Cytokine and Growth Factor Changes and Correlation With Clinical Outcomes Following Acupuncture for TMD

Study Overview
=================
Brief Summary
-----------------
Purpose: 1) To investigate differences in pro-inflammatory and anti-inflammatory cytokines and growth factors in the circulating blood (and cytokine levels only in saliva) of patients with chronic temporomandibular disorder (TMD) before and after acupuncture; 2) To determine differences in cytokine profiles between real and sham acupuncture in circulating blood of patients with chronic TMD; and 3) To explore correlations between these changes and clinical outcomes. Participants: Patients with chronic TMD pain recruited through the University of North Carolina-Chapel Hill (UNC-CH) Orofacial Pain Clinic. Procedures (methods): Participants will complete a self-administered questionnaire assessing TMD-related comorbidity. During the initial visit, study examiners will record clinical characteristics of muscles and joints of the head, neck and body according to newly recommended diagnostic criteria (DC) for TMD. Clinical outcomes include a pain index (computed from numeric rating scales) of masseter, temporalis and the supplemental painful muscles, and patient-reported symptoms (using the Measure Yourself Medical Outcome Profile; MYMOP) and pain intensity (using the Pain Scale). Blood (5 cc) will be taken before and after acupuncture treatments. Participants will self-collect pre-treatment and post-treatment saliva samples. Patients will receive 4 acupuncture treatments, once per week for 4 weeks. The primary outcome measure is change in IL-8 levels in circulating blood and saliva after 4 weeks of real acupuncture compared with sham acupuncture. Secondary outcome measures include comparing changes in levels of nerve growth factor (NGF), tumor necrosis factor-alpha (TNFα),vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and IL-1α, IL-2, IL-4, IL-6 and IL-10, before and after real acupuncture at Week 1 compared with sham acupuncture and before and after real acupuncture at Week 4 compared with sham acupuncture. The exploratory outcome measure is correlation between changes in cytokine levels and clinical variables after 4 weeks of real acupuncture compared with 4 weeks of sham acupuncture.

Detailed Description
-----------------
Temporomandibular disorder (TMD) is known to be the second most frequent musculoskeletal pain condition following low back pain. According to the NIDCR, TMD affects 5%-12% of the population at an annual cost estimated at 4 billion dollars in the US. Recent studies that have investigated acupuncture as a treatment for musculoskeletal pain have reported various results. Several meta-analyses and systematic reviews of randomized controlled trials suggest that acupuncture treatment improves TMD-related pain. Its mechanism of action in improving TMD pain, however, is largely unclear. Elevated levels of pro-inflammatory cytokines, e.g., MCP-1 and IL-8 have been found in circulating blood of patients with TMD. Upregulated pro-inflammatory cytokine levels have been correlated with greater sensitivity to pain evoking stimuli. Abnormalities in levels of pro-inflammatory cytokines are often accompanied by alterations in levels of anti-inflammatory cytokines, e.g., IL-1ra, which are associated with reductions in pain and inflammation. The effects of acupuncture on pro- and anti-inflammatory cytokines, growth factors, and clinical pain and function have not been reported in a prospective cohort of TMD patients at multiple time points in the clinical setting. The proposed mechanistic study seeks to ascertain if acupuncture compared to sham acupuncture produces measurable changes in circulating pro- and anti-inflammatory cytokines and growth factors in a manner that is associated with patient self-reports of pain and function over a 4-week treatment period. Cytokine and growth factor levels will be measured in blood and saliva; saliva will be used to measure cytokine levels only.

Official Title
-----------------
Cytokine and Growth Factor Changes and Correlation With Clinical Outcomes Following Acupuncture for TMD

Conditions
-----------------
Temporomandibular Joint Disorders

Intervention / Treatment
-----------------
* Device: Acupuncture
* Device: Sham Acupuncture


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed, informed consent; females and males aged 18-64; planning on living in the area for the next 2 months; fluent in written and spoken English; Myofascial pain with referral diagnosed according to TMD diagnostic criteria (Schiffman et al. 2014): pain in the temporalis and masseter muscles report of familiar pain with palpation of the two muscles report of pain at a site beyond the boundary of the muscle being palpated. Exclusion Criteria: Traumatic facial injury or surgery on the face or jaw; currently receiving orthodontic treatment; Systemic inflammatory disorders such as lupus, kidney failure or renal dialysis, heart disease or heart failure, chronic respiratory disease, hypertension, un- controlled diabetes, epilepsy or seizures Hyperthyroidism; chemotherapy or radiation therapy; trigeminal neuralgia; cluster headache; Drug or alcohol abuse; active or uncontrolled psychiatric disorders or recent (within 6 months) psychiatric hospitalization; pending pension or worker's claim/litigation; previous experience with acupuncture for TMD Current use of NSAIDS and/or steroidal medications.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Acupuncture<br>Acupuncture treatment for TMD | Device: Acupuncture<br>* Acupuncture using standard stainless steel acupuncture needles inserted into intramuscular tissue for 20 minutes<br>|
| Sham Comparator: Sham Acupuncture<br>Acupuncture treatment for TMD using the non-penetrating Park Sham Acupuncture Device | Device: Sham Acupuncture<br>* Acupuncture using non-penetrating Park Sham Needles for 20 minutes<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in cytokine IL-8 levels in circulating blood and saliva after 4 weeks of real acupuncture compared with 4 weeks of sham acupuncture. |  | Baseline, 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in patient-reported symptoms on the Measure Yourself Medical Outcome Profile (MYMOP; a 1-page paper questionnaire) after 4 weeks of real acupuncture compared with 4 weeks of sham acupuncture. |  | Baseline, 4 weeks | 
| Change in patient-reported pain intensity on the Pain Scale (a 1-page paper questionnaire) after 4 weeks of real acupuncture compared with 4 weeks of sham acupuncture. |  | Baseline, 4 weeks | 
| Change in cytokine MCP-1 levels in circulating blood and saliva after 4 weeks of real acupuncture compared with 4 weeks of sham acupuncture. |  | Baseline, 4 weeks | 
| Change in cytokine IL-1ra levels in circulating blood and saliva after 4 weeks of real acupuncture compared with 4 weeks of sham acupuncture. |  | Baseline, 4 weeks | 
| Change in cytokine IL-2 levels in circulating blood and saliva prior to and after real acupuncture compared with sham acupuncture at study Week 1. |  | Week 1 | 
| Change in cytokine IL-4 levels in circulating blood and saliva prior to and after real acupuncture compared with sham acupuncture at study Week 1. |  | Week 1 | 
| Change in cytokine IL-6 levels in circulating blood and saliva prior to and after real acupuncture compared with sham acupuncture at study Week 1. |  | Week 1 | 
| Change in cytokine IL-10 levels in circulating blood and saliva prior to and after real acupuncture compared with sham acupuncture at study Week 1. |  | Week 1 | 
| Change in cytokine IL-2 levels in circulating blood and saliva prior to and after real acupuncture compared with sham acupuncture at study Week 4. |  | Week 4 | 
| Change in cytokine IL-4 levels in circulating blood and saliva prior to and after real acupuncture compared with sham acupuncture at study Week 4. |  | Week 4 | 
| Change in cytokine IL-6 levels in circulating blood and saliva prior to and after real acupuncture compared with sham acupuncture at study Week 4. |  | Week 4 | 
| Change in cytokine IL-10 levels in circulating blood and saliva prior to and after real acupuncture compared with sham acupuncture at study Week 4. |  | Week 4 | 
| Change in nerve growth factor (NGF) levels in circulating blood prior to and after real acupuncture compared with sham acupuncture at study Week 1. |  | Week 1 | 
| Change in vascular endothelial growth factor (VEGF) levels in circulating blood prior to and after real acupuncture compared with sham acupuncture at study Week 1. |  | Week 1 | 
| Change in platelet-derived growth factor (PDGF) levels in circulating blood prior to and after real acupuncture compared with sham acupuncture at study Week 1. |  | Week 1 | 
| Change in basic fibroblast growth factor (bFGF) levels in circulating blood prior to and after real acupuncture compared with sham acupuncture at study Week 1. |  | Week 1 | 
| Change in tumor necrosis factor alpha (TNFa) levels in circulating blood prior to and after real acupuncture compared with sham acupuncture at study Week 1. |  | Week 1 | 
| Change in nerve growth factor (NGF) levels in circulating blood prior to and after real acupuncture compared with sham acupuncture at study Week 4. |  | Week 4 | 
| Change in vascular endothelial growth factor (VEGF) levels in circulating blood prior to and after real acupuncture compared with sham acupuncture at study Week 4. |  | Week 4 | 
| Change in platelet-derived growth factor (PDGF) levels in circulating blood prior to and after real acupuncture compared with sham acupuncture at study Week 4. |  | Week 4 | 
| Change in basic fibroblast growth factor (bFGF) levels in circulating blood prior to and after real acupuncture compared with sham acupuncture at study Week 4. |  | Week 4 | 
| Change in tumor necrosis factor alpha (TNFa) levels in circulating blood prior to and after real acupuncture compared with sham acupuncture at study Week 4. |  | Week 4 |