Trial of Auricular Vagus Nerve Stimulation in Painful Covid Long

Covid-19 is a disease that presents in several clinical forms (severity and duration). From the end of the first epidemic wave in May 2020, the persistence of symptoms several weeks or months after the first manifestations were described in more than 20% of patients after 5 weeks and more and in more than 10% of patients after 3 months.

In the acute phase, the pains are frequent: headaches / migraines about 13%, joint pain 15%, muscle pain 36%.

In the longer term, patients infected with the coronavirus whose condition necessitated a stay in intensive care have an increased risk of having sequelae (nociceptive or neuropathic) pain. A study carried out 2 years after a stay in an intensive care unit on 164 patients showed that 56% of them suffered from chronic pain. A retrospective study of 80 patients who were hospitalized in the intensive care unit for acute respiratory distress syndrome showed that 38% of them suffered from chronic pain. A meta-analysis of 9 studies and including 1419 patients shows that the incidence or prevalence of pain 3 months after discharge from the intensive care unit ranges from 28 to 77%.

Many viral infections induce neuropathic pain such as Guillain Barré syndrome with an estimated prevalence of 0.5 to 1% and more complex pain syndromes, some of which may suggest nociplastic pain (pain without lesion as in fibromyalgia). There is also a risk of painful chronicization, in particular in the event of post-traumatic stress and / or anxiety-depressive disorders and pre-existing comorbidities (anxiety-depression) There are several pain mechanisms observed during the covid epidemic: nociceptive / inflammatory pain, neuropathic pain, nociplastic pain (without injury).

Pain management is medication with the prescription of analgesics according to the classification of the International Association for the Study of Pain according to the pain-generating mechanism as well as non-drug therapeutic approaches.

Transcutaneous electrical neurostimulation is an analgesic method widely used in Pain Assessment and Treatment Centers in addition to drug analgesics.

The vagus nerve (belonging to the parasympathetic system) is the cranial nerve whose territory is the most extensive having several functions (slowing the heart rate, promoting digestion, improving sleep, etc.). It is a mixed nerve comprising 80% afferent fibers and 20% efferent fibers. It has anti-inflammatory properties both via its afferent fibers capable of activating the corticotropic axis in response to immune stress and, more recently, via its efferent fibers. The release of acetylcholine at the end of its efferent fibers is able to inhibit the release of pro-inflammatory cytokines from splenic macrophages.

This anti-TNF property of the vagus nerve has been used in the treatment of chronic inflammatory bowel diseases but also in rheumatoid arthritis. Any abnormality of the sympathovagal balance can have a pro-inflammatory effect. The reestablishment of this sympathovagal balance is therefore likely to counterbalance a pro-inflammatory process.

In addition, stress also plays a role as it causes vagal inhibition and activation of the sympathetic system thereby promoting the pro-inflammatory reaction. Depending on the environment and the circumstances, stimulation of the vagus nerve can help the body to find the right balance between the sympathetic and parasympathetic systems and therefore a good sympathovagal balance.

Stimulation of the vagus nerve by implantable device, authorized for refractory depression or epilepsy. It has also been considered for several years to treat pain. For pain, a study of 14 patients with fibromyalgia showed a decrease in pain sensitivity corroborated by QST (Quantitative Sensory Testing) before stimulation and at 4, 6, 9 and 12 months after. The use of an implantable device is invasive and is not used in routine practice (surgery).

Functional MRI studies have shown that minimally invasive and inexpensive transcutaneous atrial electrical stimulation (tVNS) (of the left cymba concha) activates the central vagal centers.

However, this stimulation technique (unlike TENS) has been little evaluated for treating pain (3 randomized controlled clinical trials). For induced experimental pain (mechanical pain, pressure pain, thermal pain), atrial tVNS at 25 Hz increased the threshold for mechanical pain and pressure and reduced sensitivity to mechanical pain in 48 healthy subjects (trial controlled cross over). In chronic migraine, a randomized controlled study including 46 patients showed a reduction in the frequency of headaches for 13 to 29% of them depending on the stimulation groups (25Hz versus 1Hz). Another open multicenter study on 50 patients showed a reduction in pain in 64.6% of patients.

tVNS can be performed effectively using a transcutaneous electrical nerve stimulation (TENS) machine. In this case, the TENS machine is coupled to an atrial electrode designed to apply anatomically to contact with the cymba concha in the left ear to avoid parasympathetic cardiovascular effects when stimulated in the right ear.

We want to set up a pilot clinical study to assess the value of this non-drug therapeutic strategy in the overall management of pain from long-term COVIDs. The objective is to have a 1st evaluation of the efficacy, tolerance and feasibility of transcutaneous atrial vagus nerve stimulation (tVNS) in the various pain mechanisms (nociceptive, neuropathic and nociplastic) observed during the Covid-19. Depending on the results, a randomized controlled trial may then be set up. ?

Colosat is a 8 weeks non randomized trial investigating the painful Covid long. tVNS will be performed using a transcutaneous lectrical nerve stimulation (TENS) device connected to an auricular electrode stimulating the cutaneous area of the left ear innervated by the auricular ascendant branch of the vagus nerve.