by Elisa F. Cascade; Amir H. Kalali, MD; Nikhil D. Nihalani, MD; and Thomas L. Schwartz, MD
Ms. Cascade is Vice President, Strategic Research and Safety, Quintiles Inc., Falls Church, Virginia; Dr. Kalali is Vice President, Global Therapeutic Group Leader CNS, Quintiles Inc., San Diego, California, and Professor of Psychiatry, University of California, San Diego; Dr. Nihalani is Clinical Assistant Professor, SUNY Upstate Medical University, Syracuse, New York; and Dr. Schwartz is Associate Professor, SUNY Upstate Medical University, Syracuse, New York.
Dr. Nihalani is a speaker for Neuroscience Education Institute; Dr. Schwartz has received research grants from Bristol-Myers Squibb, Cephalon, Cyberonics, Forest, and Wyeth, is a speaker for Bristol-Myers Squibb, Cephalon, Cyberonics, Forest, Wyeth, Pfizer, AstraZeneca, Sanofi Aventis, and Neuroscience Education Institute, and is a
consultant for Wyeth and Cephalon.
In this article, we investigate the range of treatments prescribed for fibromyalgia. The data suggest that the majority of those treated, 72 percent, receive only one pharmaceutical. An additional 18 percent of patients were prescribed two products and 10% received three products. Pregabalin (Lyrica®) monotherapy was the most commonly prescribed regimen (28% of patients) followed by duloxetine (Cymbalta®) monotherapy (6%). From a therapeutic class perspective, fibromyalgia patients received pain therapies (42%), antiepileptics (40%), antidepressants (28%), muscle relaxants (14%), and sleep agents (8%). An expert commentary is also included.
fibromyalgia, pregabalin, duloxetine, milnacipran, gabapentin, pharmacology
In June, 2007, pregabalin (Lyrica®) was approved by the US Food and Drug Administration (FDA) as the first treatment for fibromyalgia (FM). Since that time, two other companies have publicly announced submission of products for the treatment of fm: duloxetine (Cymbalta®) and milnacipran (Ixel®). To better understand current practice patterns, in this article, we investigate and discuss the range of treatments prescribed to patients with fm.
We obtained data on product treatment regimens from Verispan’s Prescription Drug and Diagnosis Audit (PDDA) database from July, 2007, to December, 2007, for patients with fibromylagia as defined by Verispan diagnosis code 729140. PDDA captures data on disease states and associated therapies from 3,100 office-based physicians representing 29 specialties across the United States. Information from physicians on reasons for drug use is translated by Verispan analysts into 3-digit, 4-digit, and 5-digit ICD-9 diagnosis codes, as well as a 6-digit code developed by Verispan for conditions, such as fm, where the ICD-9 coding is non-specific.
According to practice data from Verispan, approximately 90 percent of patients presenting with fm are women. Figure 1 displays the number of products typically prescribed to treat fm. As seen in Figure 1, 72 percent of patients are prescribed only one agent, 18 percent are prescribed two products, and 10 percent are prescribed three products.
Pregabalin monotherapy is the treatment most commonly prescribed (28% of patients); duloxetine monotherapy is the second most popular regimen accounting for an additional six percent of uses. This is a significant difference from the first six months of 2007 when only eight percent of patients received pregabalin monotherapy and three percent were prescribed duloxetine monotherapy.
From a therapeutic class perspective, the agents most commonly prescribed to patients with fm are pain products (42%) and antiepileptics (40%), primarily pregabalin, but some physicians prescribe gabapentin. Other prescribed classes include antidepressants (28%), often duloextine or tricyclic antidepressants; muscle relaxants (18%); and sleep aids (10%) (Figure 2).
FM is a complex disorder with many associated symptoms. It affects two percent, or approximately 3.7 million people, in the US. Women are affected seven times more than men; the prevalence is 3.5 percent in women compared to 0.5 percent in men. The establishment of FM as a diagnosis has been an evolving process with the absence of definitive criteria until 1990. In 1990, the American College of Rheumatology published their research-based criteria, which is now the standard when diagnosing FM.
There are four main components in FM: pain, fatigue, mood, and function. The following symptoms are often reported in descending order of occurrence: muscular pain (100%), fatigue (96%), insomnia (86%), joint pain (72%), headaches (60%), restless legs (56%), numbness and tingling (52%), impaired memory (46%), leg cramps (42%), impaired concentration (41%), nervousness (32%), and major depression (20%).
The treatment of FM symptoms has been multimodal, and the success rate has been limited at best. Due to the unknown and mixed etiology of FM, there have been multiple pharmacological and nonpharmacological treatments used to treat fm, with intermediate results. Self-medication is very common among patients with FM.
As mentioned in the data, the common agents used in FM primarily seem to be for the alleviation of pain or perhaps improvement of mood symptoms. Gabapentin, which was introduced initially as an antiepileptic agent, was also approved for neuropathic pain, which may explain why it was prescribed initially for FM patients as well. The mechanism of action for pregabalin, an isomer of gabapentin, is similar, as they both act as alpha-2 delta ligands, which causes a conformational change in neuronal calcium channels that prevents the entry of calcium into the neuron, dampening firing of the neurons and reducing afferent pain signals. Opiate pain medications use another mechanism to dampen pain, and use of both agents is similar in this population of patients (42% vs. 40%).
Antidepressants with some norepinephrine potential appear to dampen pain signals by activating descending spinal norepinephrine pathways, and this is the third most used class. FM and depression can exist comorbidly, with a comorbid rate of about 20 percent.4 Furthermore, it is clear that the pain-dampening property of these antidepressants (e.g., venlafaxine, duloxetine, milnacipran) is independent of their ability to alleviate depression.[6–8]
The use of multiple pharmacological agents is depicted in the data as low (18% for 2 agents and 10% for 3 agents); however, if one were to include the use of complementary and alternative medicine (CAM), a common self-treatment practice in this population of patients, then the prevalence of use of multimodal agents would be higher. In clinical practice, we observe that most patients are on multiple agents at any given time, including agents from the CAM realm. Furthermore, many FM patients undergo evidence-based treatments of aerobic exercise, aqua therapy, biofeedback, and cognitive behavioral therapy.
This use of multiple agents and approaches may be explained by the clear but limited efficacy of individual medications in patients with FM. The first approved agent, pregabalin, is roughly effective in 50 percent of patients and will show a 30-percent reduction of pain when higher doses are used. This suggests that the first approved agent will likely not cause FM pain to remit fully in the average patient. Therefore, use of a second or even third agent should likely be used to bring pain to full remission when possible. If clinicians were to fully address the associated symptoms of fatigue, executive dysfunction, and depression, then a higher amount of medications is likely warranted.
Clinicians must be aware that side effects and costs may increase when using this approach. If polypharmacy is to be used, then we often suggest using medications that do not overlap in regard to their mechanisms of action (i.e., the addition of an antidepressant to an antiepileptic would make more sense than adding two antidepressants together.)
The etiology and optimal treatment of FM still remain unknown, and various studies involving newer agents, such as duloxetine and milnacipran, are emerging.
The mainstay of treatment of FM remains multimodal, and a blend of both pharmacological and nonpharmacological interventions is likely warranted. Pain, insomnia, fatigue, executive dysfunction, and social function should be addressed in each FM patient to be successful. The multifaceted nature of FM suggests that multimodal individualized treatment programs may be necessary to achieve optimal outcomes in patients with this syndrome.
1. Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998;41(5):778–99.
2. Wolfe F, Ross K, Anderson J, et al. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum 1995; 38(1):19–28.
3. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990; 33(2):160–72.
4. National Fibromyalgia Research Association. The American College of Rheumatology 1990 criteria for the Classification of Fibromyalgia. Available at: www.nfra.net/Diagnost.htm. Access date: June 8, 2005.
5. Fishbain DA, Cutler R, Rosomoff HL, Rosomoff RS. Evidence-based data from animal and human experimental studies on pain relief with antidepressants: A structured review. Pain Med 2000;1(4):310–6.
6. Perahia DG, Pritchett YL, Desaiah D, Raskin J. Efficacy of duloxetine in painful symptoms: An analgesic or antidepressant effect? Int Clin Psychopharmacol 2006;21(6):311–7.
7. Brannan SK, Mallinckrodt CH, Brown EB, et al. Duloxetine 60mg once-daily in the treatment of painful physical symptoms in patients with major depressive disorder. J Psychiatr Res 2005;39(1):43–53.
8. Raskin J, Wiltse CG, Siegal A, et al. Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: An 8-week, double-blind, placebo-controlled trial. Am J Psychiatry 2007;164(6):900–9.
9. Wahner-Roedler DL, Elkin PL, Vincent A, et al. Use of complementary and alternative medical therapies by patients referred to a fibromyalgia treatment program at a tertiary care center. Mayo Clin Proc 2005;80(1):55–60.
10. Arnold LM, Crofford LJ, Martin SA, et al. The effect of anxiety and depression on improvements in pain in a randomized, controlled trial of pregabalin for treatment of fibromyalgia. Pain Med 2007;8(8):633–8.