RESUMEN
This systematic review and meta-analysis investigated the effects of non-pharmacological manipulations on experimentally induced secondary hypersensitivity in pain-free humans. We investigated the magnitude (change/difference in follow-up ratings from pre-manipulation ratings) of secondary hypersensitivity (primary outcome), and surface area of secondary hypersensitivity (secondary outcome), in 27 studies representing 847 participants. Risk of bias assessment concluded most studies (23 of 27) had an unclear or high risk of performance and detection bias. Further, 2 (of 27) studies had a high risk of measurement bias. Datasets were pooled by the method of manipulation and outcome. The magnitude of secondary hypersensitivity was decreased by diverting attention, anodal transcranial direct current stimulation, or emotional disclosure; increased by directing attention toward the induction site, nicotine deprivation, or negative suggestion; and unaffected by cathodal transcranial direct current stimulation or thermal change. Area of secondary hypersensitivity was decreased by anodal transcranial direct current stimulation, emotional disclosure, cognitive behavioral therapy, hyperbaric oxygen therapy, placebo analgesia, or spinal manipulation; increased by directing attention to the induction site, nicotine deprivation, or sleep disruption (in males only); and unaffected by cathodal transcranial direct current stimulation, thermal change, acupuncture, or electroacupuncture. Meta-analytical pooling was only appropriate for studies that used transcranial direct current stimulation or hyperbaric oxygen therapy, given the high clinical heterogeneity among the studies and unavailability of data. The evidence base for this question remains small. We discuss opportunities to improve methodological rigor including manipulation checks, structured blinding strategies, control conditions or time points, and public sharing of raw data. PERSPECTIVE: We described the effects of several non-pharmacological manipulations on experimentally induced secondary hypersensitivity in humans. By shedding light on the potential for non-pharmacological therapies to influence secondary hypersensitivity, it provides a foundation for the development and testing of targeted therapies for secondary hypersensitivity.
RESUMEN
INTRODUCTION: Many people with HIV report both distress and pain. The relationship between distress and pain is bidirectional, but the mechanisms by which distress exacerbates pain are unclear. The inflammatory response to challenge (inflammatory reactivity, IR) may be a partial mediator, given that neuroimmune interactions provide a substrate for IR to also influence neurological reactivity and, thus, pain-related neural signalling. This prospective, observational, case-control study will characterise the relationships between distress, IR, pain-related signalling as captured by induced secondary hyperalgesia (SH), and pain, in people with HIV who report persistent pain (PP) (cases) or no pain (controls). METHODS AND ANALYSIS: One hundred people with suppressed HIV, reporting either PP or no pain, will be assessed two or four times over 6 months. The primary outcomes are distress (Hopkins 25-item symptom checklist), IR (multiplex assay after LPS challenge), and PP (Brief Pain Inventory), assessed at the baseline timepoint, although each will also be assessed at follow-up time points. Induced SH will be assessed in a subsample of 60 participants (baseline timepoint only). To test the hypothesis that IR partly mediates the relationship between distress and pain, mediation analysis will use the baseline data from the PP group to estimate direct and indirect contributions of distress and IR to pain. To test the hypothesis that IR is positively associated with SH, data from the subsample will be analysed with generalised mixed effects models to estimate the association between IR and group membership, with SH as the dependent variable. ETHICS AND DISSEMINATION: Information obtained from this study will be published in peer-reviewed journals and presented at scientific meetings. The study has been approved by the Human Research Ethics Committee of the University of Cape Town (approval number: 764/2019) and the City of Cape Town (ref: 24699). TRIAL REGISTRATION NUMBER: NCT04757987.