Uncovering Neural and Immune Mechanisms of Chronic Pain in Post Treatment Lyme Syndrome

At least 5-15% of patients with Lyme disease (7,500-45,000 new cases a year) develop
Post-treatment Lyme Syndrome (PTLS) - debilitating residual symptoms that last months to
years, even after having received antibiotic treatment. Often patients with PTLS experience
chronic pain in their muscles or joints or nerves.

Because many PTLS patients have pain that persists despite antibiotics and because we know
that medicines which modulate the pain pathways in the brain can help to reduce or eliminate
pain, we plan to treat patients with a medicine that is FDA approved for the treatment of
pain. This medicine is known as Milnacipran (the trade name is "Savella"); this medicine is
not addictive and it has been shown to reduce chronic pain by its multiple actions on pain
pathways. All patients in the study will be treated with this FDA approved medicine.

Second, we wish to test whether the pain can be improved even further by adding a medicine
which is known to modulate the glutamate transmission involved with pain in the brain. This
medicine - D-Cycloserine - is actually an antibiotic, currently FDA approved for the
treatment of tuberculosis. Because of its action on glutamate receptors, we are
hypothesizing that it will help to decrease pain even further in patients with Lyme-related
pain. In order to test this hypothesis, after 6 weeks of being on Milnacipran, all patients
will then be given an additional treatment - either D-Cycloserine or a placebo pill (a
placebo is a pill that does not contain any active medication.) At the end of 12 weeks, we
will then evaluate improvement compared to when the patient started in the study using the
same clinical and neuroimaging (fMRI) tests.

Finally, we want to know whether patients with PTLS have over-active central pain circuits
in the brain. Because pain is processed through the brain's pain circuits, we wish to
examine whether people suffering from PTLS have hyper-active pain circuits that make them
more sensitive to pain than those who have normally-active pain circuits. To do this, we
will be comparing patients with PTLS to healthy volunteers by conducting careful neurologic
and brain imaging (fMRI) studies.

We hope that this study will provide valuable information about how the brain processes pain
signals in PTLS and about whether this treatment approach is effective.

Inclusion Criteria:

1. History of Lyme Disease and treatment:

2. Current chronic pain in the musculoskeletal system

3. clinically troubling sensory hypersensitivity (e.g., light or touch)

4. Able to speak and read English

5. Willing to not take other than study centrally acting pharmacologic agents prior to
MRI and for the duration of treatment with study medications

Exclusion Criteria:

1. Diagnosis of another (not LYME) general medical condition that has a major role in
the onset, severity, exacerbation or maintenance of pain, or sensory
hypersensitivity.

2. DSM-IV Axis I lifetime diagnosis of Pervasive Developmental Disorder, Autism,
Psychotic disorder, Bipolar Disorder, Substance dependence.

3. I current diagnosis of Major Depressive Disorder or substance abuse

4. History of head injury with loss of consciousness (>5min), neurologic disease,
seizures (excluding febrile seizures) or serious unstable medical condition (e.g.
cancer, diabetes)

5. Current or recent (last month) opiate use

6. For 2 weeks prior to MRI and diagnostic visit, unable to be free of centrally active
medications or treatment methods. These include medications commonly used to treat
pain (eg, antidepressants, muscle relaxants, centrallyacting analgesics), as well as
transcutaneous electrical nerve stimulation, biofeedback, tender and trigger point
injections, acupuncture, and anesthetic or narcotic patches. PRN doses of short
acting medications, e.g. acetaminophen, aspirin, and nonsteroidal antiinflammatory
agents will be allowed for pain with usage carefully monitored, but patients must be
willing to be off of these medications for 24 hours prior to the major evaluations at
intake and MRI study visit. Stable doses of non-benzodiazepines will be allowed for
sleep (but not tricyclics)

7. Ferromagnetic implants (e.g. pacemaker, etc.)

8. Metal Braces or Retainers

9. Transdermal medicinal patches that cannot be removed

10. Birth at < 37 weeks gestational age (prior studies have shown dramatic effects on
brain structure and function in prematurely born children)

11. Claustrophobia

12. Women will be excluded if they are pregnant, lactating, or not either
surgically-sterile or using appropriate methods of birth control. Women must agree to
continue using applicable birth control throughout the trial. All women of
child-bearing potential must have a negative pregnancy test at the intake visit.

13. Inability to reliably rate intensity of pain in response to a fixed thermal stimulus

14. Inability to tolerate sound intensity of fMRI

15. Individuals currently successfully treated by medications for their pain.

16. History of inability to tolerate treatment with SSRI or SNRI medications or
d-cycloserine; or medication induced mania

17. Renal insufficiency or congestive heart failure

18. Hepatic malfunction Liver Test