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Study of Orofacial Pain and PropRANOlol (SOPPRANO)

This study is currently recruiting participants.
Verified November 2017 by University of North Carolina, Chapel Hill
Sponsor:
ClinicalTrials.gov Identifier:
NCT02437383
First Posted: May 7, 2015
Last Update Posted: November 7, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
University of Florida
Rho, Inc.
National Institutes of Health (NIH)
National Institute of Dental and Craniofacial Research (NIDCR)
State University of New York at Buffalo
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill
  Purpose

Purpose:

Primary: To evaluate the efficacy of extended-release propranolol compared to placebo for reducing pain in patients with temporomandibular disorder (TMD).

Secondary: To determine if extended-release propranolol efficacy varies according to participants' catechol-O-methyltransferase (COMT) genetic diplotype.

Exploratory: To investigate whether the effect of extended-release propranolol on the incidence of adverse effects, use of rescue medication, or pain index varies according to polymorphisms in the noncoding regions of COMT, adrenergic receptor β2 (ADRβ2), or adrenergic receptor β3 (ADRβ3) genes.

Participants:

200 patients with chronic TMD will be randomly assigned, in a 1:1 parallel, double-blind fashion, to receive either extended-release propranolol or placebo at one of three study sites: University of North Carolina-Chapel Hill School of Dentistry; University of Florida-Gainesville College of Dentistry; and the State University of New York at Buffalo School of Dental Medicine.

Procedures (methods):

Randomization will be to either propranolol or placebo. The 10-week study treatment period is divided into: 1 week of drug titration, 8 weeks of drug maintenance, and 1 week of drug tapering. The titration and tapering doses are 60 mg (capsules) once per day orally; the maintenance dose is 60 mg twice per day orally. Participants will attend 6 clinic visits over 12-15 weeks as follows: screening and baseline visit (Visit [V] 0, 7-21 days prior to V1); randomization and start of treatment (titration) (V1, study day 0); maintenance visit 2 (V2, 1 week post-randomization, study day 7+3); maintenance visit 3 (V3, 5 weeks post-randomization, study day 35 +/- 7); tapering visit (V4, 9 weeks post-randomization, study day 63 +/- 7); and tapering visit 5 (V5, 11 weeks post-randomization and 1 week after drug tapering ends, study day 77 +/- 7). Depending on the visit, procedures will include: reviews of medical history, weekly alcohol consumption, concomitant therapies and medications, adverse events, compliance, and eligibility; administration/review of questionnaires; blood draw; pregnancy test in women of childbearing potential; and dispensing of study drug.


Condition Intervention Phase
Temporomandibular Disorders Drug: Propranolol ER Drug: Placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effect of COMT (Catecholamine-O-methyltransferase) Genetic Polymorphisms on Response to Propranolol Therapy in Temporomandibular Disorder

Resource links provided by NLM:


Further study details as provided by University of North Carolina, Chapel Hill:

Primary Outcome Measures:
  • Change in the weekly mean pain index after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    Weekly mean pain index computed as the arithmetic mean of daily pain index values during the week prior to randomization and prior to each study visit. Daily pain index is computed as pain intensity (0-100 numeric rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable") multiplied by pain duration (0-100 percentage scale where percent = "percent of waking day you had facial pain") as reported in the Daily Symptom Diary.

  • Change in the weekly mean pain index after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    Weekly mean pain index computed as the arithmetic mean of daily pain index values during the week prior to randomization and prior to each study visit. Daily pain index is computed as pain intensity (0-100 numeric rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable") multiplied by pain duration (0-100 percentage scale where percent = "percent of waking day you had facial pain") as reported in the Daily Symptom Diary.


Secondary Outcome Measures:
  • Change in the weekly mean pain intensity after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    Weekly mean pain intensity computed as the arithmetic mean of daily pain intensity values during the week prior to randomization and prior to each study visit. Daily pain intensity is measured on 0-100 numeric rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable") as reported in the Daily Symptom Diary.

  • Change in the weekly mean pain intensity after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    Weekly mean pain intensity computed as the arithmetic mean of daily pain intensity values during the week prior to randomization and prior to each study visit. Daily pain intensity is measured on 0-100 numeric rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable") as reported in the Daily Symptom Diary.

  • Change in the weekly mean pain duration after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    Weekly mean pain duration computed as the arithmetic mean of daily pain duration values during the week prior to randomization and prior to each study visit. Daily pain duration is measured on 0-100 percentage scale where percent = "percent of waking day you had facial pain" as reported in the Daily Symptom Diary.

  • Change in the weekly mean pain duration after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    Weekly mean pain duration computed as the arithmetic mean of daily pain duration values during the week prior to randomization and prior to each study visit. Daily pain duration is measured on 0-100 percentage scale where percent = "percent of waking day you had facial pain" as reported in the Daily Symptom Diary.

  • Change in the SF-McGill Pain Questionnaire total score after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    The SF-McGill Pain Questionnaire contains 15 descriptors (11 sensory, 4 affective) rated on a 0-3 scale where 0 = "none," 1 = "mild," 2 = "moderate," and 3 = "severe." The item scores are summed to yield a total score ranging from 0 to 45.

  • Change in the SF-McGill Pain Questionnaire total score after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    The SF-McGill Pain Questionnaire contains 15 descriptors (11 sensory, 4 affective) rated on a 0-3 scale where 0 = "none," 1 = "mild," 2 = "moderate," and 3 = "severe."The item scores are summed to yield a total score ranging from 0 to 45.

  • Change in the SF-McGill Pain Questionnaire current facial pain intensity after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    Self-reported facial pain intensity at the visit scored on 0-100 numerical rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable".

  • Change in the SF-McGill Pain Questionnaire current facial pain intensity after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    Self-reported facial pain intensity at the visit scored on 0-100 numerical rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable".

  • Change in the SF-McGill Pain Questionnaire weekly average facial pain intensity after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    Self-reported average facial pain intensity for the last week scored on 0-100 numerical rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable".

  • Change in the SF-McGill Pain Questionnaire weekly average facial pain intensity after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    Self-reported average facial pain intensity for the last week scored on 0-100 numerical rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable".

  • Change in the SF-McGill Pain Questionnaire weekly average facial pain duration after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    Self-reported average facial pain duration for the last week scored on 0-100 percentage scale where percent = "percent of waking day you had facial pain".

  • Change in the SF-McGill Pain Questionnaire weekly average facial pain duration after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    Self-reported average facial pain duration for the last week scored on 0-100 percentage scale where percent = "percent of waking day you had facial pain".

  • Change in the Graded Chronic Pain Scale (GCPS) Characteristic Pain Intensity (CPI) after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    The GCPS CPI is the mean of 0-10 ratings of pain right now, average pain and worst pain multiplied by 10 to yield a 0-100 score.

  • Change in the Graded Chronic Pain Scale (GCPS) Characteristic Pain Intensity after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    The GCPS CPI is the mean of 0-10 ratings of pain right now, average pain and worst pain multiplied by 10 to yield a 0-100 score.

  • Change in the Graded Chronic Pain Scale (GCPS) Disability Days after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    The GCPS Disability Days is the number of days of significant activity limitation due to facial pain in the past month.

  • Change in the Graded Chronic Pain Scale (GCPS) Disability Days after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    The GCPS Disability Days is the number of days of significant activity limitation due to facial pain in the past month.

  • Change in the Graded Chronic Pain Scale (GCPS) Disability Score after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    The GCPS Disability Score is the mean of three 0-10 pain interference ratings multiplied by 10 to yield a 0-100 score.

  • Change in the Graded Chronic Pain Scale (GCPS) Disability Score after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    The GCPS Disability Score is the mean of three 0-10 pain interference ratings multiplied by 10 to yield a 0-100 score.

  • Change in the Jaw Functional Limitation Scale (JFLS) global score after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    The JFLS contains 20 items that measure limitations across mastication, vertical jaw mobility, and verbal/emotional expression rated on a 0-10 scale where 0 = "no limitation" and 10 = "severe limitation."

  • Change in the Jaw Functional Limitation Scale (JFLS) global score after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    The JFLS contains 20 items that measure limitations across mastication, vertical jaw mobility, and verbal/emotional expression rated on a 0-10 scale where 0 = "no limitation" and 10 = "severe limitation."

  • Change in the Headache Impact Test (HIT-6) global score after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    The HIT-6 contains 6 items and assesses headache-related disability by the frequency of daily activity limitations ranging from "never" to "always." The 6 item scores are summed to yield a global score ranging from 36 to 78.

  • Change in the Headache Impact Test (HIT-6) global score after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    The HIT-6 contains 6 items and assesses headache-related disability by the frequency of daily activity limitations ranging from "never" to "always." The 6 item scores are summed to yield a global score ranging from 36 to 78.

  • Change in the Pittsburgh Sleep Quality Index (PSQI) global score after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    The PSQI has 19 items grouped into 7 component scores, each weighted equally on a 0-3 scale, The 7 component scores are summed to yield a global PSQI score, which has a range of 0-21.

  • Change in the Pittsburgh Sleep Quality Index (PSQI) global score after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    The PSQI has 19 items grouped into 7 component scores, each weighted equally on a 0-3 scale, The 7 component scores are summed to yield a global PSQI score, which has a range of 0-21.

  • Change in the Patient Global Impression of Change (PGIC) after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    The PGIC assesses patient overall status on a scale from 1 to 7 where 1 = "very much improved" and 7 = "very much worse."

  • Change in the Patient Global Impression of Change (PGIC) after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    The PGIC assesses patient overall status on a scale from 1 to 7 where 1 = "very much improved" and 7 = "very much worse."

  • Change in the Perceived Stress Scale (PSS) global score after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    The PSS assesses the frequency of 14 sources of stress on a scale from 0 = "never" to 4 = "very often." The item scores are summed to yield a global score ranging from 0 to 56.

  • Change in the Perceived Stress Scale (PSS) global score after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    The PSS assesses the frequency of 14 sources of stress on a scale from 0 = "never" to 4 = "very often." The item scores are summed to yield a global score ranging from 0 to 56.

  • Change in the Hospital Anxiety and Depression Scale (HADS) anxiety score after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    The HADS is a 14-item assessment of anxiety (7 items) and depression (7 items) using the relative frequency of symptoms over the past week, rated on a 4-point scale ranging from 0 = "not at all" to 3 = "very often indeed". Responses are summed to provide separate scores for anxiety and depression.

  • Change in the Hospital Anxiety and Depression Scale (HADS) anxiety score after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    The HADS is a 14-item assessment of anxiety (7 items) and depression (7 items) using the relative frequency of symptoms over the past week, rated on a 4-point scale ranging from 0 = "not at all" to 3 = "very often indeed". Responses are summed to provide separate scores for anxiety and depression.

  • Change in the Hospital Anxiety and Depression Scale (HADS) depression score after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    The HADS is a 14-item assessment of anxiety (7 items) and depression (7 items) using the relative frequency of symptoms over the past week, rated on a 4-point scale ranging from 0 = "not at all" to 3 = "very often indeed". Responses are summed to provide separate scores for anxiety and depression.

  • Change in the Hospital Anxiety and Depression Scale (HADS) depression score after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    The HADS is a 14-item assessment of anxiety (7 items) and depression (7 items) using the relative frequency of symptoms over the past week, rated on a 4-point scale ranging from 0 = "not at all" to 3 = "very often indeed". Responses are summed to provide separate scores for anxiety and depression.

  • Change in the Symptom Checklist 90-Revised (SCL-90R) Somatization Scale after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    The SCL-90R Somatization Scale is a 12-item assessment of somatic symptom distress over the past 7 days rated from 0 = "not at all" to 4 = "extremely."

  • Change in the Symptom Checklist 90-Revised (SCL-90R) Somatization Scale after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    The SCL-90R Somatization Scale is a 12-item assessment of somatic symptom distress over the past 7 days rated from 0 = "not at all" to 4 = "extremely."

  • Change in the SF-12 Health Survey v2 (SF-12v2) Physical Component Summary (PCS) after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    The SF-12v2 v2 contains 7 questions assessing 8 domains of functioning and well-being rated from: "excellent" to "poor" (for general health); "yes, limited a lot" to "no, not limited at all" (for functional level); and "all of the time" to "none of the time" (for emotional state). These 8 domains can be further summarized into a physical component summary (PCS) and a mental component summary (MCS).

  • Change in the SF-12 Health Survey v2 (SF-12v2) Physical Component Summary (PCS) after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    The SF-12v2 v2 contains 7 questions assessing 8 domains of functioning and well-being rated from: "excellent" to "poor" (for general health); "yes, limited a lot" to "no, not limited at all" (for functional level); and "all of the time" to "none of the time" (for emotional state). These 8 domains can be further summarized into a physical component summary (PCS) and a mental component summary (MCS).

  • Change in the SF-12 Health Survey v2 (SF-12v2) Mental Component Summary (MCS) after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    The SF-12v2 v2 contains 7 questions assessing 8 domains of functioning and well-being rated from: "excellent" to "poor" (for general health); "yes, limited a lot" to "no, not limited at all" (for functional level); and "all of the time" to "none of the time" (for emotional state). These 8 domains can be further summarized into a physical component summary (PCS) and a mental component summary (MCS).

  • Change in the SF-12 Health Survey v2 (SF-12v2) Mental Component Summary (MCS) after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    The SF-12v2 v2 contains 7 questions assessing 8 domains of functioning and well-being rated from: "excellent" to "poor" (for general health); "yes, limited a lot" to "no, not limited at all" (for functional level); and "all of the time" to "none of the time" (for emotional state). These 8 domains can be further summarized into a physical component summary (PCS) and a mental component summary (MCS).

  • Change in thermal pain threshold after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    Temperature values, measured in degrees of Celsius, from 4 examiner-applied contact heat stimuli will be averaged to measure the experimental thermal pain threshold (temperature at which pain is first perceived).

  • Change in thermal pain threshold after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    Temperature values, measured in degrees of Celsius, from 4 examiner-applied contact heat stimuli will be averaged to measure the experimental thermal pain threshold (temperature at which pain is first perceived).

  • Change in thermal pain tolerance after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    Temperature values, measured in degrees of Celsius, from 4 examiner-applied contact heat stimuli will be averaged to measure the experimental thermal pain tolerance (temperature at which pain can no longer be tolerated).

  • Change in thermal pain tolerance after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    Temperature values, measured in degrees of Celsius, from 4 examiner-applied contact heat stimuli will be averaged to measure the experimental thermal pain tolerance (temperature at which pain can no longer be tolerated).

  • Change in pressure pain threshold at temporalis muscle after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    Pressure values, measured in kilopascals, from up to 5 experimental pressure stimuli, bilaterally applied to the area of temporalis muscle, will be averaged to obtain a single pressure pain threshold value per anatomical site.

  • Change in pressure pain threshold at temporalis muscle after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    Pressure values, measured in kilopascals, from up to 5 experimental pressure stimuli, bilaterally applied to the area of temporalis muscle, will be averaged to obtain a single pressure pain threshold value per anatomical site.

  • Change in pressure pain threshold at masseter muscle after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    Pressure values, measured in kilopascals, from up to 5 experimental pressure stimuli, bilaterally applied to the area of masseter muscle, will be averaged to obtain a single pressure pain threshold value per anatomical site.

  • Change in pressure pain threshold at masseter muscle after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/- 7) ]
    Pressure values, measured in kilopascals, from up to 5 experimental pressure stimuli, bilaterally applied to the area of masseter muscle, will be averaged to obtain a single pressure pain threshold value per anatomical site.

  • Change in pressure pain threshold at temporomandibular joint after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    Pressure values, measured in kilopascals, from up to 5 experimental pressure stimuli, bilaterally applied to the area of temporomandibular joint, will be averaged to obtain a single pressure pain threshold value per anatomical site.

  • Change in pressure pain threshold at temporomandibular joint after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    Pressure values, measured in kilopascals, from up to 5 experimental pressure stimuli, bilaterally applied to the area of temporomandibular joint, will be averaged to obtain a single pressure pain threshold value per anatomical site.

  • Change in pressure pain threshold at trapezius muscle after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    Pressure values, measured in kilopascals, from up to 5 experimental pressure stimuli, bilaterally applied to the area of trapezius muscle, will be averaged to obtain a single pressure pain threshold value per anatomical site.

  • Change in pressure pain threshold at trapezius muscle after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    Pressure values, measured in kilopascals, from up to 5 experimental pressure stimuli, bilaterally applied to the area of trapezius muscle, will be averaged to obtain a single pressure pain threshold value per anatomical site.

  • Change in pressure pain threshold at lateral epicondyle after 5 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 3 (study day 35 +/-7) ]
    Pressure values, measured in kilopascals, from up to 5 experimental pressure stimuli, bilaterally applied to the area of lateral epicondyle, will be averaged to obtain a single pressure pain threshold value per anatomical site.

  • Change in pressure pain threshold at lateral epicondyle after 9 weeks of treatment [ Time Frame: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7) ]
    Pressure values, measured in kilopascals, from up to 5 experimental pressure stimuli, bilaterally applied to the area of lateral epicondyle, will be averaged to obtain a single pressure pain threshold value per anatomical site.


Other Outcome Measures:
  • P-value for the interaction of the COMT haplotype and treatment allocation from a multivariable model in which the pain index is the dependent variable [ Time Frame: After 9 weeks of treatment ]
    A three-way interaction term between the COMT haplotype, treatment allocation (treatment or placebo), and visit sequence (Visits 2-3).

  • P-value for the interaction of COMT Valine158Methionine genotype and treatment allocation from a multivariable model in which the pain index is the dependent variable [ Time Frame: After 9 weeks of treatment ]
    A three-way interaction term between the COMT genotype, treatment allocation (treatment or placebo), and visit sequence (Visits 2-3).


Estimated Enrollment: 200
Actual Study Start Date: August 2015
Estimated Study Completion Date: March 2018
Estimated Primary Completion Date: March 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Propranolol ER
Propranolol hydrochloride extended release (ER) capsules; 60 mg (Visit 1 and Visit 4); 120 mg (Visit 2 and Visit 3) given orally as: 60 mg once/day (Visit 1 and Visit 4) and 60 mg twice/day (Visit 2 and Visit 3).
Drug: Propranolol ER
Capsules given orally according to schedule at Visit 1, Visit 2, Visit 3, and Visit 4.
Other Name: Inderal LA (long-acting)
Placebo Comparator: Placebo
Capsules, identical in appearance to active comparator (propranolol), to be administered orally in exactly the same manner as propranolol at Visit 1 (once/day), Visit 2 (twice/day), Visit 3 (twice/day), and Visit 4 (once/day).
Drug: Placebo
Gelatin capsules with a microcrystalline cellulose filler manufactured to mimic propranolol ER 60 mg capsules

Detailed Description:

"Temporomandibular disorder" (TMD) encompasses all musculoskeletal disorders of the masticatory system and includes myalgia, arthralgia, temporomandibular joint (TMJ) disc displacements, and TMJ degenerative joint diseases. The prevalence of TMD ranges from 6% to 12% in the general population, with muscle dysfunction the most prevalent TMD diagnostic group. TMD is associated with substantial disability and suffering and negatively impacts quality of life. Jaw pain is the most common symptom that compels treatment seeking. In addition to facial pain, TMD patients frequently report comorbid pain conditions such as headache, low back pain, and fibromyalgia. New approaches to TMD therapy are urgently needed to improve clinical outcomes and reduce economic impact of this disorder.

There is currently no FDA-approved product labeled specifically to manage/treat TMD; however, classes of drugs are used to relieve TMD-associated pain, such as non-steroidal anti-inflammatory drugs (NSAIDs), anti-inflammatory drugs, corticosteroids, benzodiazepines, sedative hypnotics, muscle relaxants, opioids, antidepressants, and anticonvulsants - although evidence to establish their efficacy and safety in this population is scarce. Practitioners' justification for their use may be based on poorly controlled clinical trials or clinical trials in other pain disorders such as acute postsurgical dental pain, arthritic pain, chronic lower back pain, and neuropathic pain. Thus, there is a need for controlled clinical trials to better understand the physiological mechanisms responsible for TMD symptoms.

Evidence suggests that enhanced β-adrenergic drive contributes to the pathogenesis of TMD and other complex persistent pain conditions. For example, individuals with myofascial pain conditions have elevated catecholamine levels and augmented sympathetic responses to stressors. While increased β-adrenergic drive appears to heighten pain, β-adrenergic antagonists can reduce clinical pain and/or nociceptive sensitivity. A recent study of a single infusion of propranolol in TMD and fibromyalgia patients revealed short-term improvement in clinical pain ratings. The antagonist pindolol was similarly efficacious in alleviating cardinal symptoms of fibromyalgia pain. In addition, intramuscular injections of low-dose propranolol in rats reduced inflammatory pain associated with carrageen-induced inflammation of the gastrocnemius muscle.

The study hypothesis is that therapy with the nonselective β-adrenergic receptor antagonist propranolol extended-release capsules (FDA approved to treat many cardiac conditions, tremor, migraine, and pheochromocytoma) will provide efficacious and safe treatment for painful TMD. It has well-studied pharmacodynamic, pharmacokinetic, and side-effect profiles. Peak blood level occurs at approximately 6 hrs, and the plasma half-life is approximately 10 hrs. The primary objective is to investigate the efficacy of propranolol compared with placebo over 10 weeks to reduce pain in patients with TMD. Secondary objectives are to: investigate by treatment group whether reduction in pain varies according to polymorphisms in the COMT gene coding region; and investigate the effect of propranolol compared with placebo to affect pain sensitivity, physical and emotional function, adverse effects, and use of rescue medications. Exploratory objectives are to: investigate gene-by treatment group interaction to determine the effect of propranolol on incidence of adverse effects, use of rescue medication, and reduction in the pain index according to polymorphisms in the COMT, ADRβ2, and ADRβ3 genetic coding regions.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion:

  • Diagnostic criteria for TMD: Group II, Masticatory Muscle Disorders, Myalgia
  • Facial pain for at least 3 months (and at least 10 of the last 30 days at Visit 0)
  • Average pain intensity rating ≥30 (0-100 numeric rating scale) over the past week or average daily pain intensity rating ≥30 on the same scale on at least 3 days over the past week
  • Agrees to terms for continuing/discontinuing certain prescription/over-the-counter pain medications throughout participation
  • Agrees to not commence new prescription medication, injection therapy, occlusal splint therapy or certain other pain management techniques throughout participation
  • Agrees to limit consumption of alcohol to no more than 7 drinks/week (females) and no more than 14 drinks/week (males) throughout participation
  • If a female of childbearing potential, agrees to use of contraception (licensed hormonal method, intrauterine device, condoms with contraceptive foam, abstinence, or partner vasectomy) throughout participation
  • Able to understand and comply with study procedures and provide written informed consent

Exclusion:

  • History of congestive heart failure or certain cardiac conditions including coronary artery disease, uncontrolled hypertension, or hypotension
  • Bronchial asthma, nonallergic bronchospasm, renal failure or dialysis, diabetes mellitus, hyperthyroidism, fibromyalgia, or uncontrolled seizures
  • Currently taking a β-blocker or certain other medications including haloperidol, intravenous verapamil, or reserpine
  • Currently taking an opioid medication
  • Daily prescription medication, occlusal splint therapy, or an investigational drug or treatment for pain management within past 30 days
  • Injection therapy or certain other pain management techniques within last 2 weeks
  • Facial trauma or orofacial surgery within past 6 weeks
  • Active orthodontic treatment
  • History of major depression or other psychiatric disorder requiring hospitalization within past 6 months
  • Treatment for drug or alcohol abuse within the last year
  • Smokes 25 or more cigarettes/day
  • Currently receiving chemotherapy or radiation therapy
  • Pregnant or breastfeeding
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02437383


Contacts
Contact: Inna E. Tchivileva, MD 919-537-3291 Inna_Tchivileva@unc.edu
Contact: Gary Slade, PhD 919-537-3273 Gary_Slade@unc.edu

Locations
United States, Florida
University of Florida-Gainesville College of Dentistry Recruiting
Gainesville, Florida, United States, 32610-0404
Contact: Roger B. Fillingim, PhD    352-273-5963    RFillingim@dental.ufl.edu   
United States, New York
University at Buffalo School of Dental Medicine Recruiting
Buffalo, New York, United States, 14214
Contact: Richard Ohrbach, DDS, PhD    716-829-3590    ohrbach@buffalo.edu   
United States, North Carolina
University of North Carolina at Chapel Hill School of Dentistry Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Inna Tchivileva, MD    919-537-3291    Inna_Tchivileva@unc.edu   
Sponsors and Collaborators
University of North Carolina, Chapel Hill
University of Florida
Rho, Inc.
National Institutes of Health (NIH)
National Institute of Dental and Craniofacial Research (NIDCR)
State University of New York at Buffalo
Investigators
Principal Investigator: Inna E. Tchivileva, MD University of North Carolina, Chapel Hill
Principal Investigator: Roger B. Fillingim, PhD University of Florida-Gainesville College of Dentistry
Principal Investigator: Richard Ohrbach, DDS, PhD University at Buffalo School of Dental Medicine
  More Information

Publications:
Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT02437383     History of Changes
Other Study ID Numbers: 14-2526
1U01DE024169-01 ( U.S. NIH Grant/Contract )
14-067-E ( Other Identifier: NIDCR Protocol Number )
First Submitted: May 4, 2015
First Posted: May 7, 2015
Last Update Posted: November 7, 2017
Last Verified: November 2017

Additional relevant MeSH terms:
Temporomandibular Joint Disorders
Temporomandibular Joint Dysfunction Syndrome
Craniomandibular Disorders
Mandibular Diseases
Jaw Diseases
Musculoskeletal Diseases
Joint Diseases
Muscular Diseases
Stomatognathic Diseases
Myofascial Pain Syndromes
Propranolol
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Antihypertensive Agents
Vasodilator Agents