Could Physiotherapeutic Interventions Affect Biomarkers in Neuropathic Pain?

A systematic review of preclinical studies identified that most physiotherapeutic interventions were found to modulate expression of biomarkers related with neuropathic pain in rats. These findings were published in The Journal of Pain.

Investigators from universities in Spain searched publication databases through February 2022 for studies on the effect of physiotherapeutic or invasive interventions on biomarkers of peripheral neuropathic pain in animal models. Interventions of exercise, neural mobilization, joint mobilization, physical agents, electroacupuncture, and acupuncture were included. A total of 85 studies were reviewed.

For exercise interventions, 4 studies evaluated swimming and 23 evaluated running on a treadmill. Swimming 40 to 60 minutes 5 days per week was associated with reduced proinflammatory cytokines in injured nerve tissue and neurotrophins in the spinal cord, dorsal root ganglia, and peripheral nerve tissue. Running 60 minutes or to exhaustion 3 to 5 days per week was associated with reduced proinflammatory cytokines and increased anti-inflammatory cytokines in peripheral nerves. Some studies found reduced neurotrophins following treadmill exercise.

Five articles evaluated neural mobilization using 20 oscillations per minute for 2 minutes followed by 25 seconds of rest for a total of 10 minutes. These interventions were consistently associated with reduced neurotrophic factors in the spinal cord.

The 2 studies of joint mobilization used differing procedures. The outcomes indicated a reduction in activation of glial cells in the spinal cord dorsal horn. Changes in cytokine expression were not robust.

The physical agents of laser, therapeutic ultrasound, and transcranial direct current stimulation were evaluated in 19 studies. Therapeutic ultrasound was associated with decreased cytokine expression at the sciatic nerve. Laser therapy was associated with increased nerve growth factor concentration in the sciatic nerve, no effect on enkephalins, and decreased cytokine concentration. Transcranial direct current stimulation was associated with increased tumor necrosis factor (TNF)-a in the brain and spinal cord, decreased interleukin (IL)-1b and IL-10 in the spinal cord, and reduced glial cell activation in the spinal cord.

Electroacupuncture administered at 1 to 2 mA, 2 to 100 Hz, and 1.05 to 2.85 ms for 30 minutes was associated with reduced proinflammatory cytokine concentrations mostly in the dorsal horn. The findings regarding the effect of electroacupuncture on neurotrophins were mixed.

For acupuncture, 3 studies reported heterogeneous results. The studies used differing methods and evaluated differing biomarkers. There was insufficient consensus of findings to report.

The review authors noted that the importance of specific biomarkers in neuropathic pain remains unclear. However, some publications have related neuroinflammation with the generation and maintenance of neuropathic pain in humans.

The major limitations of this review were that 92.5% of studies used male rats only, there was a high risk for bias among the studies, and it remains unclear how generalizable these findings are for humans.

This review of the literature on physiotherapeutic interventions for neuropathic pain indicated that physiotherapeutic interventions appeared to regulate expression of potentially relevant biomarkers for the neuro-immune system, opioid system, neurotransmitters, neurotrophins, and receptors. The authors comment, “Whereas the results of this study seem to suggest promising effects of biomarker modulation of physiotherapy interventions for peripheral neuropathic pain, these findings cannot be directly translated to understand the mechanism of these therapies in humans. Nevertheless, these findings can provide guidance on the type and design of future physiotherapy interventions in clinical trials.”