Accepted

Current deficiency in our understanding of acute-to-chronic pain transition remains a hurdle for developing effective treatments against chronic pain. Whereas neurocentric mechanisms alone are insufficient to provide satisfactory explanation for such transition, neuro-immune crosstalk has attracted attention in recent pain research. In contrast to brain microglia, spinal microglia are activated immediately in various pain states. The fast-responsive enrichment and activation of spinal microglia among different pain conditions have highlighted the crucial role of neuroinflammation caused by microglia-neuron crosstalk in pain initiation. Recent studies have revealed spinal microglia-neuron interactions are also involved in chronic pain maintenance, albeit, with different anatomic distribution, cellular and molecular mechanisms, and biologic functions. Delineating the exact temporal discrepancies of spinal microglia distribution and functions along acute-to-chronic pain transition may provide additional mechanistic insights for drug development to prevent deterioration of acute pain into the chronic state. This narrative review summerizes the longitudinal alterations of spinal microglia-neuron interactions in the initiation of pain hypersensitivity, acute-to-chronic pain progression, and chronic pain maintenance, followed by an overview of current clinical translation of preclinical studies on spinal microglia. This review highlights the crucial role of the interaction between spinal microglia and neighboring neurons in the initiation and maintenance of pain hypersensitivity, in relation to the release of cytokines, chemokines, and neuroactive substances, as well as the modulation of synaptic plasticity. Further exploration of the uncharted functions of spinal microglia-neuron crosstalk may lead to the design of novel drugs for preventing acute-to-chronic pain transition.

The management of acute and chronic pain for individuals living with sickle cell disease (SCD) is a clinical challenge. This reflects the paucity of clinical SCD pain research and limited understanding of the complex biological differences between acute and chronic pain. These issues collectively create barriers to effective, targeted interventions. Optimal pain management requires interdisciplinary care.

There is an increasing recognition of the importance of using a conceptual framework covering the full range of relevant health domains and outcome measures addressed by physical therapy modalities in patients with chronic low back pain (CLBP). However, little is known about what outcome domains have been measured and through what measures in physical therapy research.

Millions of people in the United States are affected by chronic pain, and the financial cost of pain treatment is weighing on the healthcare system. In some cases, current pharmacological treatments may do more harm than good, as with the United States opioid crisis. Direct electrical stimulation of the brain is one potential non-pharmacological treatment with a long history of investigation. Yet brain stimulation has been far less successful than peripheral or spinal cord stimulation, perhaps because of our limited understanding of the neural circuits involved in pain perception. In this paper, we review the history of using electrical stimulation of the brain to treat pain, as well as contemporary studies identifying the structures involved in pain networks, such as the thalamus, insula, and anterior cingulate. We propose that the thermal grill illusion, an experimental pain model, can facilitate further investigation of these structures. Pairing this model with intracranial recording will provide insight toward disentangling the neural correlates from the described anatomic areas. Finally, the possibility of altering pain perception with brain stimulation in these regions could be highly informative for the development of novel brain stimulation therapies for chronic pain.

Pain neuroscience education (PNE) is an approach used in the management of chronic musculoskeletal pain (CMP). Previous reviews on PNE and other pain interventions, have focussed on mean treatment effects, but in the context of "precision medicine", any inter-individual differences in treatment response are also important to quantify. If inter-individual differences are present, and predictors identified, PNE could be tailored to certain people for optimising effectiveness. Such heterogeneity can be quantified using recently-formulated approaches for comparing the response variance between the treatment and control groups. Therefore, we conducted a systematic review and meta-analysis on the extracted standard deviations of baseline-to-follow up change to quantify the inter-individual variation in pain, disability and psychosocial outcomes in response to PNE. Electronic databases were searched between 01/01/2002 and 14/06/2018. The review included five randomised controlled trials (n=428) in which disability outcomes were reported. Using a random effects meta-analysis, the pooled SD (95% CI) for control group-adjusted response heterogeneity to PNE was 7.36 units /100 (95% CI: -3.93 to 11.12). The 95% prediction interval for this response heterogeneity SD was wide (-10.20 to 14.57 units /100). The control group-adjusted proportion of "responders" in the population who would be estimated to exceed a clinically important change of 10/100 ranged from 18-45%. Therefore, when baseline-to-follow up random variability in disability is taken into account (informed by the control arm), there is currently insufficient evidence for the notion of clinically important inter-individual differences in disability responses to PNE in people with CMP. The protocol was published on PROSPERO (CRD42017068436). PERSPECTIVE: We bring a novel method to pain science for calculating inter-individual differences in response to a treatment. This is conducted within the context of a systematic review and meta-analysis on PNE. We highlight how using erroneous methods for calculating inter-individual differences can drastically change conclusions when compared to appropriate methods.