Effect of neuromodulation for chronic pain on the autonomic nervous system: a systematic review

In recent years, there has been a growing interest in the use of neuromodulation as an alternative treatment option for chronic pain. Neuromodulation techniques, such as spinal cord stimulation (SCS), dorsal root ganglion (DRG) stimulation, deep brain stimulation (DBS), and peripheral nerve stimulation, have shown promising results in the management of various chronic pain conditions and involve targeted modulation of neural activity to alleviate pain and restore functional capacity. The autonomic nervous system (ANS) plays a crucial role in the regulation of various bodily functions including pain perception. However, the effects of neuromodulation on the ANS in the context of chronic pain remain poorly understood. This systematic review aimed to comprehensively assess the existing literature about the effects of neuromodulation on the ANS in chronic pain settings.

Searches were conducted using four electronic databases (PubMed, EMBASE, SCOPUS, and Web of Science). The study protocol was registered before initiation of the review process. The Office of Health Assessment and Translation (OHAT) Risk of Bias tool was used to evaluate risk of bias.

A total of 43 studies were included, of which only one was an animal study. Several studies have reported more than one outcome parameter in the same population of chronic pain patients. Cardiovascular parameters were the most frequently used outcomes. More specifically, 18 outcome parameters were revealed to evaluate the function of the ANS, namely heart rate variability (n=17), arterial blood pressure (n=15), tissue oxygenation/perfusion (n=5), blood markers (n=6), multiunit postganglionic sympathetic nerve activity (n=4), skin temperature (n=3), skin conductance (n=3), cephalic autonomic symptoms (n=2), ventilatory frequency (n=2), vasomotor tone (n=1), baroreflex sensitivity (n=1), sympathetic innervation of the heart, neural activity of intrinsic cardiac neurons (n=1), vascular conductance (n=1), arterial diameter (n=1), blood pulse volume (n=1), and vagal efficiency (n=1). Most studies evaluated SCS (62.79%), followed by DBS (18.6%), peripheral nerve stimulation (9.3%), DRG stimulation (4.65%), and vagus nerve stimulation (4.65%). Overall, inconsistent results were revealed towards contribution of SCS, DBS, and peripheral nerve stimulation on ANS parameters. For DRG stimulation, included studies pointed towards a decrease in sympathetic activity.

There are indications that neuromodulation alters the ANS, supported by high or moderate confidence in the body of evidence, however, heterogeneity in ANS outcome measures drives towards inconclusive results. Further research is warranted to elucidate the indirect or direct mechanisms of action on the ANS, with a potential benefit for optimisation of patient selection for these interventions.

PROSPERO (CRD42021297287).