Efficacy of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) in Aromatase Inhibitor-induced Arthralgia (AIA)

Efficacy of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) in Aromatase Inhibitor-induced Arthralgia (AIA): a Phase 2, Randomized, Monocentric, taVNS Versus Sham, Double Blind

Breast cancer (BCa) is the most common cancer in women. The majority of BCa are hormone receptor positive and substantial benefits have been demonstrated for adjuvant endocrine therapies in reducing recurrence and extending survival in women.

Aromatase inhibitors (AI) are commonly prescribed for women diagnosed with hormone receptor positive BCa. In parallel with this improvement in survival, women may experience a frequent adverse effect from AI therapy with arthralgia, or joint pain and stiffness. AI-induced arthralgia (AIA) is experienced by about 50 % of recipients.

The main AIA symptoms are joint pain and stiffness, mainly in the hands, wrists, and knees, symmetrically.

Although AIA can occur at any time after initiating AI, the median time to onset is approximately 6 weeks with peak symptoms at 6 months.

Additionally, AIA impairs quality of life (QoL) and pain severity is associated with premature discontinuation and non-adherence to AI therapy which in turn is significantly associated with increased mortality in BCa patients.

Declining levels of oestrogen induced by AI results in increased production of proinflammatory cytokines hitting chondrocytes resulting in joint pain and swelling.

The autonomic nervous system (ANS) plays an important role in the regulation of inflammation. Dysregulation of the ANS is observed in women treated for BCa.

Acupuncture, exercise, duloxetine, … have potential to improve AIA in BCa survivors, however, few studies have attempted to compare different modalities, resulting in a lack of evidence-based decision making for these interventions.

A novel, non-invasive, wearable vagus nerve stimulation device has been created and has the potential to modulate proinflammatory cytokine production and reduce inflammation by affecting the functioning of the autonomic nervous system.

Some studies have demonstrated the safety and efficacy of this device after several weeks of treatment, on the intensity of pain secondary to rheumatic diseases after several weeks of treatment.

We would like to study the effectiveness of transcutaneous auricular vagus nerve stimulation (taVNS) for patients with aromatase inhibitor-induced arthralgia

Inclusion Criteria:

1. Menopausal women receiving an aromatase inhibitor (AI) as adjuvant treatment for breast cancer (letrozole (Femara), anastrozole (Arimidex) or exemestane (Aromasin)). The same AI must have been the same during the 4 weeks preceding inclusion and not be intended to be changed during the study period;

2. Polyarticular and symmetrical pain that developed or worsened after the initiation of AI therapy and has persisted for at least 1 month;

3. Score greater than 4 within 7 days before randomization (range,0-10; higher scores indicate greater pain) on the average pain item of the Brief Pain Inventory-Short Form (BPI-SF) as reported by patient;

4. Patients receiving stable background analgesic treatment for AIA may be included, provided that this treatment has remained stable and that no new medication has been initiated prior to inclusion, as follows:

   • Analgesic treatment: stable for at least 2 weeks before inclusion, with no initiation of new medication.
   • Antidepressant treatment, including serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g., duloxetine, venlafaxine): stable for at least 4 weeks before inclusion, with no initiation of new medication."

5. Patients with an Eastern Cooperative Oncology Group performance status of 0 to 2;

6. Patient covered by a social security system;

7. Patient mastering the French language and able to complete the evaluation questionnaires;

8. Signed written informed consent form.

Exclusion Criteria:

1. Patients who have previously used an electrostimulation device for pain management;
2. Use of vagus nerve stimulation prior to the study;
3. Patients who have received auriculotherapy for the same indication within the previous 4 weeks or who plan to initiate such treatment during the study;
4. Symptomatic orthostatic hypotension (according to investigator) or recurrent vasovagal syncope or history of vagotomy;
5. Previously implanted electrically active medical devices (eg, cardiac pacemakers or automatic implantable cardioverter defibrillators), or significant electrocardiogram abnormalities (cardiac rhythm disturbances, atrioventricular block >first degree or total bundle branch block);
6. Current treatment with beta-blocker drugs;
7. Patient under guardianship or unable to give informed consent;
8. Patient unable to undergo medical follow-up for geographical, social or psychopathological reasons.