Effect of Milnacipran on Pain in Fibromyalgia

Fibromyalgia (FM) is a chronic pain condition with significant morbidity. Current research
suggests a primarily central mediation of the widespread pain including central
sensitization at the spinal level and abnormal pain processing at the cerebral level.
Findings in FM patients include abnormal neurotransmitter levels in cerebrospinal fluid
(CSF), abnormal activation of cerebral pain processing areas and abnormal peripheral pain
and sensory thresholds. Continuous low level spinal cord activation by primary nociceptive
afferents (C and A delta fibers) is believed to significantly drive the central
sensitization. One major spinal neurotransmitter released by these pain fibers is substance
P (SP). Several studies have shown that FM patients have up to three times higher baseline
SP levels in the CSF compared to controls. Since spinal neurotransmitter release and
therefore nociceptive afferent activity is also regulated via a descending inhibitory
pathway releasing norepinephrine (NE) and serotonin (5HT), decreased activity of this pain
modulating system could also be involved in abnormal pain processing in FM. Indeed, there is
support in the literature for decreased CSF levels of both NE and 5HT or their metabolites.
Milnacipran, a NE and 5HT reuptake inhibitor, has been shown to potentially effectively
reduce FM pain and symptoms of FM by affecting the above pathologies.

The investigators propose an open label clinical trial with milnacipran 200 mg over 12-weeks
in order to investigate the pain pathway in FM patients at peripheral and spinal levels
before and after treatment. In addition, the investigators will assess pain intensity and
symptoms of FM before, during and after treatment. To determine if there are peripheral
effects, the investigators will characterize the systemic neurotransmitter release and their
metabolites in plasma. The investigators will also measure the heart rate variability using
an electrocardiogram to look for effects on the sympathetic nervous system.

Inclusion Criteria:

- Female age 18 or older

- Written informed consent and written release of health and research study information

- Diagnosis of Fibromyalgia

- Participant has pain greater than 4 on the NRS of 0 to 10 on average over the last
week prior to initial evaluation that interferes with function most days per week

- Pain duration greater than 6 months

- Negative urine pregnancy test on experimental day 1 and 2 and on first day of
treatment prior to administration of study medication and fluoroscopy

- Ability to speak and understand English, to follow instructions, and fill out study
questionnaires

- Likely to complete all required visits

- Must be ambulatory and able to lay prone for 30 minutes

Exclusion Criteria:

- Any condition or situation that in the investigator's opinion may put the participant
at significant risk, confound the study results, or interfere significantly with the
participant's participation in the study

- Serious, unstable medical illness that could lead to hospitalization over the next
three months; and/or a DSM-IV diagnosis(es) with active problems within the last six
months, such as: schizophrenia, bipolar disorder, antisocial personality disorder, or
substance use disorder

- Known, uncontrolled, serious systemic disease, including: hypertension and/or
tachyarrythmia

- Females who are pregnant, breast feeding, or who plan to become pregnant, or who may
potentially become pregnant

- Allergy or sensitivity to any component of the study medication or to contrast dye

- Patients on coumadin, heparin, or any other known increase risk of bleeding

- Signs of increased intracranial pressure

- Patients who are unable to continue current pain medication

- Allergy or contraindication to acetaminophen

- Use of monoamine oxidase inhibitors

- Uncontrolled narrow-angle glaucoma