A Portable, Non-Pharmacological Intervention for Chronic Pain Management

Abstract

Chronic pain affects approximately 20% adults in the Western world. It is difficult to treat and has a negative impact on an individual’s physical and mental health, sleep, and overall quality of life. Globally, it costs billions of dollars in healthcare and lost productivity.

Vagus nerve stimulation (VNS), a neuromodulation technique, is a potential non-pharmacological treatment for chronic pain. VNS activates brainstem regions involved in descending pain inhibition, likely increases endogenous opioid release, modulates cortical nociceptive processing, and has anti-inflammatory effects. All these mechanisms are believed to have an antinociceptive effect. While VNS requires surgical implantation, transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive, more accessible, safer and cost-effective alternative. Research also suggests that synchronising VNS with the exhalation phase of respiration - respiratory gated (RG) stimulation - enhances activation of pain-modulating brainstem regions. However, RG taVNS studies have been limited to laboratory settings due to the lack of portable equipment.

This research aimed to develop a non-invasive portable taVNS system that offered RG stimulation. Additionally, it explored the use of heart rate variability (HRV) as a potential biomarker of stimulation efficacy, to enable future closed-loop stimulation.

In Study 1, the accuracy of the prototype in-ear and fingertip-based photoplethysmography sensors was evaluated against a gold standard 12-lead electrocardiography system for measuring vagally mediated HRV parameters, such as the root mean square of successive R-R interval differences and the high-frequency component of HRV. A prototype stretch sensor was also evaluated for detecting the onset of exhalation, compared to a gold standard sensor. Thirty healthy participants wore the prototype and the gold-standard equipment to measure HRV and changes in respiratory state during 10 minutes of normal breathing and deep slow breathing. The results showed that the prototype fingertip-based sensor and stretch sensor were sufficiently accurate for integration into the RG taVNS system. The findings of Study 1 were used to develop a custom sensing system. Additionally, a custom in-ear electrode and a mobile application were developed. A portable kit was assembled to enable home-based RG taVNS, comprising these systems and a commercial stimulator.

Study 2 evaluated the feasibility of a future single-centre clinical trial of home-based RG taVNS in individuals with rheumatoid arthritis (RA). Twelve participants with active RA participated in this study, which required three hospital visits and performing 12 RG taVNS sessions from home over 2 weeks. Feasibility outcomes were promising, with 90% session adherence, high usability ratings (9/10), and strong acceptability (average 66%, general 87%) ratings. No severe treatment-emergent adverse events were reported. While the single-arm study design precludes causal inferences regarding the effects of RG taVNS on treatment outcomes, medium to large pre- to post-intervention effects were observed in reducing pain interference, grip pain intensity and psychological distress. Medium effects were also observed in reducing resting pain and tumour necrosis factor-α levels. Effects on other outcomes were minimal. Larger effect sizes observed in some outcomes in the second week raise the potential that longer interventions may enhance benefits.

Overall, the findings of this thesis have led to the development of a novel portable RG taVNS system that could be used in future, fully powered clinical studies.