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Unilateral injection of Complete Freund's Adjuvant (CFA) into the intra-plantar surface of the rodent hindpaw elicits chronic inflammation and hyperalgesia in the ipsilateral hindlimb. Mechanisms contributing to this hyperalgesia may act over multiple time courses and can include changes in ion channel expression and post-translational SUMOylation. Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels mediate the hyperpolarization-activated current, I . An HCN2-mediated increase in C-nociceptor I contributes to mechanical hyperalgesia in the CFA model of inflammatory pain. Changes in HCN2 post-translational SUMOylation and protein expression have not been systematically documented for a given DRG throughout the time course of inflammation.
Learn More >Exposure-response (E-R) models were developed to provide a description of the time-course of treatment effect for monthly and quarterly dosing regimens of fremanezumab.
Learn More >Precise cannabis treatment dosing remains a major challenge, leading to physicians' reluctance to prescribe medical cannabis.
Learn More >Mounting evidence indicates that disruptions in bidirectional communication pathways between the central nervous system (CNS) and peripheral immune system underlie the etiology of pathologic pain conditions. The purpose of this review is to focus on the cross-talk between these two systems in mediating nociceptive circuitry under various conditions, including nervous system disorders. Elevated and prolonged proinflammatory signaling in the CNS is argued to play a role in psychiatric illnesses and chronic pain states. Here we review current research on the dynamic interplay between altered nociceptive mechanisms, both peripheral and central, and physiological and behavioral changes associated with CNS disorders.
Learn More >In response to the opioid epidemic, the Centers for Disease Control and Prevention issued guidelines (CDCG) in 2016 for the prescription of opioids for chronic pain. To facilitate research into whether CDCG implementation will lead to reductions in opioid prescribing and improved patient safety, we sought to validate a tool that quantifies CDCG adherence based on clinical documentation.
Learn More >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.
Learn More >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.
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