An interventional study of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) and Sham Transcutaneous Auricular Vagus Nerve Stimulation (Sham taVNS) in Fibromyalgia (FM) OR Fibromyalgia Syndrome, Manuel Therapy and Chronic Widespread Pain, sponsored by Hasan Kalyoncu University. Not yet recruiting at 1 site in Turkey (Türkiye). Open to female participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2026-10-26.
Sponsored by Hasan Kalyoncu University · Not applicable, Interventional, and Treatment
The aim of this study is to investigate the effect of transcutaneous auricular vagus nerve stimulation (taVNS) added to manual therapy on pain, autonomic nervous system function, and illness perception in female patients diagnosed with fibromyalgia, using a randomized sham-controlled design.
Fibromyalgia syndrome (FMS) is a disease characterized by widespread musculoskeletal pain, fatigue, sleep disturbances, and cognitive impairment, and it markedly reduces quality of life. It is more prevalent in women, and it is thought to affect approximately 2-3% of the general population.
Although the etiology and pathogenesis of widespread pain are not yet known, it is thought to have a multifactorial basis. In this context, the interaction of various biopsychosocial mechanisms, such as increased central nervous system sensitivity (central sensitization), neurohormonal dysregulation, genetic predisposition, and environmental stress factors, is emphasized.
Chronic widespread pain is the most important reason for presentation in fibromyalgia (FM). According to the FM classification criteria reported by the American College of Rheumatology (ACR), in addition to a history of chronic widespread pain, the presence of tenderness at 11 or more of 18 specific anatomical sites on examination is required.
Although many people experience an illness during their lifetime, the experience is not the same for every individual. People try to make sense of their illness in light of their values, beliefs, and needs. Illness perception is the cognitive representation of the illness state.
The vagus nerve, the body's "great protector," comprises a mixed neuro-endocrine-immune network that maintains homeostasis. With reciprocal neural connections to multiple regions of the brain, the vagus nerve serves as a control center that integrates sensory information and provides appropriate feedback responses. Recent studies show that the vagus nerve is involved in the regulation of inflammation, mood, and pain, all of which can be modulated by vagus nerve stimulation. Vagus nerve stimulation, together with the broad vagal neural network, may produce a neuromodulatory effect that activates certain natural protective pathways to restore health. Non-invasive transcutaneous devices stimulate the vagus nerve via the auricular route or at the carotid. They are also used in the treatment of various conditions such as epilepsy, pain, and headache. A medical device has made it possible to stimulate the auricular branch of the vagus nerve without any surgery. As a result, an increase in pain threshold and a decrease in mechanical pain sensitivity have been found.
The effect of repeated-session stimulation of the auricular and cervical vagal branches on FM symptomatology has not been tested to date in a randomized or sham-controlled study. A double-blind, sham-controlled study initiated in 2024 at the National and Kapodistrian University of Athens, and still ongoing, explicitly cited this gap as its rationale and stated that it aims to test, for the first time, the effect of multi-session tVNS on pain and quality of life in FM patients. This shows that, although vagus nerve stimulation is regarded as a promising method in the treatment of fibromyalgia, direct clinical evidence on the subject remains quite limited, and current knowledge is largely based on inferences from closely related conditions.
The literature on the effects of manual therapy in FM carries a similar uncertainty. A systematic review published in Pain Physician, which pooled seven randomized controlled trials including a total of 368 patients, reported that various manual therapy approaches, particularly myofascial release, showed partial positive effects on pain, disease impact, and quality of life. However, it emphasized that the level of evidence ranged from very low to moderate, and that no definitive judgment on efficacy could be reached because of inconsistency between studies. Although individual studies exist showing that connective tissue massage-based manual therapy applications reduce neck pain in women with FM, it remains largely unclear in the literature which manual therapy approach is superior and how the physiological mechanisms underlying this effect operate. Moreover, no study has been found that applies manual therapy and vagus nerve stimulation together and examines the possible combined effect of these two methods.
The aim of this study is to investigate the effect of transcutaneous auricular vagus nerve stimulation (taVNS) added to manual therapy on pain, autonomic nervous system function, and illness perception in female patients diagnosed with fibromyalgia, using a randomized sham-controlled design.
A comprehensive systematic review published in 2026 clearly demonstrated that the methodological quality of existing taVNS studies is inadequate and that there are no randomized controlled trials examining its combination with standard clinical practices such as manual therapy. This critical gap in the literature constitutes the main motivation for the study.
In addition, recently published studies with similar designs, in which the combination of taVNS and manual therapy was tested in temporomandibular disorders and taVNS was applied alone in FMS, strongly support the need to systematically investigate this combination in the FMS population.
Another aim is to determine the additional contribution of vagal neuromodulation (taVNS + diaphragmatic breathing) to manual therapy, to test whether changes in HRV parameters mediate FIQ-R improvement (mediation analysis), and to relate changes in illness perception, measured with the Brief IPQ, to clinical outcomes.
1,369 studies on the registry are indexed under Fibromyalgia; 272 are open to participants now.
This study's planned enrollment of 44 is below the median of 60 across 1,056 interventional studies indexed under Fibromyalgia.
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Participants will receive a manual therapy program combined with active transcutaneous auricular vagus nerve stimulation (taVNS). The manual therapy program includes myofascial release, Maitland spinal mobilization, elastic band-assisted diaphragmatic breathing training, and static stretching exercises. Myofascial release will be applied to the upper trapezius, levator scapulae, rhomboids, cervical-lumbar paraspinal regions, and gluteal region, including the tender point areas defined in the ACR fibromyalgia criteria; pressure will be held for approximately 60-90 seconds per region. Maitland postero-anterior mobilization will be applied to painful cervical, thoracic, and lumbar segments (3 sets of 2 minutes with 1-minute rests). Diaphragmatic breathing training will last 10-15 minutes per session, and static stretching exercises will be held for 20-30 seconds with 2-3 repetitions. During myofascial release (approximately 25 minutes per session), taVNS will be delivered simultaneously
Device: Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) · Other: Manual Therapy Program · Behavioral: Diaphragmatic Breathing and Stretching Exercises
Participants will receive the same manual therapy program as the active taVNS group (myofascial release, Maitland mobilization, elastic band-assisted diaphragmatic breathing training, and static stretching exercises). During myofascial release, an electrode identical in appearance to that of the active group will be placed on the left cymba concha, but no electrical current will be delivered (sham taVNS). Sessions will last 45 minutes, 3 days per week for 8 weeks.
Device: Sham Transcutaneous Auricular Vagus Nerve Stimulation (Sham taVNS) · Other: Manual Therapy Program · Behavioral: Diaphragmatic Breathing and Stretching Exercises
Non-invasive stimulation delivered through an electrode placed on the left cymba concha, at 25 Hz frequency and 250-500 μs pulse width, with current intensity titrated to the individual sensory threshold below the pain threshold (approximately 0.1-10 mA, in 0.1 mA increments). Applied simultaneously with myofascial release (approximately 25 minutes per session), 3 days per week for 8 weeks.
Also known as: taVNS
An electrode identical in appearance to that of the active group is placed on the left cymba concha, but no electrical current is delivered. Applied during myofascial release (approximately 25 minutes per session), 3 days per week for 8 weeks.
Also known as: Sham taVNS
Myofascial release applied to the upper trapezius, levator scapulae, rhomboids, cervical-lumbar paraspinal regions, and gluteal region, including the tender point areas defined in the ACR fibromyalgia criteria (static, low-intensity pressure held approximately 60-90 seconds per region), and Maitland postero-anterior mobilization of painful cervical, thoracic, and lumbar segments (3 sets of 2 minutes with 1-minute rests). Sessions last 45 minutes, 3 days per week for 8 weeks.
Also known as: Myofascial Release and Maitland Mobilization
Elastic band-assisted diaphragmatic breathing training (10-15 minutes per session, sets of 8-10 repetitions) and static stretching of the upper trapezius, pectoral muscles, hamstrings, quadriceps, and gastrocnemius (held 20-30 seconds, 2-3 repetitions), delivered in the same sessions as the manual therapy program, 3 days per week for 8 weeks.
Also known as: Elastic Band-Assisted Breathing Training
Pressure Pain Threshold (PPT)
Pressure pain threshold will be measured with a manual pressure algometer at the 18 tender points defined in the ACR fibromyalgia criteria (bilateral occiput, low cervical, trapezius, supraspinatus, second rib, lateral epicondyle, gluteal, greater trochanter, and knee). Pressure will be applied perpendicular to the skin at a steady rate, and the participant will report the moment the pressure first becomes painful. The value at that moment will be recorded at each point. The total algometric score will be calculated as the sum of the values from all 18 points. Higher scores indicate a higher pain threshold (lower pain sensitivity), and an increase from baseline indicates improvement. Measurements will be performed under standardized conditions at baseline and after the 8-week intervention.
Time frame: Baseline and 8 weeks (after the intervention period)
Short-Form McGill Pain Questionnaire (SF-MPQ)
The SF-MPQ is a 15-item questionnaire assessing the sensory and affective dimensions of pain. Participants rate each descriptor on a 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). The total score ranges from 0 to 45. Higher scores indicate greater pain. The Turkish validated version will be used.
Time frame: Baseline and 8 weeks
Heart Rate Variability (HRV)
Autonomic nervous system function will be assessed objectively by heart rate variability. R-R intervals will be recorded with a Polar H10 chest strap and analyzed with Kubios HRV Scientific Lite software. Time-domain parameters (e.g., RMSSD, SDNN) and frequency-domain parameters (e.g., LF, HF, LF/HF ratio) will be calculated in line with the Task Force standards. Higher RMSSD and HF values indicate greater parasympathetic (vagal) activity.
Time frame: Baseline and 8 weeks
Brief Illness Perception Questionnaire (Brief IPQ)
The Brief IPQ assesses the participant's cognitive and emotional representation of her illness. Eight items (consequences, timeline, personal control, treatment control, identity, concern, coherence, emotional response) are rated from 0 to 10, and the ninth item is an open-ended question about perceived causes. The total score of the first eight items ranges from 0 to 80 (after reverse-scoring the control and coherence items). Higher scores indicate a more threatening perception of the illness.
Time frame: Baseline and 8 weeks
Revised Fibromyalgia Impact Questionnaire (FIQ-R)
The FIQ-R is a 21-item self-report questionnaire assessing the overall impact of fibromyalgia over the past 7 days. It has three domains: function (9 items), overall impact (2 items), and symptoms (10 items). The total score ranges from 0 to 100. Higher scores indicate a greater impact of the disease on daily life. The Turkish validated version will be used.
Time frame: Baseline and 8 weeks
Pittsburgh Sleep Quality Index (PSQI)
The PSQI assesses sleep quality and sleep disturbances over the past month. Seven components (subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medication, daytime dysfunction) are each scored from 0 to 3. The global score ranges from 0 to 21. Higher scores indicate poorer sleep quality (a global score above 5 indicates poor sleep).
Time frame: Baseline and 8 weeks
State-Trait Anxiety Inventory (STAI)
The STAI consists of 40 items rated on a 4-point scale (1-4): 20 items assess state anxiety (how the person feels at the moment) and 20 items assess trait anxiety (how the person generally feels). After reverse-scoring the relevant items, each subscale score ranges from 20 to 80. Higher scores indicate higher anxiety. The Turkish validated version will be used.
Time frame: Baseline and 8 weeks
Plan to share: No
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