Study of Orofacial Pain and PropRANOlol
Condition: Temporomandibular Disorders
MeSH terms: Temporomandibular Joint Disorders; Temporomandibular Joint Dysfunction Syndrome
Study type: Interventional
Phase: Phase 2

Summary: 
      Purpose:

      Primary: To evaluate the efficacy of extended-release (ER) propranolol compared to placebo in
      the reduction of a pain index in patients with temporomandibular disorder (TMD).

      Secondary: To determine if extended-release propranolol efficacy varies according to
      participants' catechol-O-methyltransferase (COMT) genetic polymorphisms and to investigate
      the efficacy of extended-release propranolol compared with placebo using secondary endpoints.

      Exploratory: To investigate whether the efficacy of extended-release propranolol in the
      reduction of the pain index varies according to participants' polymorphisms in 3 other
      genetic regions and according to various phenotypic characteristics.

      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.
    

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 9
      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 reduction in the pain index according to polymorphisms in the
      COMT, beta-2 adrenergic receptor (ADRβ2), and beta-3 adrenergic receptor (ADRβ3) genetic
      coding regions.
    

Intervention name(s): Propranolol ER; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Capsules given orally according to schedule at Visit 1, Visit 2, Visit 3, and Visit 4.; Gelatin capsules with a microcrystalline cellulose filler manufactured to mimic propranolol ER 60 mg capsules
Other intervention name(s): Inderal (long-acting); Sugar pill
Intervention MeSH terms: Propranolol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment