In Complex Regional Pain Syndrome (CRPS), tactile sensory deficits have motivated the therapeutic use of sensory discrimination training. However, the hierarchical organisation of the brain is such that low-level sensory processing can be dynamically influenced by higherlevel knowledge, e.g. knowledge learnt from statistical regularities in the environment. It is unknown whether the learning of such statistical regularities is impaired in CRPS. Here, we employed a hierarchical Bayesian model of predictive coding to investigate statistical learning of tactile-spatial predictions in CRPS. Using a sensory change-detection task, we manipulated bottom-up (spatial displacement of a tactile stimulus) and top-down (probabilistic structure of occurrence) factors to estimate hierarchies of prediction and prediction error signals, as well as their respective precisions or reliability. Behavioural responses to spatial changes were influenced by both the magnitude of spatial displacement (bottom-up) and learnt probabilities of change (top-down). The Bayesian model revealed that patients' predictions (of spatial displacements) were found to be less precise, deviating further from the ideal (statistical optimality) compared to healthy controls. This imprecision was less contextdependent, i.e. more enduring across changes in probabilistic context and less finely-tuned to statistics of the environment. This caused greater precision on prediction errors, resulting in predictions that were driven more by momentary spatial changes and less by the history of spatial changes. These results suggest inefficiencies in higher-order statistical learning in CRPS. This may have implications for therapies based on sensory re-training whose effects may be more short-lived if success depends on higher-order learning..
Preclinical studies suggest that type 2 hyperpolarization-activated cyclic nucleotide gated ion channels (HCN2) are necessary for neuropathic pain. This trial assessed the influence of ivabradine, a nonselective HCN channel blocker, on capsaicin-induced hyperalgesia and pain in healthy human subjects. An enriched population comprising subjects who developed >20 cm2 of punctate hyperalgesia from topical capsaicin (0.5% cream applied onto 9 cm2 area) was identified. These subjects then received ivabradine (15 mg) or placebo 1 hour before capsaicin application in randomly allocated order in a crossover study. The forearm site for capsaicin alternated with each application of the cream. The interval of time from screening to the first and to the second treatment visits was at least 3 and 5 weeks, respectively, to minimize carryover effects. Fifty-five participants were screened, of which 25 completed at least 1 treatment visit. Intention-to-treat hierarchical analysis revealed no significant effects of the drug on primary trial outcome, defined as a difference in effects of placebo and ivabradine on the area of punctate hyperalgesia (ivabradine − placebo: mean = 3.22 cm2, 95% confidence interval: = −4.04 to 10.48, P = 0.37). However, ivabradine caused a slowing of heart rate (difference of 10.10 beats per minute [95% confidence interval −6.48 to −13.73; P‐value <0.0001]). We conclude that ivabradine lacks analgesic effects in the capsaicin pain model at a dose that caused appreciable slowing of heart rate and, hence, is unlikely to prove a useful analgesic in humans. More selective drugs are required to establish a role of HCN2 for pain in humans.
Background Pain affects 60% of the Autosomal Dominant Polycystic Kidney Disease (ADPKD) population. Despite being an early and debilitating symptom, it is poorly characterised and management is suboptimal. This study aimed to develop an ADPKD-specific pain assessment tool (APAT) to facilitate pain research. Methods Following a systematic review of PATs used in ADPKD studies and against international recommendations for pain trials, our multi-disciplinary team of clinical experts and patients constructed an ADPKD-pain conceptual framework of key pain evaluation themes. We compiled a new APAT covering domains prioritised within our framework using components of questionnaires validated in other chronic pain disorders. The APAT was administered longitudinally within a randomised high-water intake trial (NCT02933268) to ascertain feasibility and provide pilot data on ADPKD pain. Results Thirty-nine ADPKD participants with CKD stages 1-4 provided 129 APAT responses. Each participant completed a median 3 (range 1-10) assessments. Respondents’ mean age was 47 ± 13 years; 59% (23) female; 69% (27) had enlarged kidneys with median time from diagnosis 14.2 (IQR7.0-25.9) years. Pain (52%) and associated analgesic use (29%) were common. Pain severity was associated with increasing age (OR 1.07, p = 0.009), female gender (OR 4.34, p = 0.018), eGFR < 60mls/min/1.73m2 (OR 5.45, p = 0.021), and hypertension (OR 12.11, p = 0.007), but not with kidney size (p = 0.23). The APAT achieved good internal consistency (Cronbach’s alpha coefficient =0.91) and test-retest reliability (domain intra-class correlation coefficients ranging from 0.62-0.90). Conclusion The APAT demonstrated good acceptability and reliability, and following further validation in a larger cohort could represent an invaluable tool for future ADPKD pain studies.
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel receptors mediate neuropathic pain in preclinical models. Here, exploratory analysis reveals a dose-dependent reduction in pain with HCN blockade in patients with neuropathic pain.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.