The Perfect Enemy | Study evaluates transcutaneous vagus nerve stimulation as treatment for long COVID-chronic fatigue
December 1, 2022
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In a recent study posted to the medRxiv* server, researchers evaluated non-invasive transcutaneous vagus nerve stimulation [tVNS] as a treatment for long COVID-related chronic fatigue syndrome (CFS).

Study: Transcutaneous Vagus Nerve Stimulation in the Treatment of Long Covid-Chronic Fatigue Syndrome. Image Credit: fizkes / Shutterstock


In one of their other recent study, the authors showed that nearly half of the long COVID patients fulfilled the 1994 case criteria for myalgic encephalomyelitis (ME)/CFS, assessed via a five-point Likert scale. On the Likert scale, zero, one, two, three, four, and five indicated no to very severe CFS, respectively. The 1994 case definition for CFS requires an individual to experience over six months of chronic fatigue that does not improve by taking rest and is not the result of ongoing exertion. Additionally, it substantially reduces one’s activity in one of the following spheres: work, school, personal or social.

Long COVID shares many ME/CFS symptoms, including fatigue, problems with attention and concentration (brain fog), diffuse muscular pain, and post-exertional malaise. However, in their current work, the researchers focused primarily on CFS. Since there is no treatment for long COVID, they reviewed a Belgian paper reporting improved symptoms in long COVID patients following the application of tVNS. They further confirmed these preliminary findings about the tVNS treatment in the current study.

About the study

The current study was an open-label pilot study wherein the researchers enrolled 16 subjects who had survived coronavirus disease 2019 (COVID-19) but experienced its symptoms for at least six months following recovery. They fulfilled the 1994 case definition for CFS and also signed Institutional Review Board (IRB)-approved informed consent to participate in this study via RedCap.

All the participating patients endorsed having at least one of the following problems: sore throat, headache, myalgia, tender lymph glands, arthralgia, brain fog, and post-exertional malaise. In addition, subjects completed the visual analog scales (VAS) for fatigue, brain fog, and widespread pain. Also, they completed the SF-36 questionnaire, which indicated their health-related quality of life, a profile of mood states (POMS), and the Chalder fatigue scale (CFS) questionnaires.

All the participants had to wear a Parasym device, with its electrode attached to their left tragus. They had to receive stimulations via this device for at least 35 minutes/day, every day for six weeks. The team called all the study participants every two weeks during the six-week trial to ask about problems related to tVNS use. At the end of the trial, the study participants again completed these same questionnaires and the Patient Global Impression of Change (PGIC) scale. The priori** criteria for the primary outcome was an improvement in at least two of the following:

  • a 14% improvement in the physical function subscale of the SF-36;
  • reduction in at least 2 points on the VAS;
  • no longer a “fatigue case” on the Chalder;
  • scores in the range of +2 or +3 on the PGIC.

Likewise, the priori criterion for the secondary outcome and successful outcome was an improvement by at least 10 points on the POMS short version and at least a third of patients fulfilling the criteria for the primary outcome, respectively.

Study findings

The researchers could analyze only 14 patients till the end of the study duration and noted no adverse events during this study. Only two patients showed improvement on all four outcome measures. The remaining three and five showed improvements on three and two outcome measures, respectively. Unfortunately,  one and five other patients showed improvements on only one and no outcome measure, respectively.

The Global Clinical Assessment of Change and improvement in at least one symptom on the VAS best predicted a successful outcome, followed by the SF-36 and the Chalder. Intriguingly, brain fog was the only symptom that showed no improvement in any study participant.


To summarize, 8/14 patients fulfilled a priori criteria for improvement. Additionally, five patients, including four fulfilling criteria for successful improvement and one who did not show improvement, also showed reductions of at least 10 points on the POMS.

The study results suggested that non-invasive stimulation of the auricular branch of the vagus nerve of tVNS treatment is a possible therapeutic modality for treating long COVID. Though, it is possible that the positive result was simply a placebo response to treatment in the absence of a control group for comparison. Nevertheless, since at least a third of patients improved (57% improvement rate), it was a successful trial.

In this trial, researchers did not forbid the participants to take medications. They only asked them not to increase the current medication dosages or start new ones. Additionally, they measured more than one outcome measure, which reduced patient pool heterogeneity. Also, it helped them select patients with a broad set of symptoms at greater severity, including brain fog, fatigue, widespread pain, and post-exertional malaise. The authors plan to expand this study by adding a sham control limb to validate the efficacy of tVNS in treating long COVID. If such a trial would show tVNS efficacy, this will open up more possibilities for the treatment of those patients for whom specific treatment is currently unavailable.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.


The Latin term a priori, or “from the past,” is traditionally contrasted with the term a posteriori, which means “after the fact.” A priori often indicates that one is reasoning from the general to the specific or that one is examining causes and effects.

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