Most subjects reported improvement across all four subjective measures, including lower pain, disability, and depression, and increased activity levels. Regression analysis showed a steady improvement for all four subjective measures from baseline to week eight. At week eight, the average reduction in pain was 38.5%, the average reduction in depression was 43.6%, the average reduction in disability was 38.6%, and the average increase in activity level was 26.1%.

Chronic pain levels improved in the majority of subjects ( Figure 2 ). Low Pain, the minimum level of chronic pain, was reduced by 16.7%-100% in 71.0% of subjects. High Pain, the maximum level of chronic pain, was reduced by 10.0%-100% in 77.4% of subjects. Average Pain, the average of High Pain and Low Pain, was reduced by 11.1%-100% in 83.9% of all subjects. Weekly Low Pain was reduced by 44.0%, weekly High Pain levels were reduced by 29.8%, and weekly Average Pain was reduced by 38.5%. Average Pain was reduced by 50%-100% in 36.4% of subjects. While most subjects reported at least a modest improvement in pain levels, some reported a 100% reduction in pain. Ten subjects reported zero low-level pain, two subjects reported zero high-level pain, and three subjects had zero Average Pain at week eight.

Disability levels were reduced in almost all subjects ( Figure 3 ). The level of disability was reduced by 10.0%-100% in 93.5% of subjects. Disability was reduced by 50%-100% in 36.4% of subjects. The average disability reduction was 38.6%. The overwhelming majority of subjects reported improved disability, with two reporting a 100% reduction in disability. 

Most subjects reported a reduction in depression (Figure 4 ) Reduced depression was reported in 74.2% of subjects with a range of 10.0%-100% reduction. Depression was reduced by 50%-100% in 48.5% of subjects. The average reduction in reported depression was 43.6%, five points on the PHQ-9.

Physical activity increased in more than half of the subjects ( Figure 5 ). Activity levels increased in 56.3% of patients, with an average increase of 26.1%. Activity levels were doubled in five subjects.

Average opiate/opioid medication use was reduced by 42.9%, with three subjects discontinuing all opioid medications.

Only one subject reported an adverse side effect during the study: discomfort during sleep due to the implanted electrode. This subject was one of two who dropped out of the study (6.1% dropout rate); the other subject dropped out due to weather-related difficulties traveling to the clinic. Both subjects dropped out after week four, but both had reported improvement in pain, disability, and depression. One subject reported an improvement in activity levels, while the other reported a decrease in activity.

Sixteen pain-related cytokines showed improvement in response to therapy (Figure 6, Figure 7, Figure 8). Assessments of pain-related hormones and other analytes showed high variability between individuals and did not correlate with the treatment protocol; data are not reported here.

For all reported cytokines except IL-10, reduced levels indicate improvement in inflammation. IL-10 levels increased by an average of 144.5% above baseline at week eight. The decreases seen in all other average cytokine levels were: IL-1β 21.1%, IL-2 22.5%, IL-3 56.5%, IL-7 29.0%, IL-15 21.2%, IL-17α 21.7%, IL-21 14.2%, TNF-α 11.4%, IFN-γ 27.5%, and FLT-3 Ligand 37.8%.

Most subjects reported a reduction in their need for opiate pain medications, with three subjects discontinuing opiate pain medications entirely. None of the subjects reported any major negative adverse events related to the treatment. The subject dropout rate was 6.1% (2 of 33 subjects). One subject withdrew due to discomfort while sleeping with the device implanted, while the other withdrew due to transportation difficulties.

The picture painted by researchers to explain the mechanisms and pathways involved in chronic pain is complex. Chronic pain can be summarized as a dysfunctional interaction between inflammatory and immune mechanisms, and autonomic dysfunction leading to maladaptive neuroplasticity. Vagus nerve stimulation has proven to be a valuable tool for treating pain and other pathologies that involve autonomic dysfunction, including heart disease and metabolic syndrome121314. The vagus nerve is a desirable target for therapeutic intervention. Cervical and auricular branches of the vagus nerve are easy to non-invasively access, allowing external, transcutaneous electrical stimulation of both afferent and efferent nerve fibers. Additionally, the vagus nerve is involved in multiple bodily mechanisms and influences the hippocampal-pituitary-adrenal (HPA) axis, brain-gut axis, and other pathways413.

The underlying mechanisms of chronic pain have slowly been elucidated over the past few decades, revealing the important roles of inflammation, immunefunction, autonomic dysfunction, and central sensitization (CS)31214151617182021222324252627.

Research has also shown a complex interplay between inflammation and the immune system in pain, including syndromes with chronic pain161723242628. Elevated levels of pro-inflammatorycytokines1421232526272829303132333435,hormones13363738, and altered neurotransmitter levels939are associated with a wide range of chronic pain conditions66891112171825262829303134404142 These cytokines and other peptides can serve as both biomarkers of inflammation and chronic pain151825313440 as well as therapeutic targets2835434445. Neuroinflammation is one important aspect of chronic pain conditions associated with depression, a significant comorbidity of these conditions46. Neuroinflammation also influences maladaptive neuroplasticity, rewiring the brain to be more sensitive to pain319, due in part to a shift in the function of GABA-ergic neurons from inhibitory to excitatory activity193946.

Central sensitization is a relatively new unifying concept to describe the pathological amplification of otherwise non-noxious stimuli1947in chronic pain and disorders such as fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and others3192022. The sympathetic nervous system plays an important role in modulating the communication between peripheral sensory nerves and the central nervous system and has proven to be a good target for therapy to address conditions with chronic pain44,48. The vagus nerve (cranial nerve 10) is the primary parasympathetic innervation of the body, affecting everything from heart rate to gastrointestinal motility. Auricular branches of the vagus nerve travel through the outer ear, making it a useful location to access the vagus non-invasively. Transcutaneous vagal nerve stimulation is known to induce the release of neurotransmitters and endogenous opioid peptides, such as endorphins9,48, and improve inflammatory cytokine levels49 in patients with chronic inflammation.

The results of this study demonstrate that pVNS can decrease chronic pain, disability, and depression while improving pain-related limited activity in persons with chronic pain that has not responded satisfactorily to other treatments. Additionally, pVNS can lower elevated pro-inflammatory cytokines and raise levels of the anti-inflammatory cytokine IL-10. This adds further credence to other studies that have shown similar types of symptomatic and physiological improvement in study populations with various chronic conditions45689104548495051. Notably, patients in this study showed symptomatic improvement within a relatively short time frame of eight weeks, with several subjects reporting complete remission of pain, disability, or depression at the end of the study. Symptomatic improvement was seen in the majority of subjects after only one week of neurostimulation. For pain-related cytokines, results were mixed at the end of week two, with some showing improvement and others worsening. However, at the end of week eight, there was a clear improvement in the average levels of pain-related cytokines.

While lacking statistical significance, this study's improvement in subjective and objective pain-related measures was clinically significant. A definitive majority of subjects saw at least modest improvement in one or more measured domains, with several reporting a 100% reduction in pain, depression, or disability. These results are encouraging, especially for a minimally invasive treatment with no adverse events reported in any subjects aside from one subject who quit the study due to ear discomfort from the implanted electrodes during sleep.

A correlation between improved symptoms and decreased biomarkers of inflammation is expected, given what is known about the effects of cytokines in the body. Only two blood samples were collected from subjects during treatment. While this minimizes the risk of adverse events, it may limit the analysis of potentially illuminating alterations to the cytokine profile throughout treatment. However, a much larger sample size would be needed to detect statistically significant changes in pain-related biomarkers since cytokine levels and subjective assessments showed high variability within the study population. The results of this study both support and are supported by the results seen by numerous other researchers45891049.

The most important outcome of this study is the impact of symptomatic improvement on the quality of life. With only 33 subjects in the study, two patients experienced complete remission of their chronic pain and 10 patients in total experienced reduced low-level pain to zero throughout the study. All subjects experienced at least a low level of chronic pain at baseline, meaning they had no pain-free days in the week prior to treatment. Such improvement is remarkable and potentially life-changing, especially in individuals who have suffered from chronic pain for years without finding relief. The reduction in opioid medication use is also important. There was an average 42% reduction in opioid use, with three subjects discontinuing opioid pain medication entirely. Any reduction in chronic opioid use is potentially significant on both an individual and societal level, given the high potential for dependence, abuse, and hyperalgesia, as well as their dubious effectiveness for treating chronic pain525354555657. Wider use of pVNS therapy can potentially improve the lives of people with chronic pain and other conditions ranging from metabolic syndrome to inflammatory arthritis, as well as unusual and difficult-to-treat conditions like fibromyalgia and ME/CFS.

The primary limitation of this study is the small sample size (n=33). For all reported measures variability within the sample group was high, resulting in a high standard error. Given the small sample size and high SEM, it is unclear how well the study population represents a broader population with chronic pain. However, the exclusion criteria for this study were intentionally somewhat broad to diminish any confounding effects from serious medical conditions which can potentially affect the subjective and objective measures used. Many complex medical conditions are associated with chronic pain, but they can have vastly different overall pathologies.

Further studies with larger population samples are needed to achieve statistical significance with these measures. Additionally, longer term surveillance of patient outcomes may prove useful to reveal how long these symptomatic and physiologic changes persist after treatment. A larger sample could also facilitate the analysis of multiple factors that may influence treatment response, such as age, sex, site of pain, and underlying injuries or illnesses. A large-scale study with a large number of participants with various central sensitivity syndromes (including fibromyalgia, ME/CFS, and other conditions) could prove to be highly effective at uncovering how pVNS specifically affects central sensitivity as it relates to chronic pain.