From left: Myron Chu, DO, assistant professor, Department of Internal Medicine (rheumatology); Karen Maslowski, RN, coordinator, clinical trials, Department of Internal Medicine; and Stephen L. Burnstein, DO, professor and vice chair, Department of Internal Medicine; chief, section of rheumatology, at UMDNJ-School of Osteopathic Medicine

Many rheumatologists head for the back door when a patient with fibromyalgia syndrome (FMS) enters. As professor and vice chair of the Department of Internal Medicine and chief of the Section of Rheumatology at the School of Osteopathic Medicine (SOM), this is not an option. To date there are no specifically effective medicines to treat this common musculoskeletal disorder, which affects approximately 2 to 4% of the population. To make matters worse, many patients with FMS are not diagnosed correctly or promptly and ineffective therapies may be prescribed, in part because some physicians are not familiar with FMS. Since a significant percentage of FMS patients have psychiatric or psychological co-morbidities, their pain is often ascribed to depression, anxiety or other behavioral disorders.

Although the etiology of FMS is not known, there is evidence that it includes a dysfunction of the autonomic nervous system. Nonetheless, a large sector of the medical community still believes that these patients’ chronic pain is due to damage or inflammation of peripheral structures. Therefore, in the FMS patient, where radiographs and lab tests are consistently negative, pain is mistakenly ascribed to psychological factors or diseases. This has resulted in the use of a variety of medications “off-label” by rheumatologists and other physicians treating those with FMS. Specifically, antidepressants are prescribed for this reason. This class of drugs does help alleviate symptoms, especially since it affects CNS neurotransmitters, including serotonin and norepinephrine. Research has focused on antidepressants; and my research on Milnacipran, an antidepressant which has been on the market in 30 countries for several years, is one such study. More studies are underway looking at possible disorders of the hypothalamic-pituitary axis in FMS patients and factors that point to disordered sensory processing.

An important clue to the diagnosis of FMS lies in the fact that these patients generally do not respond to NSAIDs, opiates or other analgesics. Furthermore, physical therapy may increase their pain, and the majority of those with FMS do not exercise for this reason.

Figure 1: Diagram of areas often associated with pain in individuals with fibromyalgia. During a routine exam, the circled areas are assessed for tenderness, swelling, deformity, limitation of motion, or effusion.

In addition, the American College of Rheumatology has developed diagnostic criteria as a guideline to the diagnosis of FMS. One of these criteria refers to the presence of 11 to 18 tender points in various muscle regions. However, this is misleading in that it is not only arbitrary, but also implies that the problem is in the muscle. Interestingly, muscle biopsies are consistently negative or normal.

When Cypress Bioscience, Inc., a California-based pharmaceutical company, approached me to study Milnacipran, a dual noradrenalin and serotonin re-uptake inhibitor with a novel chemical structure, I was excited. This was an opportunity to be involved in a controlled, double-blind clinical trial to look at this drug for the treatment of FMS. Although other dual reuptake inhibitors have been studied, their efficacy in the treatment of FMS had never been demonstrated convincingly.

The 30-week study commenced in 2004. I was particularly interested because patients who finished the study were given the opportunity to participate in an open label extension, during which all participants would receive Milnacipran. Many prospective study participants were also intrigued by this opportunity. However, I did not recruit patients for this trial based on the fact that they were looking for a treatment option. I do not believe that any patient should enter a clinical trial in an attempt to be treated.

Cypress Bioscience was looking for 50 sites across the U.S. that would enlist and randomize 800 patients. Their objective was to demonstrate the safety and efficacy of Milnacipran in the treatment of FMS. Standard primary and secondary endpoints were analyzed and the frequency and intensity of adverse events were reported. Various inclusion and exclusion criteria were listed and, interestingly, patients needed to be able to use a PED device, which was provided to them in order to record pain scores repeatedly. Patients with documented autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosis were excluded. Patients were allowed to continue various medications during the study, but other medications required a washout period that varied depending on the compound. As the study continued, the dose of study medication was escalated. Analgesic and hypnotic rescue medication was allowed, but the type and quantity were carefully monitored and recorded, as per protocol.

I am awaiting analysis of the Milnacipran FMS data. I hope this drug will show promise in helping these patients to regain their lives. Certainly, more bench research in the area of FMS is necessary. On the horizon, and now in study and development, is a diagnostic assay for identifying FMS patients. This assay detects IgG anti-polymer antibodies in serum, since these antibodies are found in the majority of FMS patients. However, nothing can replace the physician’s clinical skills in diagnosing any medical condition.

Stephen L. Burnstein, DO, received his medical degree from the Philadelphia College of Osteopathic Medicine. He completed his internship at Albany Medical Center and residency at Nassau County Medical Center. Dr. Burnstein completed his fellowship in rheumatology at the University of Massachusetts Medical Center. He has participated in more than 50 clinical trials in his career, which now spans almost 30 years. Dr. Burnstein witnessed the development of many excellent compounds, some of which have gone on to become “wonder drugs.” His clinical research team in the Department of Internal Medicine at SOM includes clinical trial nurses Karen Maslowski, Patti DeVita and Marcia Fogle. §