Milnacipran for Treatment of Pain in Older Adults With Rheumatoid Arthritis

This is a 12-week open-label trial of milnacipran for the treatment of pain in rheumatoid
arthritis in older adults. The investigators are interested in the relationship of chronic
pain to inflammation, resilience, fatigue, and physical and mental functioning. The
investigators anticipate that effective pain reduction will result in improved fatigue,
resilience, physical and mental functioning and reduced levels of inflammation. The
investigators are seeking to examine this directly in 30 older adults (55 years of age or
older) with rheumatoid arthritis who will be using milnacipran for treatment of pain in the
absence of clinical major depression. This proposed trial will serve as a pilot study to
estimate the effect of the drug on pain and functional outcomes, as well as aid in
dose-finding in this population.

Inclusion Criteria: Diagnosis. RA subjects will be evaluated by a board certified
rheumatologist using revised criteria established by the American College of Rheumatology
(ACR). This requires at least four of the following seven criteria: 1) morning joint
stiffness; 2) arthritis in 3 or more joint areas; 3) arthritis of hand joints; 4) symmetric
arthritis; 5) rheumatoid nodules; 6) presence of serum rheumatoid factor and 7) changes on
posteroanterior hand and wrist radiographs. In addition, criteria 1-4 must be present for
at least four weeks. Individuals diagnosed with juvenile RA will be excluded.

Inclusion Criteria: Medication Use for RA patients. RA subjects taking disease modifying
anti-rheumatic drugs (DMARDs) must be on a stable regime for one month before study and
stable throughout study. RA subjects using DMARDs will be categorized as follows: 1) no
DMARDs; 2) DMARD monotherapy with sulfasalazine, hydroxychloroquine, minocycline, or
azothioprine, 3) DMARD monotherapy with methotrexate or leflunomide, 4) biologic therapy
with or without concomitant DMARDs.

Exclusion Criteria: Medical conditions. Subjects will not be eligible for the study based
on the following criteria: (1) presence of acute or uncontrolled co-morbid medical
conditions not limited to but including cardiovascular (e.g., history of acute coronary
event, stroke, uncontrolled HTN) and neurological diseases (e.g., Parkinson's disease), as
well as pain disorders; (2) presence of co-morbid inflammatory disorders such as Crohn's
disease and ulcerative colitis and other autoimmune disorders; (3) presence of an
uncontrolled medical condition that is deemed by the investigators to interfere with the
proposed study procedures, or put the study participant at undue risk; (4) presence of
chronic infections (e.g. positive purified protein derivative (PPD) test)) due to
contraindication of tumor necrosis factor (TNF) antagonist use in these individuals and
also because chronic infection can produce elevations in proinflammatory cytokines; (5)
presence of an acute infectious illness in the two weeks prior to an experimental session;
(6) pregnancy or breast-feeding because of the effects on neuroendocrine systems and sleep;
(7) in women, the presence of vasomotor symptoms due to the effects of such symptoms on
measures of sleep; (8) use of hormone containing medications including steroids; (9)
current and/or regular use of nonsteroidal anti-inflammatory drug (NSAID) medications.

Exclusion Criteria: Psychiatric Disorders. RA subjects with a current or lifetime history
of a major Depressive Disorder or other Diagnostic and Statistical Manual of Mental
Disorders IV (DSM-IV) psychiatric disorder (e.g. substance dependence) will be excluded due
to the known effects of major depression on pain. Although depressive symptoms can occur in
as many as 40% of RA patients, the prevalence of syndromal major depressive disorder is
considerably less, and we do not anticipate that exclusion of current or lifetime history
of major depressive disorder will substantially alter subject flow. More than 75% of a
selected sample of RA subjects at University of California, Los Angeles (UCLA) affiliated
clinics does not have a history of co-morbid psychiatric disorder.

Exclusion Criteria: Medication use. Subjects who have used the following medications in the
past two months will be excluded from the study: (1) previous use of Nitrogen Mustard,
Cyclosporin, Cytotoxin, or Cyclophosphamide; (2) regular use of analgesics such as opioids,
(3) regular use of prednisone >10mg of prednisone, (4) psychotropic medications, including
selective serotonergic reuptake inhibitors, antidepressants, anxiolytics, hypnotics,
sedatives and barbiturates. We will also exclude current smokers because of the known
effects of tobacco use on proinflammatory cytokine levels. (Helen, I would suggest to
remove this sentence. It is clear from studies that patients are higher risk for
susceptibility and increased disease activity with smoking. It may decrease our
enrollment.)