Fibromyalgia (FM) OR Fibromyalgia SyndromeNCT07894588
Effects of Adding Vagal Neuromodulation to Manual Therapy in Women With Fibromyalgia
A study testing Transcutaneous Auricular Vagus Nerve Stimulation (taVNS), Manual Therapy Program and Diaphragmatic Breathing and Stretching Exercises in people with Fibromyalgia (FM) OR Fibromyalgia Syndrome and Manuel Therapy, run by Hasan Kalyoncu University at 1 site in Turkey (Türkiye).
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 65 years, women only
- Conditions the study is for
- Fibromyalgia (FM) OR Fibromyalgia Syndrome, Manuel Therapy, Chronic Widespread Pain
- What is being tested?
- Transcutaneous Auricular Vagus Nerve Stimulation (taVNS), Manual Therapy Program and Diaphragmatic Breathing and Stretching Exercises
- Type of treatment
- Medical device, Lifestyle or therapy programme
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 44 participants
- Where
- 1 siteTurkey (Türkiye)
- Study dates
- 2 Nov 2026to 9 Mar 2027
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Diagnosis of fibromyalgia according to the 2016 American College of Rheumatology (ACR) criteria, made by a physician
- Female, aged 18-65 years
- Symptomatic for at least 3 months
- Pain intensity of 4 or higher on the Numeric Rating Scale (NRS ≥ 4; moderate to severe pain)
- Able to read and write and understand Turkish
- Willing to participate in the study (voluntary informed consent)
Who cannot join
- Inflammatory rheumatologic disease (e.g., rheumatoid arthritis, systemic lupus erythematosus)
- Active cardiac arrhythmia or implanted pacemaker
- History of vagus nerve damage or vagotomy
- Uncontrolled psychiatric disorder
- Pregnancy or breastfeeding
- Manual therapy or electrotherapy treatment within the last 3 months
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Turkey (Türkiye)1 site
Physiotherapist Taha Emre Baz Private health professional service unit
Mersin, 33140
About this study
Official title: Effect of Vagal Neuromodulation Added to Manual Therapy on Pain, Autonomic Nervous System, and Illness Perception in Women With Fibromyalgia
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.
Read the detailed description
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.
- Conditions
- Fibromyalgia (FM) OR Fibromyalgia Syndrome, Manuel Therapy, Chronic Widespread Pain, Autonomic Nervous System Dysfunction, taVNS
- Being tested
- Transcutaneous Auricular Vagus Nerve Stimulation (taVNS), Sham Transcutaneous Auricular Vagus Nerve Stimulation (Sham taVNS), Manual Therapy Program, Diaphragmatic Breathing and Stretching Exercises
- Keywords
- Fibromyalgia, Transcutaneous auricular vagus nerve stimulation, Manual therapy, Vagal neuromodulation, Heart rate variability, Sham-controlled, Illness perception
- Medical subject headings
- Fibromyalgia, Chronic Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Transcutaneous Auricular Vagus Nerve Stimulation (taVNS)Device
Also called taVNS
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.
Sham Transcutaneous Auricular Vagus Nerve Stimulation (Sham taVNS)Device
Also called Sham 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.
Manual Therapy ProgramOther
Also called Myofascial Release and Maitland Mobilization
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.
Diaphragmatic Breathing and Stretching ExercisesBehavioural
Also called Elastic Band-Assisted Breathing Training
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.
| Study group | Role | What they receive |
|---|---|---|
| Manual Therapy + Active taVNS | Experimental | 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 Receives: Device: Transcutaneous Auricular Vagus Nerve Stimulation (taVNS); Other: Manual Therapy Program; Behavioral: Diaphragmatic Breathing and Stretching Exercises |
| Manual Therapy + Sham taVNS | Sham comparator | 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. Receives: Device: Sham Transcutaneous Auricular Vagus Nerve Stimulation (Sham taVNS); Other: Manual Therapy Program; Behavioral: Diaphragmatic Breathing and Stretching Exercises |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline and 8 weeks (after the intervention period)
Secondary outcomes (6)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: Baseline and 8 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Oct 2026
- Study start2 Nov 2026 (estimated)
- Primary completion1 Feb 2027 (estimated)
- Study completion9 Mar 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (18)Papers the sponsor has linked to this study.
- Other trials for Fibromyalgia (FM) OR Fibromyalgia SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- This is a two-arm, parallel-group, randomized, sham-controlled trial. Female patients diagnosed with fibromyalgia will be randomly allocated in a 1:1 ratio, using opaque sealed envelopes, to either the study group (manual therapy plus active taVNS combined with diaphragmatic breathing) or the sham control group (manual therapy plus sham taVNS). Outcomes will be assessed at baseline and after the intervention period.
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 44 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Hasan Kalyoncu University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Taha Emre Baz, Hasan Kalyoncu University
- Investigators
- Tuğba Gönen, PhD, Principal investigator, Hasan Kalyoncu University, Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07894588
- Sponsor's protocol ID
- 2026/111
- Status last verified
- Oct 2026
- First submitted
- 17 Oct 2026
- Last updated
- 26 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Hauser W, Katz RL, Mease PJ, Russell AS, Russell IJ, Walitt B. 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin Arthritis Rheum. 2016 Dec;46(3):319-329. doi: 10.1016/j.semarthrit.2016.08.012. Epub 2016 Aug 30.
PubMed 27916278Torres JR, Martos IC, Sanchez IT, Rubio AO, Pelegrina AD, Valenza MC. Results of an Active Neurodynamic Mobilization Program in Patients With Fibromyalgia Syndrome: A Randomized Controlled Trial. Arch Phys Med Rehabil. 2015 Oct;96(10):1771-8. doi: 10.1016/j.apmr.2015.06.008. Epub 2015 Jul 2.
PubMed 26143052Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation. 1996 Mar 1;93(5):1043-65. No abstract available.
PubMed 8598068Schaffarczyk M, Rogers B, Reer R, Gronwald T. Validity of the Polar H10 Sensor for Heart Rate Variability Analysis during Resting State and Incremental Exercise in Recreational Men and Women. Sensors (Basel). 2022 Aug 30;22(17):6536. doi: 10.3390/s22176536.
PubMed 36081005Perin JP, Pastora-Sesin C, Kang S, Navarro-Flores A, Fregni F, Pacheco-Barrios K. Potential of Vagus Nerve Stimulation to Modulate Fibromyalgia's Network Physiology: A Systematic Review. J Funct Morphol Kinesiol. 2025 Dec 29;11(1):15. doi: 10.3390/jfmk11010015.
PubMed 41562733Percin A, Basat H, Ozden AV, Yenisehir S. The effect of auricular vagus nerve stimulation in women with temporomandibular joint disorders: a randomized controlled study. Rev Assoc Med Bras (1992). 2025 Jun 2;71(4):e20241739. doi: 10.1590/1806-9282.20241739. eCollection 2025.
PubMed 40465996Paccione CE, Stubhaug A, Diep LM, Rosseland LA, Jacobsen HB. Meditative-based diaphragmatic breathing vs. vagus nerve stimulation in the treatment of fibromyalgia-A randomized controlled trial: Body vs. machine. Front Neurol. 2022 Nov 3;13:1030927. doi: 10.3389/fneur.2022.1030927. eCollection 2022.
PubMed 36438970Wang D, Zhu J, Li N, Lu H, Gao Y, Zhuang L, Chen Z, Mao W. GC-MS-based untargeted metabolic profiling of malignant mesothelioma plasma. PeerJ. 2023 May 18;11:e15302. doi: 10.7717/peerj.15302. eCollection 2023.
PubMed 37220527Nadal-Nicolas Y, Rubio-Arias JA, Martinez-Olcina M, Reche-Garcia C, Hernandez-Garcia M, Martinez-Rodriguez A. Effects of Manual Therapy on Fatigue, Pain, and Psychological Aspects in Women with Fibromyalgia. Int J Environ Res Public Health. 2020 Jun 26;17(12):4611. doi: 10.3390/ijerph17124611.
PubMed 32604939Yakut Y, Yakut E, Bayar K, Uygur F. Reliability and validity of the Turkish version short-form McGill pain questionnaire in patients with rheumatoid arthritis. Clin Rheumatol. 2007 Jul;26(7):1083-7. doi: 10.1007/s10067-006-0452-6. Epub 2006 Nov 15.
PubMed 17106618Melzack R. The short-form McGill Pain Questionnaire. Pain. 1987 Aug;30(2):191-197. doi: 10.1016/0304-3959(87)91074-8.
PubMed 36708707. Kutlu, N. R. (2019). Fibromiyalji sendromlu hastalarda auriküler vagus sinir uyarımının ağrı ve yaşam kalitesi üzerine etkisi [Yüksek lisans tezi, Bahçeşehir Üniversitesi]. YÖK Ulusal Tez Merkezi.
Ediz L, Hiz O, Toprak M, Tekeoglu I, Ercan S. The validity and reliability of the Turkish version of the Revised Fibromyalgia Impact Questionnaire. Clin Rheumatol. 2011 Mar;30(3):339-46. doi: 10.1007/s10067-010-1546-8. Epub 2010 Aug 12.
PubMed 20703890Dolcini G, Favretti M, Franculli D, Buoncuore G, Pellegrino G, Di Carlo M, Sarzi-Puttini P, Conti F, Iannuccelli C, Di Franco M. Vagal nerve stimulation and fibromyalgia: an additional therapeutic option. Clin Exp Rheumatol. 2025 Jun;43(6):1095-1104. doi: 10.55563/clinexprheumatol/johqvo. Epub 2025 Jun 27.
PubMed 40576705Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213. doi: 10.1016/0165-1781(89)90047-4.
PubMed 2748771
Study at a glance
From the registry record, last updated by the sponsor on 26 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Vagal Neuromodulation Added to Manual Therapy on Pain, Autonomic Nervous System, and Illness Perception in Women With Fibromyalgia
- ClinicalTrials.gov ID
- NCT07894588
- Acronym / sponsor ID
- 2026/111
- Conditions
- Fibromyalgia (FM) OR Fibromyalgia Syndrome, Manuel Therapy, Chronic Widespread Pain, Autonomic Nervous System Dysfunction, taVNS
- Keywords
- Fibromyalgia, Transcutaneous auricular vagus nerve stimulation, Manual therapy, Vagal neuromodulation, Heart rate variability, Sham-controlled, Illness perception
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 44 participants (estimated)
- Lead sponsor
- Hasan Kalyoncu UniversityUniversity, hospital or other
- Study start
- 2 Nov 2026 (estimated)
- Primary completion
- 1 Feb 2027 (estimated)
- Study completion
- 9 Mar 2027 (estimated)
- First posted
- 26 Oct 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
- Model description
- This is a two-arm, parallel-group, randomized, sham-controlled trial. Female patients diagnosed with fibromyalgia will be randomly allocated in a 1:1 ratio, using opaque sealed envelopes, to either the study group (manual therapy plus active taVNS combined with diaphragmatic breathing) or the sham control group (manual therapy plus sham taVNS). Outcomes will be assessed at baseline and after the intervention period.
| Arm | Type | Receives |
|---|---|---|
| Manual Therapy + Active taVNS | Experimental | Device: Transcutaneous Auricular Vagus Nerve Stimulation (taVNS), Other: Manual Therapy Program, Behavioral: Diaphragmatic Breathing and Stretching ExercisesParticipants 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 |
| Manual Therapy + Sham taVNS | Sham comparator | Device: Sham Transcutaneous Auricular Vagus Nerve Stimulation (Sham taVNS), Other: Manual Therapy Program, Behavioral: Diaphragmatic Breathing and Stretching ExercisesParticipants 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. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Diagnosis of fibromyalgia according to the 2016 American College of Rheumatology (ACR) criteria, made by a physician
- Female, aged 18-65 years
- Symptomatic for at least 3 months
- Pain intensity of 4 or higher on the Numeric Rating Scale (NRS ≥ 4; moderate to severe pain)
- Able to read and write and understand Turkish
Key exclusion criteria (6 listed)
- Inflammatory rheumatologic disease (e.g., rheumatoid arthritis, systemic lupus erythematosus)
- Active cardiac arrhythmia or implanted pacemaker
- History of vagus nerve damage or vagotomy
- Uncontrolled psychiatric disorder
- Pregnancy or breastfeeding
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Transcutaneous Auricular Vagus Nerve Stimulation (taVNS)Also: taVNSNon-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. | Device | Manual Therapy + Active taVNS |
| Sham Transcutaneous Auricular Vagus Nerve Stimulation (Sham taVNS)Also: Sham taVNSAn 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. | Device | Manual Therapy + Sham taVNS |
| Manual Therapy ProgramAlso: Myofascial Release and Maitland MobilizationMyofascial 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. | Other | Manual Therapy + Active taVNS, Manual Therapy + Sham taVNS |
| Diaphragmatic Breathing and Stretching ExercisesAlso: Elastic Band-Assisted Breathing TrainingElastic 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. | Behavioural | Manual Therapy + Active taVNS, Manual Therapy + Sham taVNS |
Primary outcome
Pressure Pain Threshold (PPT)
Time frame: Baseline and 8 weeks (after the intervention period)
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.
6 secondary outcomes
Short-Form McGill Pain Questionnaire (SF-MPQ)
Time frame: Baseline and 8 weeks
Heart Rate Variability (HRV)
Time frame: Baseline and 8 weeks
Brief Illness Perception Questionnaire (Brief IPQ)
Time frame: Baseline and 8 weeks
Revised Fibromyalgia Impact Questionnaire (FIQ-R)
Time frame: Baseline and 8 weeks
Pittsburgh Sleep Quality Index (PSQI)
Time frame: Baseline and 8 weeks
State-Trait Anxiety Inventory (STAI)
Time frame: Baseline and 8 weeks
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Oct 2026.
- Results publication: PubMed 27916278Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Hauser W, Katz RL, Mease PJ, Russell AS, Russell IJ, Walitt B. 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin Arthritis Rheum. 2016 Dec;46(3):319-329. doi: 10.1016/j.semarthrit.2016.08.012. Epub 2016 Aug 30.
- Results publication: PubMed 26143052Torres JR, Martos IC, Sanchez IT, Rubio AO, Pelegrina AD, Valenza MC. Results of an Active Neurodynamic Mobilization Program in Patients With Fibromyalgia Syndrome: A Randomized Controlled Trial. Arch Phys Med Rehabil. 2015 Oct;96(10):1771-8. doi: 10.1016/j.apmr.2015.06.008. Epub 2015 Jul 2.
- Results publication: PubMed 8598068Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation. 1996 Mar 1;93(5):1043-65. No abstract available.
- Results publication: PubMed 36081005Schaffarczyk M, Rogers B, Reer R, Gronwald T. Validity of the Polar H10 Sensor for Heart Rate Variability Analysis during Resting State and Incremental Exercise in Recreational Men and Women. Sensors (Basel). 2022 Aug 30;22(17):6536. doi: 10.3390/s22176536.
- Results publication: PubMed 41562733Perin JP, Pastora-Sesin C, Kang S, Navarro-Flores A, Fregni F, Pacheco-Barrios K. Potential of Vagus Nerve Stimulation to Modulate Fibromyalgia's Network Physiology: A Systematic Review. J Funct Morphol Kinesiol. 2025 Dec 29;11(1):15. doi: 10.3390/jfmk11010015.
- Results publication: PubMed 40465996Percin A, Basat H, Ozden AV, Yenisehir S. The effect of auricular vagus nerve stimulation in women with temporomandibular joint disorders: a randomized controlled study. Rev Assoc Med Bras (1992). 2025 Jun 2;71(4):e20241739. doi: 10.1590/1806-9282.20241739. eCollection 2025.
- Results publication: PubMed 36438970Paccione CE, Stubhaug A, Diep LM, Rosseland LA, Jacobsen HB. Meditative-based diaphragmatic breathing vs. vagus nerve stimulation in the treatment of fibromyalgia-A randomized controlled trial: Body vs. machine. Front Neurol. 2022 Nov 3;13:1030927. doi: 10.3389/fneur.2022.1030927. eCollection 2022.
- Results publication: PubMed 37220527Wang D, Zhu J, Li N, Lu H, Gao Y, Zhuang L, Chen Z, Mao W. GC-MS-based untargeted metabolic profiling of malignant mesothelioma plasma. PeerJ. 2023 May 18;11:e15302. doi: 10.7717/peerj.15302. eCollection 2023.
- Results publication: PubMed 32604939Nadal-Nicolas Y, Rubio-Arias JA, Martinez-Olcina M, Reche-Garcia C, Hernandez-Garcia M, Martinez-Rodriguez A. Effects of Manual Therapy on Fatigue, Pain, and Psychological Aspects in Women with Fibromyalgia. Int J Environ Res Public Health. 2020 Jun 26;17(12):4611. doi: 10.3390/ijerph17124611.
- Results publication: PubMed 17106618Yakut Y, Yakut E, Bayar K, Uygur F. Reliability and validity of the Turkish version short-form McGill pain questionnaire in patients with rheumatoid arthritis. Clin Rheumatol. 2007 Jul;26(7):1083-7. doi: 10.1007/s10067-006-0452-6. Epub 2006 Nov 15.
- Results publication: PubMed 3670870Melzack R. The short-form McGill Pain Questionnaire. Pain. 1987 Aug;30(2):191-197. doi: 10.1016/0304-3959(87)91074-8.
- Results publication7. Kutlu, N. R. (2019). Fibromiyalji sendromlu hastalarda auriküler vagus sinir uyarımının ağrı ve yaşam kalitesi üzerine etkisi [Yüksek lisans tezi, Bahçeşehir Üniversitesi]. YÖK Ulusal Tez Merkezi.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Tuğba Gönen, PhD principal investigator
Hasan Kalyoncu University, Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Transcutaneous Auricular Vagus Nerve Stimulation (taVNS), Manual Therapy Program and Diaphragmatic Breathing and Stretching Exercises in people with Fibromyalgia (FM) OR Fibromyalgia Syndrome and Manuel Therapy, run by Hasan Kalyoncu University at 1 site in Turkey (Türkiye).
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 26 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Turkey (Türkiye). Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Taha Emre Baz, BSc (+905067534530, baztahaemre@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Pressure Pain Threshold (PPT) (time frame: Baseline and 8 weeks (after the intervention period)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07894588, which also lists 18 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Oct 2026.