• Incidence of adverse events at acute study exit
  

• FM 20 multidimensional response index (FM 20)
  
• Assessment of pain intensity at acute study exit
  
• Assessment of function at acute study exit
  
• Assessment of patient global perception at acute study exit
  

FMS affects about 4% of the general population and is the second most common rheumatic disease after osteoarthritis. More than 80% of patients in the community with confirmed FMS report that pain is the symptom limiting their ability to work, about one third of patients are work disabled, and approximately 45% collect Social Security Disability insurance. In order to improve these statistics, it is important and necessary to identify a treatment option that will reduce the unrelenting pain in patients with severe FMS. The literature indicates that if severe pain continues unabated, there is an increased probability of functional disability and mood disturbances. Based on our clinical experience, once at this level of FMS 'refractoriness', these patients rarely recover.

We propose VNS therapy as a novel treatment to interrupt the progression from severe to incapacitating pain. However, while safety and tolerability of VNS therapy have been demonstrated in treatment resistant epileptic and depressed patient populations, they have not been established in refractory patients with FMS. Individuals with FMS have generally lower pain thresholds than healthy adults or even patients with epilepsy or depression. Thus, it is possible that the surgical recovery or the ramp up procedure to attain an analgesic response may be more than FMS patients can tolerate. Lack of knowledge as to whether VNS therapy is safe and tolerable for patients with FMS precludes fielding an efficacy study of this promising treatment for FMS at this time. Thus, the overall goal of this pilot study is to provide knowledge about the safety and tolerability of VNS in patients with refractory FMS that must precede the design and implementation of a Phase III trial testing the efficacy of VNS therapy in this population. For the purposes of this pilot study, 'refractory' is operationally defined as failing at least the first 3 levels of a 4 level conventional, pharmacological pain management regimen for FMS, including nonsteroidal anti-inflammatory drugs (NSAIDs), tricyclic antidepressants (TCAs), at least two anti epileptic drugs (AEDs), and a short-acting analgesic, Tramadol.

The primary aim of this pilot study is to define the limits of VNS safety and tolerability in patients with refractory FMS following implantation, activation and ramp up, as well as use over an acute study period and follow-up over 24 months post-implantation. We will sample across a representative range of FMS 'refractoriness' that will consist in equal proportions of FMS patients who are work-disabled with concurrent depression, who are working but have concurrent depression, and who are working and free of depression.

The secondary aim of this study, assuming VNS is tolerated, is to assess the impact of VNS therapy on symptoms of FMS (including pain intensity, physical function, patient's global impression of change [FM20], mood, and quality of life, as well as laboratory measures of pain sensitivity). In addition, this study will provide data regarding the range of VNS output current tolerated, the onset, time course, and degree of potential benefit. This information will inform the design of a Phase III trial about "dosing" of stimulation and the minimum duration of a trial that is necessary in these patients.

Inclusion Criteria:

1. Patient is diagnosed with fibromyalgia for at least 2 years according to the 1990 guidelines of the American College of Rheumatology (ACR) criteria. In addition, other medical illness to which pain can be attributed will be ruled out;
2. Patient's FMS pain remained severe despite good treatment efforts using standard pharmacological pain management. In order to be enrolled into the Study, the patient has had to have been unable to achieve sufficient FMS pain relief despite treatment using NSAIDs with addition of one TCA or NSRI (i.e., Duloxetine), adding or switching to one anti-epileptic drugs (AEDs), and adding or switching to Tramadol, a short-acting analgesic medication. Either the medications were tried and failed to reduce pain to a tolerable level or the patient is off those medications because they were not efficacious at all or because the patient was not able to tolerate the side effects associated with these medications. Only patients who are work disabled due to their FMS pain remain eligible for participation in the study if they are on opioid maintenance therapy;
3. Patient has overall FM pain at an intensity of 5 or greater on a 0-10 verbally anchored pain intensity scale (0=no pain; 10=most intense pain imaginable) on more than 50% of days over a consecutive 7-day period (between Study Visits 1 and 2) before enrollment into the Study (determined by the median of all readings during this time period ).
4. Patient is an individual between 21 and 60 years of age. Holter monitoring will be performed on patients over the age of 50;
5. Patient may or may not have been unable to work for at least the past 6 months due to Fibromyalgia symptoms. Work disability is operationally defined as the patient's report of not being able to fulfill the required tasks and activities associated with the primary occupation (including going to work, sitting at a computer, completing work assignments);
6. Patient has not changed the pharmacological (medication) and/or non-pharmacological (i.e., yoga, exercise) treatment regimen for the past 4 weeks prior to Study Visit 1 and is experiencing severe pain, as defined in items 2 and 3. All patients will be allowed (but not required) to take pain and/or mood stabilizer medications after surgery or use non-pharmacologic treatments as long as they continue to use the same medication types and doses or types of non-pharmacologic treatments during the 16 weeks following the surgery that they used during the 4 weeks prior to Study Visit 1. After consultation with their doctor, medications can be decreased, but not increased during the 16 weeks after surgery;
7. Patient has an at least average premorbid IQ as assessed by the Vocabulary subtest of the WAIS-III, a standardized well validated index of premorbid intellectual function;
8. Female patients must not be pregnant and adequately protected from conception. Females of childbearing potential must use an acceptable method of birth control. Abstinence is an acceptable means of birth control;
9. Patient is able to comply with all testing and follow-up visit requirements defined by the Study Protocol;
10. Patient currently lives within a 2 hour driving commute to the study site;
11. Patient has voluntarily signed an informed consent in accordance with institutional policies.

Exclusion Criteria:

1. Patient does have a rheumatologic condition other than FMS. If FM is comorbid with another rheumatologic condition, it is considered to be secondary FM. Participants enrolled in this Study will only have primary FM, that is a chronic pain condition not due to another rheumatologic disorder;
2. Patient reports FMS pain began following physical trauma;
3. Patient is in litigation in association with patient's condition of FMS at time of enrollment;

4. Based on patient's psychiatric phone evaluation:

   1. Patient has a severe lifetime or current diagnosis of psychotic depression, bipolar disorder, schizophrenia, schizoaffective or other psychotic disorders or has a clear history of other psychiatric illness prior to the onset of FMS;
   2. Patient is an individual diagnosed with major depressive disorder and has attempted to commit suicide in the past or has active suicidal ideation;
   3. Patient has a lifetime or current history of dependence or abuse of pain medication or alcohol;
5. Patient has taken an antipsychotic drug within 3 months of enrollment;
6. Patient has demonstrated a known placebo response in a previous study;
7. Patient has had botulinum toxin or local steroid injection for FMS within 2 months of enrollment;
8. Patient has a history of myocardial infarction or cardiac arrest;
9. Patient has received general anesthesia within 30 days of implantation;
10. Patient has taken an investigational drug within a clearance duration of five times the half-life of the investigational drug or within 4 weeks of enrollment;
11. Patient is currently using another investigational device or drug;
12. Patient has a significant cardiac or pulmonary condition currently under treatment resulting in an ASA score greater III;
13. Patient has had a unilateral or bilateral cervical vagotomy;
14. Patient has a demand cardiac pacemaker, implantable defibrillator, or other implantable stimulator;
15. Patient is at least 50 years of age and the following conditions are present: cardiac conductance abnormalities, e.g., heart block, bradycardia, arrhythmia, that have been treated or are untreated, Wolf-Parkinson-White Syndrome, surgical intervention for bradycardia, history of prolonged QT interval, or a history of syncopal or pre-syncopal episodes;
16. Patient is likely to require a whole body MRI after VNS Therapy System implantation;
17. Patient is currently receiving or likely to receive short-wave diathermy, microwave diathermy, or therapeutic ultrasound diathermy after implantation;
18. Patient plans to relocate or move to a location distant from the Study site within one year of enrollment in the Study;
19. Patient was previously enrolled in this or any other VNS Therapy System Study.