Duloxetine in Osteoarthritis (OA) Pain

This study and the hypotheses to be tested arise from work done in our group evaluating
brain cortical changes in people with chronic back pain. These studies demonstrated a loss
of about 1.5 cc of neocortical gray matter per year of living with the condition, not
including gray matter lost due to aging. Since this original publication, more than ten
studies have replicated this basic result, showing that distinct chronic pain conditions are
associated with specific brain anatomical reorganization, characterized by regional
decreases in grey matter density. Recently, other studies have shown that when chronic pain
is completely reversed, these anatomical changes seem to at least partially reverse within
the time span of 4-12 months, providing evidence for a time window for reversal of grey
matter abnormalities A fundamental question that arises from these recent studies is the
extent of reversibility of the brain atrophy associated with chronic pain following
continuous use of a pain-relieving drug. Apkarian's lab has generated strong evidence that
the brain anatomy of subjects with osteoarthritis (OA) is dramatically different from that
of healthy subjects. Given that recent data show that hip replacement OA reverses brain
atrophy, the investigators can now hypothesize with greater confidence that an effective
analgesic should also reverse at least some of the brain atrophy observed in OA. Thus, a
study in patients with chronic knee OA treated with duloxetine provides a unique opportunity
to answer this question. Since OA patients in this study will have a single new agent for
four months, one can directly examine the effects of treatment in relation to progression or
regression of brain atrophy. One can also examine whether or not a placebo, which is thought
to reflect attentional and motivational states, affects changes in atrophy, and if so, to
what extent.

The investigators consider the brain atrophy in chronic pain to be an overall marker of the
extent of nervous system reorganization a subject has developed while living with the
condition. Animal models of various chronic pain conditions repeatedly provide evidence for
this idea, showing, for example, dramatic changes in the way pain is processed in the
periphery, the spinal cord, and at the level of individual neurons. The investigators
presume that these changes are the same ones contributing to atrophy in human chronic pain.
However, most of underlying mechanisms remain to be uncovered. In addition, humans suffering
from chronic pain exhibit a large number of cognitive and emotional deficits. The
investigators presume that these deficits are directly related to the brain atrophies
discovered in chronic pain conditions. Unfortunately, there are no direct studies linking
brain regional atrophies to cognitive abilities in chronic pain, although such preliminary
studies are underway in Apkarian's lab. Thus, in addition to the answering the previous
questions, the present study will also allow us to investigate the extent to which reversing
atrophy corresponds to reversing plasticity at multiple levels in the nervous system, as
well as whether such reversal also corresponds to improvements in cognitive and emotional
abilities.

Inclusion Criteria:

- Age: 45-80 years

- ACR criteria for OA including Kellgren-Lawrence radiographic OA grades II-IV

- VAS pain score >5/10 within 48 hrs of the phone screen and visit 1 (Screening)

- Knee OA for a minimum of 12 months

- Need for daily pain medication to manage symptoms of OA

Exclusion Criteria:

Currently taking MAO inhibitors or any centrally acting drug for analgesia, depression

- Narrow angle glaucoma

- Uncontrolled hypertension

- Co-existing inflammatory arthritis, fibromyalgia or other chronic pain state.

- If a female, pregnant, trying to become pregnant, or lactating

- Major depressive disorder

- Substantial alcohol use or history of significant liver disease

- Use of MAO inhibitors, triptans, serotonin precursors (tryptophan)

- Use of potent CYP1A2 inhibitors, Thioridazine, and anti-depressants

- Diabetes, type 1 or type 2

- Condition in which the Investigator believes would interfere with the subject's
ability to comply with study instructions, or might confound the interpretation of
the study results or put the subject at undue risk

- MRI safety necessitates the exclusion of subjects having one or more of the
following:

- Metal fragments in the eye or face, or having worked previously in the metal
industry

- Implantation of any electronic devices such as (but not limited to) cardiac
pacemakers, cardiac, defibrillators, and cochlear implants or nerve stimulators.

- Surgery on the blood vessels of the brain

- Claustrophobia (fear of enclosed places)

- Piercings or tattoos

- More than 250 lbs in weight

- Obvious brain abnormalities