Modulation of offset analgesia in patients with chronic pain and healthy subjects – a systematic review and meta-analysis

Abstract

Abstract Objectives Offset analgesia (OA) induces a brief pain inhibition and studies suggest OA impairment in patients with chronic pain when compared to healthy subjects. Conditioned pain modulation remains the most studied descending pain inhibitory control mechanism and is modulated by centrally-acting analgesics. Since OA may be mediated by similar neural substrates as conditioned pain modulation, understanding if OA is a peripheral or central proxy of pain modulation is important. The modulatory effect of centrally-acting drugs on OA in healthy and chronic pain populations has not yet been systematically reviewed and meta-analyzed, and this systematic review and meta-analysis aimed to identify studies employing interventions for modulating OA magnitude. Methods A systematic search of PubMed, Embase, Web of Science, and the Cochrane Library yielded 146 records of which 11 (172 healthy pain-free subjects, 106 chronic pain patients) were eligible for qualitative synthesis, and 10 for meta-analysis on overall modulatory effect of interventions on OA, and subgroup analysis of patients and healthy pain-free subjects. Results Risk of bias was evident for study participation and study confounding in the included studies. Several different methods for assessing and calculating OA magnitude were identified, which may affect interpretability of findings and warrants standardization. The meta-analysis showed no modulatory effects on OA overall (standardized mean difference (SMD) [95%CI]: 0.04 [−0.22, 0.30], Z=0.29, p=0.77), or in the subgroup analysis for patients (SMD [95%CI]: −0.04 [−0.63, 0.71], Z=0.13, p=0.90) or healthy pain-free subjects (SMD [95%CI]: 0.01 [−0.21, 0.24], Z=0.11, p=0.91). Moderate to substantial heterogeneity was found for the overall analysis (I2=47%, p=0.03) and patient subgroup analysis (I2=75%, p=0.003). Conclusions The current systematic review and meta-analysis conclude that centrally-acting drugs and exercise do not influence OA. Evidence on the peripheral contribution to OA response requires further investigations. Preclinical models of OA should be established to identify the neurophysiology and -biology behind OA.