Physician's Weekly Article - Emerging Therapeutic Approaches to Fibromyalgia

       An increasing understanding of fibromyalgia, once thought of as a psychosomatic complaint, has led to the emergence of new treatments that offer hope for patients.

      Fibromyalgia, a chronic pain condition occurring in 2% to 4% of the general population, is associated with widespread pain, fatigue, sleep disturbances, and mood disorders. Although fibromyalgia is not considered life threatening, symptoms can significantly affect patient quality of life and function. “Many physicians don’t give fibromyalgia credence as an illness because of a lack of objective evidence,” says Philip J. Mease, MD. “However, recent research is revealing new information about the neurobiological mechanisms underlying this condition. This helps explain the positive results of controlled trials of neuromodulatory drugs that target specific receptors in pain processing centers in the central nervous system. Additionally, newer epidemiology studies demonstrate that it’s a relatively common condition, which represents a significant burden to patients, their families, and society.”

      A Challenging Diagnosis

      In 1990, the American College of Rheumatology developed two major criteria for diagnosing fibromyalgia: 1) a history of chronic widespread pain for 3 months, and 2) the presence of tenderness in at least 11 of 18 “tender points” on the body when digitally palpated (Figure 1). “Physicians can perform this test by pressing down on a tender point with their thumb until a quarter of the nail bed is whitened from the tip—this equals 4 kg/cm² of pressure,” explains Dr. Mease. “Patients with fibromyalgia will experience increased tenderness or pain when pressure is applied. In addition, functional MRI (fMRI) scans can be used to detect activation in the pain processing centers of the brain with minimal stimuli of various sorts and used to compare the amount of stimulus required to induce pain in a normal individual. The disorder is one of generalized sensory processing.”

      The symptomatology of fibromyalgia is extensive; in addition to pain, patients may experience fatigue, sleep disturbances, and/or subtle cognitive dysfunction, which is sometimes referred to as “dyscognition” or “fibrofog,” characterized by impaired memory or concentration (Table 1). Dr. Mease says establishing a diagnosis can be challenging because of the condition’s multifaceted nature and its tendency to overlap with other chronic pain conditions. “Approximately 25% of patients with rheumatoid arthritis, 30% of those with lupus, and 50% of those with Sjögren’s syndrome also have fibromyalgia. As a result, physicians must distinguish signs and symptoms to understand how to initiate or adjust treatment appropriately.”

      Understanding Underlying Abnormalities

      According to Dr. Mease, clinicians have gained an improved understanding of the neuro-dysregulation that is at the root of the central nervous system disturbance in fibromyalgia. This disturbance often leads to the key telltale symptoms of fibromyalgia (increased pain sensitivity, sleep disturbance, and fatigue). “In research settings,” explains Dr. Mease. “objective measures such as fMRI demonstrate consistent areas of brain activation with sensory stimuli or proton magnetic resonance spectroscopy. This can detect altered levels of neurotransmitters, such as glutamine and glutamate in key brain areas. It can lead the way to biologic underlying processes and other difficult-to-explain conditions such as irritable bowel syndrome and interstitial cystitis. Fibromyalgia patients have an abnormality of increased central sensitization. Given a specific stimulus, there’s a higher amount of signaling through the ascending sensory pathways in the central nervous system to the brain due to an increased expression of irritative neuropeptides, such as glutamate and substance P, leading to a much lower threshold for pain.”

      Data have shown positive results from studies with drugs to modulate these pathways. “Pregabalin, for example, reduces the expression of nociceptive neuropeptides (eg, glutamate and substance P) through its modulatory effect on the ⓬dς receptor in ascending pain fibers and in the brain,” Dr. Mease says. “Dual reuptake inhibitors such as duloxetine and milnacipran help augment norepinephrine and serotonin in the brain and spinal cord. Despite the fact that these medications target different parts of the central nervous system, we’re seeing similar effects on pain and other symptom domains of fibromyalgia. In other areas, however, there are distinctions. For example, pregabalin may help more with sleep and the dual reuptake inhibitors may better benefit fatigue. It will be of great interest to test combinations of these medicines in the future to see if they have an additive or synergistic effect on fibromyalgia symptoms.”

      New Treatment Options

      In 2007, pregabalin became the first FDA-approved drug specifically for treating fibromyalgia; in clinical trials, it significantly reduced pain and improved function. “This approval is significant because pharmacological companies are starting to dedicate more time and effort into evaluating the effect of their drugs in fibromyalgia,” says Dr. Mease. “Duloxetine may be approved specifically for fibromyalgia in 2008, and milnacipran could also be approved for the disease in the relatively near future.” In addition, several different classes of medications are being evaluated in patients with fibromyalgia (Table 2).

      According to Dr. Mease, newer drugs are proving to be more effective and tolerable for patients with fibromyalgia than previously used agents. “These drugs appear to have fewer side effects, allowing physicians to prescribe more effective doses,” he says. “Data from recent trials have shown that pregabalin, duloxetine, and milnacipran typically improve pain by at least 30% in as many as half of patients with fibromyalgia. And about 30% to 35% of patients will experience at least a 50% improvement in pain.” New pathways of treatment are also being explored as a result of a better understanding of fibromyalgia, including the testing of dopamine agonists, newer anti-epileptics, and drugs with novel pain-relieving mechanisms.

      Consider the Role of Depression

      Structured psychiatric diagnostic interviews will reveal that 20% to 30% of patients with fibromyalgia will have a current diagnosis of major depressive disorder. A greater percentage of fibromyalgia patients have had a diagnosis of depression at some point in their life. “Although there is a meaningful association between mood disorders and fibromyalgia,” says Dr. Mease, “physicians must understand that this isn’t the case for all patients with fibromyalgia. There should not be a stigma associated with fibromyalgia that the disease is simply a somatic manifestation of depression. A multimodal approach beyond the use of antidepressants may be required to treat depression and fibromyalgia.”

      Going Beyond Pharmacological Treatment

      Clinical investigations of pharmacologic therapies have examined various measures of improving pain and other key aspects of fibromyalgia, including fatigue, sleep disturbances, and functioning. Although the emerging drugs are effective in each of these domains, Dr. Mease says physicians should still consider non-pharmacologic approaches. “Utilizing these strategies—which include exercise, physical therapy, massage, acupuncture, and cognitive behavioral therapy—may further improve outcomes. The disease is multidimensional, so using multimodal, individualized treatment programs that combine pharmacologic and non-pharmacologic therapies may be necessary to optimize outcomes.”

      Dr. Mease has indicated to Physician’s Weekly that he has or has had the following financial interest: Pfizer, Eli Lilly, Cypress Bioscience, Forest, Boeringer-Ingelheim, and Fralex.