. Transient spikes in the prevalence of rapid tapering also occurred two months following Ontario's delisting of publicly funded high-strength opioids and the release of updated Canadian Opioid Prescribing Guideline for Chronic Pain, reaching 2.3% in March 2017 and July 2017, respectively. However this prevalence decreased to 1.2% in December 2018 (p<.0001). Although the prevalence of abrupt opioid discontinuation was lower, similar trends were observed. Our sensitivity analysis examining longer-lasting rapid tapering found similar trends but lower prevalence, with no changes in complete discontinuation. These temporary increases in rapid tapering events highlight the need for improved communication and evidence-based resources for prescribers to minimize negative consequences of evolving policies and guidelines.
Learn More >In recent years, long-term prescribing and use of strong opioids for chronic non-cancer pain (CNCP) has increased in high-income countries. Yet existing uncertainties, controversies and differing recommendations make the rationale for prolonged opioid use in CNCP unclear. This systematic review and meta-analyses (MAs) compared the efficacy, safety and tolerability of strong opioids with placebo/non-opioid therapy in CNCP, with a special focus on chronic low back pain (CLBP). Systematic literature searches were performed in four electronic databases (Medline, Web of Science, Cochrane Library and CINAHL) in July 2019 and updated by regular alerts until December 2020. We included 16 placebo-controlled RCTs for CLBP and five studies (2 RCTs and 3 non-randomized studies) of opioids vs non-opioids for CNCP in the quantitative and qualitative synthesis. Random effects pairwise MAs were performed for efficacy, safety and tolerability outcomes and subgroup analyses for treatment duration, study design, and opioid experience status. Very low- to low-certainty findings suggest that 4-15 weeks (short-/intermediate term) opioid therapy in CLBP (compared to placebo) may cause clinically relevant reductions in pain but also more gastrointestinal and nervous system adverse events (AEs), with likely no effect on disability. In contrast, long-term opioid therapy (≥ 6 months) in CNCP may not be superior to non-opioids in improving pain or disability/pain-related function, but seems to be associated with more AEs, opioid abuse/dependence, and possibly an increase in all-cause mortality. Our findings also underline the importance and need for well-designed trials assessing long-term efficacy and safety of opioids for CNCP and CLBP.
Learn More >Sleep problems and regular leisure time physical activity (LTPA) are interrelated and have contrasting effects on risk of back pain. However, no studies have investigated the influence of long-term poor sleep quality on risk of back-related disability, or if LTPA modifies this association. The study comprised data on 8601 people who participated in three consecutive surveys over ~ 22 years, and who reported no chronic back pain at the two first surveys. Adjusted risk ratios (RRs) for back-related disability were calculated at the last survey, associated with the joint effect of changes in sleep quality between the two first surveys and meeting physical activity guidelines at the second survey. Compared to people with long-term good sleep, people with long-term poor sleep had nearly twice the risk of back-related disability (RR 1.92, 95% CI 1.48-2.49). There was no statistical interaction between sleep and LTPA but people who reported long-term poor sleep and meeting the physical activity guidelines had 35% lower risk of back-related disability compared to people with same level of sleep problems, but who not met the guidelines. These findings suggest that long-term poor sleep quality contributes to a substantially increased risk of chronic and disabling back pain irrespective of LTPA.
Learn More >Neuronal calcium sensor 1 (NCS1), a calcium-binding protein, and transient receptor potential V4 (TRPV4), a plasma membrane calcium channel, are fundamental in the regulation of calcium homeostasis. The interactions of these proteins and their regulation by paclitaxel (PTX) were investigated using biochemical, pharmacological, and electrophysiological approaches in both a breast cancer epithelial cell model and a neuronal model. TRPV4 and NCS1 reciprocally immunoprecipitated each other, suggesting that they comprise a signaling complex. The functional consequence of this physical association was that TRPV4 currents increased with increased NCS1 expression. Calcium fluxes through TRPV4 correlated with the magnitude of TRPV4 currents and these calcium fluxes depended on NCS1 expression levels. Exposure to PTX amplified the acute effects of TRPV4 expression, currents, and calcium fluxes, but decreased the expression of NCS1. These findings augment the understanding of the properties of TRPV4, the role of NCS1 in the regulation of TRPV4, and the cellular mechanisms of PTX-induced neuropathy. TRPV4 and NCS1 physically and functionally interact. Increased expression of NCS1 enhances TRPV4 dependent currents, which are further amplified by treatment with the chemotherapeutic drug, paclitaxel, an effect associated with adverse effects of chemotherapy, including neuropathy.
Learn More >Opioids are still widely prescribed to long-term pain patients although they are no longer recommended for long-term treatments due to poor evidence for long-term efficacy, risks of serious side effects, and the possibility of inducing opioid hyperalgesia. In a Cochrane study from 2017, the authors identified an urgent need for more randomized controlled trials investigating the efficiency and effects of opioid tapering. The study aimed to assess (1) the efficiency of a structured intervention in causing stable reductions of opioid consumption in a population with long-term non-malignant pain and (2) effects on pain, pain cognitions, physical and mental health, quality of life, and functioning in response to opioid tapering.
Learn More >To assess the efficacy and harms of adding medical cannabis to prescription opioids among people living with chronic pain.
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