Duloxetine for Treatment of Painful Temporomandibular Joint Disorder

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.

Inclusion Criteria:

- Patients with chronic TMJD pain of two weeks duration

- Age 18 and older

- Confirmed craniofacial pain of nonodontogenic origin by the Research Diagnostic
Criteria for temporomandibular disorders (TMD-RDC)

- Concomitant medications are permitted, except those which may convey analgesia

- Females who are neither pregnant, as verified by a urine-based pregnancy test, nor
breast-feeding

- Female subjects of childbearing potential and those who are post-menopausal for less
than 2 years must be using/willing to use a medically approved method of contraception
(i.e., oral, transdermal or implanted contraceptive devices, intrauterine device,
diaphragm, condom, abstinence, or surgical sterility during the course of the study

- Able to read and comprehend the rating scales, study instructions, and the consent
form

- Pain score of 4 or greater on the baseline VAS (0-10)

Exclusion Criteria:

- Undergone any type of TMJ surgery or had TMJ growth disturbances, neoplasm, or injury
to the TMJ area within the past six months

- Taking analgesic or anti-inflammatory drugs, steroids, antidepressants,
antiepileptics, or opioid medications that may confound the assessment of analgesia

- Subjects with primary psychiatric diagnosis of major depression, suicidal ideation, or
history of suicide attempt as assessed by medical history and the Mini International
Neuropsychiatric Interview (MINI) are not eligible. Subjects with a score above
average or higher in comparison with normative scores on the Beck Depression Inventory
(BDI) will be allowed to participate

- Exclusions based on the effects of duloxetine:

- Known hypersensitivity to duloxetine or its inactive ingredients

- Subjects with: renal impairment or end stage renal disease; urinary retention or
hesitation, delayed gastric emptying; substantial alcohol use or evidence of
chronic liver disease, hepatic insufficiency and hepatotoxicity; bleeding
disorders, orthostatic hypotension, uncontrolled high blood pressure; recent
history of myocardial infarction or unstable coronary artery disease; seizure
disorder, history of bipolar disorder or mania, general anxiety disorder (GAD);
hyponatremia; uncontrolled narrow-angle glaucoma.

- Treatment with an monoamine oxidase inhibitor (MAOI) within 30 days of
randomization, or potential need to use an MAOI during the study or within 5 days
of discontinuation of the drug

- Concomitant use of medications such as: NSAIDs, warfarin, aspirin or other drugs
that affect coagulation; Thioridazine and inhibitors of CYP1A2 which affect
metabolism of duloxetine; serotonergic drugs like triptans and MAOIs which
increase the risk of Serotonin Syndrome; drugs that affect gastric acidity

- Contraindications to acetaminophen use

- Ever been treated with duloxetine