Pharmacological manipulations of secondary hypersensitivity: a systematic review and meta-analysis

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 secondary hypersensitivity. Of the 222 datasets, nine assessed only magnitude, 175 assessed only surface area, and 38 assessed both magnitude and surface area. The most commonly used manipulations were: opioid receptor agonist (n=45 datasets), N-methyl-D-aspartate (NMDA) receptor antagonist (n=40), voltage-gated sodium channel (VGSC) blocker (n=28), alpha-2-delta subunit of voltage-gated calcium channel (VGCC) ligands (n=21). For magnitude, NMDA receptor antagonists and VGSC blockers had ambiguous effects as seen in both narrative and meta-analytical results. Alpha-2-delta subunit of VGCC ligands had a pooled effect size ranging from of medium (-0.39) to negligible (-0.08). For surface area, the results of the narrative analysis for NMDA receptor antagonists, alpha-2-delta subunit of VGCC ligands and VGSC blockers were all ambiguous. However, for NMDA receptor antagonists, the pooled effect estimate was a consistent decrease in surface area, but the effect size ranged from large (-1.60) to small (-0.17). For alpha-2-delta subunit of VGCC ligands, the pooled estimated effect was a consistent decrease, but the effect size had a large range from medium (-0.59) to small (-0.18) (Fig 9). Similarly, for VGSC blockers the pooled estimated effect was a consistent decrease, with the effect size ranging from very large effect (-1.63) to a medium effect (-0.42). Lastly, opioid receptor agonists had ambiguous effects, as seen in both narrative and meta-analytical results.