Duloxetine for Treatment of Painful Temporomandibular Joint Disorder
Condition: Temporomandibular Joint Disorders
MeSH terms: Joint Diseases; Temporomandibular Joint Disorders; Temporomandibular Joint Dysfunction Syndrome
Study type: Interventional

Summary: 
      Temporomandibular joint disorders (TMJD) are a family of musculoskeletal disorders that
      represent the most common chronic orofacial pain condition. TMJD is associated with
      persistent pain in the region of the temporomandibular joint and muscles of the head and
      neck. The purpose of this study is to test duloxetine (Cymbalta) as a potential treatment for
      chronic facial pain. Duloxetine is FDA approved as an antidepressant and for the chronic pain
      conditions of fibromyalgia and diabetic neuropathy. Chronic facial pain may be linked to
      Temporomandibular Joint Disorder (TMJD) which currently has no standard treatment.
    

Detailed description: 
      The proposed clinical trial will evaluate the analgesic and adverse effects of duloxetine, a
      serotonin and norepinephrine reuptake inhibitor, in comparison to placebo in patients with
      temporomandibular joint disorder (TMJD). Duloxetine is approved as an antidepressant and has
      been shown effective in the chronic pain conditions of fibromyalgia and diabetic neuropathy.
      Decrease in pain and dysfunction and improvement in quality of life and global satisfaction
      will be assessed over 6 weeks. Successful demonstration of a therapeutic effect may provide a
      basis for clinical use of duloxetine in patients with painful TMJD.

      Background

      TMJD is a heterogeneous family of musculoskeletal disorders associated with the
      temporomandibular joint, the periauricular region, and the muscles of the head and neck. TMJD
      has been identified as a major cause of nondental, chronic pain in the craniofacial region,
      second only to headache (NIH Technology Assessment Conference, 1997). Although few
      population-based epidemiological studies have been conducted, studies report the prevalence
      of TMJD as up to 20% in the adult population (Dworkin et al 1990, Schiffman et al 1990).
      Dworkin and colleagues conducted a series of studies of TMJD using valid and reliable
      examination and survey procedures (Von Korff et al 1988, Dworkin et al 1990, Carlsson and
      LeResche 1995) and identified 12.1% of the test population with painful TMJD with a female to
      male ratio of approximately 7:1. They also found the annual incidence of developing TMJD to
      be just over 2% with females tending to show a higher incidence rate than males (Von Korff et
      al 1993). Hence, TMJD is common in the general population, but it has also been reported that
      about 20% of patients with early signs and symptoms of TMJD will progress to a persistent
      pain state (Schiffman et al 1990).

      Several studies of TMJD suggest that patients exhibit a state of CNS hypersensitivity similar
      to that reported in fibromyalgia (Maixner et al 1995, Maixner et al 1998, Sarlani and
      Greenspan 2003, Sarlani et al 2004) that contributes to the predicted widespread
      characteristics of the pain. Genetic factors that impact increased pain sensitivity,
      psychological traits and sex differences, and often coupled with environmental stress, may
      result in a phenotype that is vulnerable to musculoskeletal disease and susceptible to
      selective pharmacological treatment.

      In addition to female gender, two other factors predict an elevated incidence of these
      disorders: a history of musculoskeletal pain at other body sites and quality of life symptoms
      typically associated with depression (Von Korff et al 1988, Raphael and Marbach 2001, John et
      al 2003). Patients diagnosed with fibromyalgia often exhibit concurrent orofacial
      symptomatology that mimics TMJD (Ta et al 2002, Sarlani and Greenspan 2003, Sarlani et al
      2004). These observations and findings suggest that drugs useful for depression, affecting
      musculoskeletal systems, and effective in improving central monoaminergic neurotransmission,
      are prime candidates for the treatment of TMJD. For these reasons, we hypothesize that
      selective noradrenergic or combined noradrenergic and serotonin reuptake inhibitors should be
      effective for TMJD.

      Lack of research has resulted in a paucity of evidence-based treatment approaches for TMJD
      (Antczak- Bouckoms 1995, List 2003). While NSAIDs are sometimes used, there is little
      evidence for their effectiveness for TMJD (Dionne 1997, Gordon et al 1990, 1991) except in
      frank joint involvement (Ta et al 2004), and gastrointestinal and renal toxicity limit their
      long-term use (Gabriel et al 1991, Allison et al 1992, Schafer et al 1995, Champion et al
      1997) for treatment of chronic pain. Use of opioids has been discouraged for this chronic
      pain condition due to the limitations of long-term use for this drug class (DeNucci et al
      1996, Dionne 1997). The most promising pharmacologic therapy for TMJD to date has been
      antidepressants, but it is important to note that indication for their clinical use has
      primarily been extrapolated from other chronic pain conditions (McQuay et al 1992, Onghena et
      al 1992). Only two randomized controlled trials have examined one of the tricyclic
      antidepressants (amitryptyline) for TMJD specifically (Sharav et all 1987, Rizzatti-Barbosa
      2003). Amitryptyline for TMJD demonstrated an average response rate of 40% in these two
      studies, but its adverse effects result in a large percentage of patients discontinuing the
      drug before achieving pain relief (DeNucci et al 1996), resulting in an unfavorable risk to
      benefit ratio (Zitman et al 1990). Taken together, there has been insufficient evidence to
      adopt a pharmacologic standard of care for treatment of TMJD.

      Duloxetine has shown efficacy for several chronic pain conditions (Sultan 2008) including
      fibromyalgia, and appears to be more effective in women than men (Arnold 2004, 2005). It is
      well tolerated and effective at a dose of 60 mg daily ( Sultan 2008). Studies in patients
      with fibromyalgia (Arnold 2004, 2005), diabetic neuropathy (Goldstein 2005), low back pain
      (Skijaravala 2008), and osteoarthritis (Chappell 2008) have shown an analgesic effect at this
      dose with fewer adverse effects and a lower drop out rate than higher doses. In the proposed
      study, subjects randomized to the intervention will use 60 mg of duloxetine given as 30 mg
      twice daily after a one-week period of 30 mg daily.

      Given the prevalence of TMJD and the controversial nature of non-pharmacologic therapies such
      as occlusal alteration, intraoral devices, and surgery, the need exists for pharmacologic
      treatment that is efficacious but avoids adverse effects that discourage long-term use. This
      study will also provide a basis for future investigations of the etiology and management of
      painful TMJD.

      Purpose/Objective of this study? TMJD represents a prototypic musculoskeletal disease whose
      characteristics of associated depression, comorbidity of fibromyalgia, female prevalence,
      increased CNS sensitivity to pain, and likely genetic differences among susceptible
      individuals, makes it a disorder that will likely be responsive to duloxetine treatment.The
      overall objective is to investigate duloxetine as a potential treatment for chronic pain of
      TMJD. We hypothesize that subjects receiving duloxetine will experience greater analgesia
      than those receiving placebo.

      Specifically we will:

      1. Evaluate the analgesic effect of 30 mg duloxetine twice daily in comparison to matching
      placebo at baseline (BL) and follow up over a six week period using the primary outcome
      measure of change in spontaneous pain. 2. Evaluate jaw functioning and evoked pain as
      measured by range of motion, pain with jaw movement, and pain pressure thresholds. 3. Assess
      frequency of adverse effects and their impact on patient global satisfaction and study
      adherence. 4. Examine sleep in relationship to pain. 5. Evaluate genetic susceptibilty to
      pain and response to duloxetine.

      These aims and outcome measures are listed in prioritized order. The study is powered on the
      primary outcome measure of spontaneous pain; other measures are exploratory. The study is not
      powered to detect subgroup differences for variables such as gender, depression, type of TMJD
      diagnosis, or concurrent medications, as described later in the Analysis Plan.

      Research Design: The study is a double blind, placebo-controlled parallel groups prospective
      study of duloxetine versus placebo. Subjects will be randomized to the investigational
      treatment group (duloxetine) or the placebo group. At the time of enrollment they will be
      randomly assigned to study drug or placebo by block randomization for order in a 1:1 ratio.
      Subjects will be provided acetominophen as a rescue analgesic to use if they feel their pain
      is not adequately controlled. The examiners and subjects will be blind to the group
      assignment.
    

Intervention name(s): duloxetine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Evaluate the analgesic effect of 30 mg duloxetine twice daily in comparison to matching placebo at baseline (BL) and follow up over a six week period; Placebo match duloxetine for 6 week period.
Other intervention name(s): Cymbalta
Intervention MeSH terms: Duloxetine Hydrochloride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment