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Both persistent pain and cognitive decline prevalence increase with advancing age and are associated with functional decline. However, the association of pain and cognitive decline has not been evaluated yet by a systematic assessment of longitudinal studies. We aimed to assess the association of persistent pain as a risk factor for cognitive decline in community older adults, using data from longitudinal studies in a systematic review and meta-analysis. Publications were identified using a systematic search on PubMed, EMBASE and Cochrane Library databases from inception to June 2019. Since heterogeneity across studies was high, we used random-effects meta-analysis to calculate the pooled relative risk for the association between persistent pain and cognitive decline incidence. We investigated sources of heterogeneity among studies using meta-regression and stratified analyses. We included ten prospective longitudinal studies with 57,495 participants with a mean age at the baseline ranging from 61.8 to 88.4 years old and mean follow-up times ranging from 2.75 to 11.8 years. Persistent pain at baseline was not associated with the development of cognitive decline during the follow-up (pooled RR = 1.05, 95% CI = 0.92-1.21). In sensitivity analyses, only length of follow-up time ≤ 4.5 years was associated with a higher risk of cognitive impairment (pooled RR = 1.19, 95% CI = 1.10-1.28). Persistent pain was not associated with the incidence of cognitive decline.
In clinical trials of treatments for chronic pain, the percentage of participants who withdraw early can be as high as 50%. Major reasons for early withdrawal in these studies include perceived lack of efficacy and adverse events. Commonly employed strategies for accommodating missing data include last observation carried forward, baseline observation carried forward, and more principled methods such as mixed model repeated measures and multiple imputation. All of these methods require strong and untestable assumptions concerning the conditional distribution of outcomes after dropout given the observed data. We review recent developments in statistical methods for handling missing data in clinical trials, including implications of the increased emphasis being placed on precise formulation of the study objectives and the estimand (treatment effect to be estimated) of interest. A flexible method that appears to be well-suited for the analysis of chronic pain clinical trials is control-based imputation, which allows a variety of assumptions to be made concerning the conditional distribution of post-dropout outcomes that can be tailored to the estimand of interest. These assumptions can depend, for example, on the stated reasons for dropout. We illustrate these methods using data from four clinical trials of pregabalin for the treatment of painful diabetic peripheral neuropathy and postherpetic neuralgia. When planning chronic pain clinical trials, careful consideration of the trial objectives should determine the definition of the trial estimand, which in turn should inform methods used to accommodate missing data in the statistical analysis.
Our goal was to examine the association between mental health disorders (MHD) and subsequent risk of opioid use among commercially insured youth and adults (ages 14-64) with co-morbid chronic non-cancer pain (CNCP) conditions. We conducted a retrospective cohort study utilizing IQVIA Health Plan Claims database from January 1, 2006 to December 31, 2015. CNCP was defined as any diagnosis of back, head, neck, arthritis, or chronic pain (index date). MHD was assessed in the 12-months prior to the index pain diagnosis. Based on days supply (none, acute, chronic) and average daily dose (none, low, medium, and high), we constructed a 7-level categorical dependent measure of opioid use. We estimated the overall prevalence of MHD and opioid receipt. Among those with CNCP, multinomial logistic regression (AOR; 95 CI) was used to estimate the association of MHD with opioid receipt. Among 879,815 individuals diagnosed with CNCP, 143,923 (16.4%) had co-morbid MHD. Chronic/high dose use of opioids was more common among those with CNCP and MHD compared to those with only CNCP. After adjusting for demographic and clinical factors, individuals with co-morbid CNCP and MHD were significantly more likely to be prescribed opioids compared to those with only CNCP conditions. This effect varied by average daily dose and days supply: acute/low dose (1.08; 1.07-1.08); chronic/low dose (1.49; 1.49-1.50); acute/medium dose (1.07; 1.07-1.08); chronic/medium dose (1.61; 1.61-1.62); acute/high dose (1.03; 1.02-1.03); and chronic/high dose (1.53; 1.53-1.54). In individuals with CNCP, having a MHD was a strong predictor of prescription opioid use, particularly chronic use.
Chronic pain resulting from nerve injury, tissue inflammation, and tumor invasion or treatment, is a major health problem impacting the quality of life and producing a significant economic and social burden. However, the current analgesic drugs including non-steroidal anti-inflammatory drugs and opioids are inadequate to relieve chronic pain due to the lack of efficacy or severe side-effects. Chemokines are a family of small secreted proteins that bind to G protein-coupled receptors to trigger intracellular signaling pathways and direct cell migration, proliferation, survival, and inflammation under homeostatic and pathological conditions. Accumulating evidence supports the important role of chemokines and chemokine receptors in the peripheral and central nervous system in mediating chronic pain via enhancing neuroinflammation. In this review, we focus on recent progress in understanding the comprehensive roles of chemokines and chemokine receptors in the generation and maintenance of different types of chronic pain, including neuropathic pain, inflammatory pain, cancer pain, and visceral pain. The current review also summarizes the upstream signaling of transcriptional and epigenetic regulation on the expression of chemokines and chemokine receptors as well as the downstream signaling of chemokine receptors underlying chronic pain. As chronic itch and chronic pain share some common mechanisms, we also discuss the emerging roles of chemokines and chemokine receptors in chronic itch. Targeting specific chemokines or chemokine receptors by siRNAs, blocking antibodies, or small-molecule antagonists may offer new therapeutic potential for the management of chronic pain.
The δ-opioid receptor (DOP) is an attractive pharmacological target due to its potent analgesic, anxiolytic and anti-depressant activity in chronic pain models. However, some but not all selective DOP agonists also produce severe adverse effects such as seizures. Thus, the development of novel agonists requires a profound understanding of their effects on DOP phosphorylation, post-activation signaling and dephosphorylation. Here we show that agonist-induced DOP phosphorylation at threonine 361 (T361) and serine 363 (S363) proceeds with a temporal hierarchy, with S363 as primary site of phosphorylation. This phosphorylation is mediated by G protein-coupled receptor kinases 2 and 3 (GRK2/3) followed by DOP endocytosis and desensitization. DOP dephosphorylation occurs within minutes and is predominantly mediated by protein phosphatases (PP) 1α and 1β. A comparison of structurally diverse DOP agonists and clinically used opioids demonstrated high correlation between G protein-dependent signaling efficacies and receptor internalization. In vivo, DOP agonists induce receptor phosphorylation in a dose-dependent and agonist-selective manner that could be blocked by naltrexone in DOP-eGFP mice. Together, our studies provide novel tools and insights for ligand-activated DOP signaling in vitro and in vivo and suggest that DOP agonist efficacies may determine receptor post-activation signaling.
Retrospective analysis of inpatient and outpatient medical insurance claims data from a database containing over 100 million individuals.
One of the potential mechanisms of motor cortex stimulation by non-invasive brain stimulation (NIBS) effects on pain is through the restoration of the defective endogenous inhibitory pain pathways. However, there is still limited data on quantitative sensory testing (QST), including conditioned pain modulation (CPM), supporting this mechanism. This systematic review and meta-analysis aimed to evaluate the effects of non-invasive motor cortex stimulation on pain perception as indexed by changes in QST outcomes. Database searches were conducted until July 2019 to included randomized controlled trials that performed sham-controlled NIBS on the motor cortex in either healthy and/or pain population and assessed the QST and CPM. Quality of studies was assessed through the Cochrane tool. We calculated the Hedge's effect sizes of QST and CPM outcomes, their 95% confidence intervals (95% CI) and performed random-effects meta-analyses. Thirty-eight studies were included (1178 participants). We found significant increases of pain threshold in healthy subjects (ES=0.16, 95% CI=0.02 to 0.31, I=22.2%) and pain population (ES=0.48, 95% CI=0.15 to 0.80, I=68.8%); and homogeneous higher CPM effect (pain ratings reduction) in healthy subjects (ES=-0.39, 95% CI=-0.64 to -0.14, I2=17%) and pain population (ES=-0.35, 95% CI=-0.60 to -0.11, I2=0%) in active NIBs group compared with sham. These results support the idea of top-down modulation of endogenous pain pathways by motor cortex stimulation as one of the main mechanisms of pain reduction assessed by QST, which could be a useful predictive and prognostic biomarker for chronic pain personalized treatment with NIBS.
The aim of this study was to determine if headache profile can predict future disability in patients with TTH.
Although most patients with chronic pain are women, the preclinical literature regarding pain processing and the pathophysiology of chronic pain has historically been derived overwhelmingly from the study of male rodents. This Review describes how the recent adoption by a number of funding agencies of policies mandating the incorporation of sex as a biological variable into preclinical research has correlated with an increase in the number of studies investigating sex differences in pain and analgesia. Trends in the field are analysed, with a focus on newly published findings of qualitative sex differences: that is, those findings that are suggestive of differential processing mechanisms in each sex. It is becoming increasingly clear that robust differences exist in the genetic, molecular, cellular and systems-level mechanisms of acute and chronic pain processing in male and female rodents and humans.
Chronic itch can be a debilitating medical condition with clinical characteristics and impact akin to chronic pain. Itch severity is subjective and clinicians depend on patient reported numerical ratings scales (NRS); most commonly 24-hour worst itch (WI-NRS) has been validated including large scale studies. WI-NRS does not attempt to take into account itch duration or the variability that is often experienced throughout the day and night by chronic itch patients.