Duloxetine: A New Indication for the Treatment of Fibromyalgia
On June 16th, 2008, duloxetine (Cymbalta®, Eli Lilly & Co.) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of fibromyalgia (FM). Only one drug had been previously approved by the FDA for this indication (i.e., pregabalin—Lyrica®, Pfizer, Inc.), a state of affairs that limited treatment options for patients with FM. The approval of duloxetine represents an important milestone in the history of the disorder and affords patients another potential means by which to improve their pain and quality of life.
Fibromyalgia is a chronic pain disorder that affects approximately 2% of the general population.1 According to research criteria established by the American College of Rheumatology, a diagnosis of FM is based on: (1) a self-reported history of widespread chronic pain of at least three months duration that must be present in all four body quadrants; and (2) pain in response to palpation with 4 kilograms of force in at least 11 out of 18 prescribed tender points.2 In addition to pain and tenderness, patients frequently experience a variety of other symptoms, including sleep disturbances, functional bowel disturbances, restless legs syndrome, chronic fatigue, and morning stiffness. The disorder is also associated with an increased incidence of co-morbid anxiety and depression. Recent research has demonstrated abnormalities in brain structure and function, as well as abnormal processing of auditory and thermal stimuli, which has resulted in the development of theories related to multi-system sensory amplification as causative in symptom generation.3,4 FM patients also have abnormalities in norepinephrine, serotonin, dopamine, glutamate, and endogenous opioid concentrations in cerebrospinal fluid.
Antidepressants are commonly used to treat FM symptoms and were originally prescribed due to the observation that affective disturbances tend to co-exist in patients with the disorder.5 However, studies have shown that, in addition to their role in mood and affect, serotonin and norepinephrine play an important role in pain modulation.6,7 Accordingly, serotonin-norepinephrine reuptake inhibitors (SNRIs) appear well-suited for the treatment of the chronic pain conditions, including FM. Indeed, studies have indicated that agents capable of dual reuptake are more efficacious than those that inhibit the reuptake of either serotonin or norepinephrine separately.8 Duloxetine, a recently-developed SNRI, thus appeared to represent an ideal candidate for the treatment of FM. Duloxetine had previously been approved by the FDA for the treatment of major depressive disorder, pain diabetic neuropathy and, more recently, generalized anxiety disorder.9 It has also been demonstrated to be an effective analgesic against headache, back pain, stomach aches and regional musculoskeletal pain associated with major depressive disorder,10 and is effective in reducing pain related to diabetic neuropathy in non-depressed patients.11,12 As a dual reuptake inhibitor, duloxetine has almost no affinity for adrenergic, cholinergic, or histaminergic receptors, which reduces the occurrence of side-effects normally seen with the use of tricyclic antidepressants.13,14 The drug has been shown to be a safe and well-tolerated effective antidepressant over the entire clinically-relevant dose range.15-17
Several controlled studies have demonstrated the efficacy and safety of duloxetine in the treatment of FM symptoms. The first of these comprised a study of 207 patients with FM by ACR criteria—with and without comorbid major depression—who underwent an initial forced titration to 60 mg twice a day over a two-week period.18 Outcome measures included the total score and pain sub-score on the Fibromyalgia Impact Questionnaire (FIQ), a 20-item self-report questionnaire that measures the patient’s overall function and symptoms in the past week and includes such items as number of days feeling well, missed work, difficulty with work accomplishment, pain, morning tiredness, fatigue, stiffness, anxiety, and depression.19 Patients in the duloxetine treatment group demonstrated significantly improved FIQ total scores in comparison to those receiving placebo, but the FIQ pain score did not significantly differ between groups. In addition, investigators used the Brief Pain Inventory (BPI) as an additional measure, as well as the average pain interference score. The tender point count and tender point thresholds were measured using standard dolorimeter methods at the 18 tender points defined by ACR criteria. Patients treated with duloxetine had significantly greater improvement in BPI scores across the 12-week study and showed significant improvement in tender point count and mean threshold compared to placebo-treated controls. Patients on active treatment also showed significant improvement on the Quality of Life in Depression Scale, the Patient Global Assessment of Improvement Scale, Sheehan Disability Scale, and the Medical Outcomes Study Short Form (SF-36). Effects of duloxetine appeared to be gender-related, with greater improvement among female patients on most measures compared to placebo-treated controls. The authors speculated that the reason for gender-specific results may have been related to the small number of males in their sample, i.e., only 11% of the study population.
Notably, clinical trials in FM commonly exclude candidates from participation who have psychiatric co-morbidities. However, the study discussed above incorporated patients with and without major depressive disorder (MDD) because the inclusion of MDD in this case was judged to be important to study design given that many FM patients suffer with MDD,5 and medication effects on depression and FM pain have not been widely studied in this population. Notably, duloxetine improved pain in patients with FM regardless of depressive status, and the effects on pain were independent of the effects on mood or anxiety. The authors concluded that duloxetine was well-tolerated with similar numbers of discontinuations of treatment between the placebo and treatment groups due to side-effects, which included insomnia, constipation, and dry mouth at a more frequent incidence than among placebo-treated controls. Adverse events were considered to be mild to moderate in severity.