Effect of Neurostimulation on Chronic Pancreatic Pain: A Systematic Review

Chronic pancreatic pain is one of the most severe causes of visceral pain, and treatment response is often limited. Neurostimulation techniques have been investigated for chronic pain syndromes once there are pathophysiological reasons to believe that these methods activate descending pain inhibitory systems. Considering this, we designed this systematic literature review to investigate the evidence on neuromodulation techniques as a treatment for chronic pancreatic pain.

We performed a literature search using the databases MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase until April 2024. The included studies used neurostimulation techniques in participants with chronic pancreatic pain and reported pain-related outcomes, with a focus on pain scales and opioid intake. Two reviewers screened and extracted data, and a third reviewer resolved discrepancies. We assessed the risk of bias using the Jadad scale. The authors then grouped the findings by the target of the neurostimulation, cortex, spinal cord, or peripheral nerves; described the findings qualitatively in the results section, including qualitative data reported by the articles; and calculated effect sizes of pain-related outcomes.

A total of 22 studies were included (7 randomized clinical trials [RCTs], 14 case series, and 1 survey), including a total of 257 clinical trial participants. The two outcomes most commonly reported were pain, measured by the visual analogue scale (VAS), numeric rating scale (NRS), and pressure pain threshold scores, and opioid intake. Two RCTs investigated repetitive transcranial magnetic stimulation (rTMS), showing a reduction of 36% (±16) (d = 2.25; 95% CI, 0.66-3.83) and 27.2% (±24.5%) (d = 2.594; 95% CI, 1.303-3.885) in VAS pain scale. In another clinical trial, transcranial direct-current stimulation (tDCS) and transcranial pulsed current stimulation were not observed to effect a significant reduction in VAS pain (χ2 = 5.87; p = 0.12). However, a complete remission was reported in one tDCS case. Spinal cord stimulation (SCS) and dorsal root ganglion stimulation were performed in a survey and 11 case series, showing major pain decrease and diminished opioid use in 90% of participants after successful implantation; most studies had follow-up periods of months to years. Two noninvasive vagal nerve stimulation (VNS) RCTs showed no significant pain reduction in pain thresholds or VAS (d = 0.916; 95% CI, -0.005 to 1.838; and d = 0.17; -0.86 to 1.20; p = 0.72; respectively). Splanchnic nerve stimulation in one case report showed complete pain reduction accompanied by discontinuation of oral morphine and fentanyl lozenges and a 95% decrease in fentanyl patch use. Two RCTs investigated transcutaneous electrical nerve stimulation (TENS). One found a significant pain reduction effect with the NRS (d = 1.481; 95% CI, 1.82-1.143), and decreased opioid use, while the other RCT did not show significant benefit. Additionally, one case report with TENS showed pain improvement that was not quantitatively measured.

The neuromodulation techniques of rTMS and SCS showed the most consistent potential as a treatment method for chronic pancreatic pain. However, the studies have notable limitations, and SCS has had no clinical trials. For VNS, we have two RCTs that showed a non-statistically significant improvement; we believe that both studies had a lack of power issue and suggest a gap in the literature for new RCTs exploring this modality. Additionally, tDCS and TENS showed mixed results. Another important insight was that opioid intake decrease is a common trend among most studies included and that adverse effects were rarely reported. To further elucidate the potential of these neurostimulation techniques, we suggest the development of new clinical trials with larger samples and adequate sham controls.