A systematic review and meta-analysis of pharmacological methods to manipulate experimentally induced secondary hypersensitivity.

Understanding the physiology of specific clinical features of persistent pain, such as secondary hypersensitivity, is crucial for developing effective treatments. This systematic review and meta-analysis investigated the effects of pharmacological manipulations on the magnitude (primary outcome) and surface area (secondary outcome) of experimentally induced secondary hypersensitivity. Following Cochrane Collaboration guidelines and a published and registered protocol, we conducted an electronic search on February 7, 2024. After screening articles in duplicate, we included 117 articles, consisting of 222 datasets. Risk of bias assessments identified potential flaws in methodological quality. Datasets were pooled by the mechanism of action of the manipulation and by outcome. Effect sizes were estimated using standardised mean difference (SMD). Most datasets (207 of 222) had an unclear risk of performance and detection bias for inadequate reporting of blinding procedures. Thirteen different methods were used to induce, and 23 different drug classes were used to manipulate secondary hypersensitivity. The pooled SMDs [95% CI] suggested that alpha-2-delta subunit of voltage-gated calcium channel ligands reduced both the magnitude (-0.24 [-0.39; -0.08]) and surface area (-0.38 [-0.59; -0.18]) of secondary hypersensitivity, and that both N-methyl-D-aspartate receptor antagonists (-0.36 [-0.55; -0.17]) and voltage-gated sodium channel blockers (-1.02 [-1.63; -0.42]) reduced only the surface area of secondary hypersensitivity. These results suggest a need to understand and compare the physiological underpinnings of magnitude and area of secondary hypersensitivity, and to clarify the relative importance of magnitude vs anatomical spread (ie, surface area) of secondary hypersensitivity to people living with pain.