Caring for the Patient With Fibromyalgia: What Primary Care Providers Need to Know
ABSTRACT: Fibromyalgia (FM) is a chronic condition that causes widespread pain and reduces the quality of life of persons with it. Most patients seek care for FM in the primary care setting; thus, clinicians in this setting need to be familiar with the diagnosis and management of FM. This article provides a review of FM and its pharmacologic and nonpharmacologic management options, with a focus on the interventions that have shown at least some benefit in clinical trials and other studies.
KEYWORDS: Fibromyalgia, duloxetine, milnacipran, pregabalin, cognitive behavioral therapy, exercise, massage therapy, supplements, electrotherapy, hydrotherapy, balneotherapy, trigger point injections
Fibromyalgia (FM) is a chronic condition characterized by widespread musculoskeletal pain that often is accompanied by comorbid fatigue, cognitive disturbance, psychiatric symptoms (eg, depression, anxiety), somatic symptoms (eg, gastrointestinal tract disorders, headache, muscle weakness), multiple tender points on the body, and nonrestorative sleep. The etiology and pathophysiology of FM still are not thoroughly understood.1,2 The prevalence is approximately 2% to 3% in many countries, and it becomes more common with increasing age.3 FM can occur in children and adults of both sexes, but between 80% and 90% of people receiving an FM diagnosis are women.4 FM is reported to be the most common cause of generalized musculoskeletal pain in women between the ages of 20 and 55 years.3,5,6
Although awareness of FM and its treatments is growing, many patients report the persistence of distressing symptoms,7 which can lead to devastating outcomes. A 2010 cohort study reported a markedly increased rate of suicide among women with FM.8 Although the reasons for this risk remained unclear, the investigators postulated that it may be due to the increased prevalence of lifetime depression, anxiety, and psychiatric disorders among persons with FM.
Because many patients with chronic pain first seek care in the primary care setting, prompt diagnosis and management of FM and other chronic pain disorders in this setting are essential for improving outcomes. This article provides an overview of the causes, symptoms, diagnosis, and management of FM, including pharmacologic and nonpharmacologic interventions that have been shown to improve FM symptoms.
Causes of Fibromyalgia
The cause of FM remains unclear; however, numerous physical or emotional stressors have been postulated to trigger FM or aggravate its symptoms. These may include certain infections such as a viral illnesses or Lyme disease, as well as emotional or physical trauma.1,2,9 Some researchers have suggested that disturbances in serotonin or catecholamine metabolic or signaling pathways could increase susceptibility to FM, a theory supported by placebo-controlled trials that show a significant improvement in symptoms following the use of serotonin and norepinephrine reuptake inhibitors (SNRIs), particularly duloxetine and milnacipran.10 Evidence also suggests that genetic changes can contribute to FM and its symptoms. In 2013, an experimental pain study provided additional evidence that central pain in patients with FM is influenced by haplotypes of the catechol-O-methyltransferase gene and genotypes of the methionine/valine polymorphism at codon 158.11 It is likely that a combination of factors contribute to the development of FM, rather than a single individual factor.
Common Symptoms of Fibromyalgia
Characteristic findings of FM include chronic widespread musculoskeletal pain, chronic fatigue, sleep and cognitive disturbances, depression, anxiety, headache, paresthesia, and multiple tender points on the body. Many patients report that particular weather conditions or changes in the weather aggravate their symptoms, but consistent effects of such conditions upon daily pain or fatigue have not been found in most studies. A questionnaire-based study12 that assessed the influence of weather on pain and fatigue in 333 women in the Netherlands with FM found that while the weather had a statistically significant effect on these symptoms, the effect was small and inconsistent, with patients differentially affected by the weather conditions (eg, high and low atmospheric pressure led to reports of increased pain).
The 1990 American College of Rheumatology (ACR) criteria for classifying FM included symptoms of widespread pain occurring above and below the waist and affecting both sides of the body, and the presence of at least 11 of 18 defined tender points on physical examination. These criteria had more than 85% sensitivity and specificity for differentiating FM from other rheumatic diseases.13
In 2010, the ACR published new diagnostic criteria, which eliminated the identification of tender points on physical examination, relied on questionnaires to determine symptom severity, and recognized the importance of cognitive problems and somatic symptoms in patients with FM.13,14 Because clinicians in primary care may not be experienced in performing tender-point examinations, the use of a patient-reported questionnaire with or without a brief physical examination may improve the identification of patients who require a rheumatology referral.15
In 2011, the ACR criteria were further modified to include 19 objective pain locations and a subjective patient assessment for the following 6 symptoms: fatigue, impaired sleep, poor cognition, headaches, depression, and abdominal pain.16 It has been suggested that the use of these modified criteria may reduce the need for a rheumatology referral to make the diagnosis of FM.17
Clinicians should keep in mind that many patients with FM have other chronic comorbid conditions such as rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and Ehlers-Danlos syndrome.4 Many of these conditions can cause similar or overlapping symptoms and should be assessed for in the diagnostic workup of any patient presenting with chronic pain. Genetic testing using whole exome sequencing, which enables examination of all 23,000 genes, can be useful in identifying the gene changes that contribute to multifactorial conditions such as FM.18
Management of Fibromyalgia
Patients with FM generally respond best to a multidisciplinary, individualized treatment program implemented by clinician and nonclinician providers, including primary care physicians, rheumatologists, psychiatrists, physical therapists, and mental health specialists. Many health care providers, including rheumatologists, recommend that the initial management of FM be carried out in the primary care setting.19,20 In 2012, a questionnaire-based study20 of 80 rheumatologists in Ontario, Canada, revealed that 71% thought that rheumatologists should not retain ownership of FM, 55% considered FM to be primarily a psychosomatic illness and not a physical illness, and 89% thought patients with FM should have a family physician as their primary care provider. Rheumatologists who considered FM a physical illness were significantly more likely to believe that rheumatologists should retain ownership of this disease and were more likely to continue treating patients with FM in their practice. Although most of the rheumatologists did not wish to retain ownership of FM, most continued to care for these patients, likely because patients could not get the necessary care through their primary care providers.
Management of FM as a chronic pain disorder demands the use of efficacious, long-term interventions. This includes a number of pharmacologic and nonpharmacologic therapies that often are provided in combination (Table). Although there is no cure for FM, proper management can significantly improve patients’ symptoms and quality of life, and patients must be educated about their disease and the importance of adhering to their treatment regimen.
Three medications have been approved by the US Food and Drug Administration (FDA) to treat FM: duloxetine, milnacipran, and pregabalin. Many other medications are used off-label and have shown varying results.
Duloxetine and milnacipran. These 2 agents are SNRI antidepressants. They increase the activity of serotonin and norepinephrine, which are neurotransmitters that have been associated with emotion, mood, and the brain’s ability to suppress pain.21,22 Many experts believe that these effects on the brain are the mechanism by which these agents alleviate the pain associated with FM. There is also low- to moderate-quality evidence that pain relief is achieved by alleviating depressive symptoms.23 In clinical trials, duloxetine and milnacipran were significantly more likely to reduce FM pain than placebo and were well tolerated by patients, which led the FDA to approve these agents in 2008 and 2009, respectively. More recent studies continue to show benefit.23-25 Authors of a 2013 systematic review and meta-analysis concluded that duloxetine and milnacipran provided a small benefit over placebo in reducing pain, but these agents showed no significant advantage over placebo in reducing other FM symptoms, including fatigue and sleep problems. Another study reported a sustained improvement in FM symptoms in patients who received up to 3.25 years of milnacipran treatment.25 A 2014 meta-analysis reported that duloxetine, 60 mg daily, was significantly more likely than placebo to decrease pain by at least 50% at 12 weeks in patients with FM.23 The most commonly reported adverse effects with these agents include nausea, dry mouth, constipation, headache, somnolence, dizziness, and insomnia.24
Pregabalin and gabapentin. Pregabalin, an anticonvulsant, was the first drug approved by the FDA for the treatment of FM. It received approval in 2007 after 2 double-blind, controlled trials enrolling 1800 participants found pregabalin to reduce pain and improve daily function for some patients with FM.26
Gabapentin has not been approved for FM and is prescribed off-label; however, to date, gabapentin and pregabalin are the only 2 anticonvulsants that have shown benefit in treating FM and other chronic pain conditions. A 2013 clinical trial27 provided evidence supporting the use of these 2 agents in managing FM. Although only a small number of patients achieved acceptably good pain relief with either drug, there was a marked improvement in quality of life and function, with a reduction in pain intensity of at least 50%. Other anticonvulsants in the study, including carbamazepine, had no evidence or insufficient evidence showing benefit in FM. A 2013 meta-analysis28 of data from 5 randomized, controlled trials also supports the use of pregabalin or gabapentin as the only anticonvulsants to manage FM. The meta-analysis showed these agents to significantly improve pain, sleep, quality of life, fatigue, and anxiety. They did not, however, improve symptoms of depression.
Opioids. Little evidence supports the long-term use of opioids in persons with FM. In 2014, an American Academy of Neurology position paper29 concluded that the risks associated with chronic opioid therapy (eg, overdose, dependence, addiction) for chronic pain conditions such as FM likely outweigh the benefits, and that opioid therapy should be used only as part of a multifaceted approach to pain management. Similarly, a 2015 systematic review30 of the effectiveness and risks of long-term opioid therapy found evidence of a dose-dependent risk for a range of serious harms, such as overdose, opioid abuse, fractures, myocardial infarction, and sexual dysfunction.
When selecting an opioid, it is important to choose carefully. Oxycodone, for example, has shown no value in treating people with FM,31 whereas naltrexone and quetiapine extended-release (ER) have shown some benefits. A 2013 randomized, controlled trial32 found low-dose naltrexone to have a specific and clinically beneficial effect on FM pain. Naltrexone is widely available, inexpensive, safe, and well-tolerated, but additional clinical trials are needed to better determine its efficacy.32 A 2014 study33 was the first to demonstrate that quetiapine ER significantly improves depression, pain, and quality of life compared with placebo in patients with a dual diagnosis of major depression and FM.
Memantine. Memantine blocks glutamate, a neurotransmitter that has been associated with increased pain perception. Because elevated glutamate levels have been found in several brain regions in persons with FM, it has been postulated that glutamate-blocking drugs such as memantine might be beneficial in reducing FM-related pain. The results of a 2014 double-blind, randomized, controlled trial34 assessing the efficacy of memantine in treating FM lends support to this theory. In the study, memantine was found to significantly reduce pain and raise the pain threshold in patients with FM. The drug was generally well tolerated, with dizziness and headache being the most commonly reported adverse effects. The study included only 63 patients and had a follow-up of 6 months, so additional studies with larger sample sizes and longer follow-up times are needed to better determine the role of memantine in managing FM.34
Esreboxetine. Esreboxetine is a selective serotonin-reuptake inhibitor. In a 2010 proof-of-concept clinical study,35 patients with FM who received flexible-dosage esreboxetine (2-8 mg daily) had significant reductions in pain scores, improved function, and less fatigue compared with those receiving placebo.
Based on these findings, a follow-up study36 was conducted, which compared 4-mg, 8-mg, and 10-mg fixed daily dosages of esreboxetine in an expanded patient population. All esreboxetine dosages were associated with statistically significant improvements in pain scores compared with placebo, with participants receiving the 4-mg and 8-mg dosages also having statistically significant improvements in fatigue compared with those receiving placebo. Esreboxetine was generally well tolerated, with insomnia, constipation, dry mouth, nausea, dizziness, hot flush, headache, hyperhidrosis, and palpitations being the most commonly reported adverse effects. Because no dose-response relationship was observed in the efficacy and safety analyses, the study investigators concluded that the 4-mg daily dosage of esreboxetine would offer clinical benefit with the least risk of drug exposure.36
Numerous nonpharmacologic interventions have shown benefit in managing FM symptoms, including mental health interventions, lifestyle changes, relaxation techniques, and nerve-stimulating therapies. However, these interventions are most effective when used in combination with pharmacologic treatments, and careful patient selection is required for these therapies.
Mental health interventions. A large study37 published in 2012 showed that 22% of patients with FM had current major depression. In the study, depression was associated with younger age, being female, being unmarried, food insecurity, the number of chronic conditions, and restrictions in activities. Mental health concerns were not discussed in the previous year with any health professionals in approximately 40% of FM patients, indicating the underuse of mental health services and the urgency for health care professionals to improve depression screening in patients presenting with chronic pain.37
A mental health intervention that has shown benefit in improving FM symptoms is the use of cognitive behavioral therapy (CBT), a form of psychotherapy that strives to improve negative thinking and enable a more effective response to challenging situations.38,39 One study showed that CBT led to a slight but statistically significant improvement over control interventions in reducing pain, negative mood, and disability at the end of treatment and at follow-up approximately 6 months later.38
Exercise. Another effective modality to reduce pain and improve function is exercise. A 2012 study40 suggested that a long-term exercise program can result in immediate improvements in key health domains in women with FM. A 2014 study41 suggested that gradually adding at least 5000 steps to the daily routine may lead to clinically significant improvements in FM outcomes. Resistance training has also shown benefit in several studies. In one study,42 a moderate to high-intensity regimen improved multidimensional function, pain, tenderness, and muscle strength in women with FM. In another study,43 strength and aerobic exercise were found to have equivalent effects on reducing pain severity among patients with FM. Meditative movement therapies, such as qigong, tai chi, and yoga, also have been evaluated.44-48 A 2013 meta-analysis44 of 7 randomized, controlled trials showed these therapies significantly improved FM-related sleep disturbances, fatigue, depression, and quality of life. Only yoga provided significant pain relief. However, other studies45,48 have shown tai chi and qigong to provide pain relief in addition to improving other FM symptoms.
Based on the literature, it appears that almost any exercise program can benefit patients with FM; thus, it may be best for patients to pick activities that accommodate their fitness level and that they enjoy to ensure they remain active in the long term.
Massage therapy. Many patients seek massage therapy to obtain relief of their FM symptoms. A 2014 systemic review and meta-analysis49 of randomized trials assessing the effects of massage therapies on FM reported that massage therapy with a duration of 5 weeks or more had immediate beneficial effects on improving pain, anxiety, and depression in patients with FM. The study investigators concluded that massage therapy should be one of the viable complementary and alternative treatments for FM. In 2015, researchers in Brazil conducted a similar study50 to determine the effect of different styles of massage on FM symptoms. They found moderate evidence that myofascial release improves FM symptoms, limited evidence that connective-tissue massage and shiatsu improve FM symptoms, and no evidence that Swedish massage improves symptoms.
Supplements. Numerous supplements have been assessed for managing FM symptoms. Several have shown some benefit, including creatine, vitamin D, and growth hormone (GH). In 2013, a randomized, controlled trial51 assessing the impact of creatine supplementation on FM reported an increase in intramuscular phosphorylcreatine content and improved lower- and upper-body muscle function, as demonstrated by increased muscle strength during leg press and chest press exercises, but no changes in other FM symptoms such as pain, cognitive function, and quality of sleep and life. Despite such tenuous findings, the study investigators suggest creatine supplementation could be a useful dietary intervention to improve muscle function in patients with FM.
In a 2014 randomized, controlled trial52 that included 30 women with FM, vitamin D supplementation was reported to lead to a statistically significant reduction in pain perception compared with placebo. The investigators’ main hypothesis was that high levels of serum calcifediol would reduce pain, and patients were given oral cholecalciferol with a goal to achieve serum calcifediol levels between 32 and 48 ng/mL for 20 weeks. Because vitamin D is inexpensive, has a low adverse effect profile, and improves pain perception, the study investigators concluded that this treatment should be considered for patients with FM.
Use of GH treatment was studied in a 2012 trial53 that is reported to be the largest and longest placebo-controlled trial performed in FM. In the trial, adding GH to standard FM treatment was effective in reducing pain and showed sustained action over time.
Electrotherapy. Electrotherapy uses electrical impulses to alleviate pain by sending out electrical charges that interrupt or block pain signals, reducing pain perception. Several types of electrotherapy have shown promise as potential adjunct treatments for patients with FM, including noninvasive cortical electrostimulation, repetitive transcranial magnetic stimulation (rTMS), and transcutaneous electrical nerve stimulation (TENS). A 2012 randomized, controlled trial54 showed noninvasive cortical electrostimulation to be a well-tolerated treatment that provided small improvements in pain, tender-point measures, fatigue, and sleep. A 2014 study55 that compared rTMS with sham rTMS provided class 2 evidence that rTMS improves quality of life in patients with FM. In 2013, a randomized crossover trial56 suggested that TENS may have short-term efficacy in reducing FM symptoms. The study investigators reported a substantial decline in pain and fatigue with movement immediately after a single course of active TENS compared with placebo TENS and no TENS.
Water-based therapy. Water is considered to be one of the world’s oldest health remedies. Hydrotherapy uses water, often regular tap water, to help treat illness and pain. Balneotherapy, sometimes referred to as spa therapy, is a form of hydrotherapy that uses mineral-rich water. Although these treatments can take many forms, baths are the most popular. Hydrotherapy and balneotherapy have been shown to improve pain symptoms and quality of life in patients with FM, although higher-quality studies are needed to confirm the efficacy of these treatments.57 The mechanisms by which water-based treatments alleviate FM symptoms remain unknown; however, water temperature and buoyancy are thought to play key roles by promoting muscle relaxation, alleviating joint and muscle strain, and calming nerve impulses.58 Hydrotherapy is not appropriate for all patients, such as those who are pregnant or have circulation disorders, but it may serve as a useful adjunct for patients in whom this treatment is not contraindicated.
Trigger point injections. Trigger point injections involve inserting acupuncture-like needles into myofascial trigger points in an effort to reduce pain and restore range of motion. A 2013 meta-analysis and systematic review58 reported that dry needling decreased pain immediately after the procedure and at 4-week follow-up in patients with upper-quarter myofascial pain syndrome. However, additional well-designed studies are needed to confirm these findings.
Wayel Zanjir, MBBS, is a recent medical graduate of Gulf Medical University in Ajman, United Arab Emirates.
Samer Nuhaily, MD, is head of rheumatology at Healthpoint Hospital in Abu Dhabi, United Arab Emirates.
- Sarzi-Puttini P, Atzeni F, Mease PJ. Chronic widespread pain: from peripheral to central evolution. Best Pract Res Clin Rheumatol. 2011; 25(2):133-139.
- Schmidt-Wilcke T, Clauw DJ. Fibromyalgia: from pathophysiology to therapy. Nat Rev Rheumatol. 2011;7(9):518-527.
- Queiroz LP. Worldwide epidemiology of fibromyalgia. Curr Pain Headache Rep. 2013;17(8):356.
- What is fibromyalgia? Fast facts: an easy-to-read series of publications for the public. National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases. http://www.niams.nih.gov/Health_Info/Fibromyalgia/fibromyalgia_ff.asp. Published November 2014. Accessed March 28, 2016.
- Clauw DJ. Fibromyalgia: a clinical review. JAMA. 2014;311(15):1547-1555.
- Sumpton JE, Moulin DE. Fibromyalgia. Handb Clin Neurol. 2014;119:513-527.
- Walitt B, Fitzcharles M-A, Hassett AL, Katz RS, Häuser W, Wolfe F. The longitudinal outcome of fibromyalgia: a study of 1555 patients. J Rheumatol. 2011;38(10):2238-2246.
- Dreyer L, Kendall S, Danneskiold-Samsøe B, Bartels EM, Bliddal H. Mortality in a cohort of Danish patients with fibromyalgia: increased frequency of suicide. Arthritis Rheum. 2010; 62(10):3101-3108.
- Goldenberg DL. Do infections trigger fibromyalgia? Arthritis Rheum. 1993;36(11):1489-1492.
- Moret C, Briley M. Antidepressants in the treatment of fibromyalgia. Neuropsychiatr Dis Treat. 2006;2(4):537-548.
- Martínez-Jauand M, Sitges C, Rodríguez V, et al. Pain sensitivity in fibromyalgia is associated with catechol-O-methyltransferase (COMT) gene. Eur J Pain. 2013;17(1):16-27.
- Bossema ER, van Middendorp H, Jacobs JWG, Bijlsma JWJ, Geenen R. Influence of weather on daily symptoms of pain and fatigue in female patients with fibromyalgia: a multilevel regression analysis. Arthritis Care Res (Hoboken). 2013;65(7):1019-1025.
- Goldenberg DL. Clinical manifestations and diagnosis of fibromyalgia in adults. UpToDate. http://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-fibromyalgia-in-adults. Accessed March 28, 2016.
- Wolfe F, Clauw DJ, Fitzcharles M-A, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken). 2010;62(5):600-610.
- Arnold LM, Stanford SB, Welge JA, Crofford LJ. Development and testing of the fibromyalgia diagnostic screen for primary care. J Womens Health (Larchmt). 2012;21(2):231-239.
- Wolfe F, Clauw DJ, Fitzcharles M-A, et al. Fibromyalgia criteria and severity scales for clinical and epidemiological studies: a modification of the ACR Preliminary Diagnostic Criteria for Fibromyalgia. J Rheumatol. 2011;38(6):1113-1122.
- Ferrari R, Russell AS. A questionnaire using the modified 2010 American College of Rheumatology criteria for fibromyalgia: specificity and sensitivity in clinical practice. J Rheumatol. 2013; 40(9):1590-1595.
- Wilson GN. Common tragedies of lax joint syndromes: broken hearts, fallen men, and loose women. Consultant. 2015;55(2):102-110.
- Arnold LM, Clauw DJ, Dunegan LJ, Turk DC; FibroCollaborative. A framework for fibromyalgia management for primary care providers. Mayo Clin Proc. 2012;87(5):488-496.
- Ghazan-Shahi S, Towheed T, Hopman W. Should rheumatologists retain ownership of fibromyalgia? A survey of Ontario rheumatologists. Clin Rheumatol. 2012;31(8):1177-1181.
- FDA approves Cymbalta(R) for the management of fibromyalgia [news release]. Indianapolis, IN: Eli Lilly and Co; June 16, 2008. https://investor.lilly.com. Accessed March 28, 2016.
- Forest and Cypress announce FDA approval of Savella(TM) for the management of fibromyalgia [news release]. New York, NY: Forest Laboratories Inc; January 14, 2009. Accessed March 28, 2016.
- Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev. 2014;(1):CD007115. doi:10.1002/14651858.CD007115.pub3.
- Häuser W, Urrútia G, Tort S, Üçeyler N, Walitt B. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome. Cochrane Database Syst Rev. 2013;(1):CD010292. doi:10.1002/14651858.CD010292.
- Arnold LM, Palmer RH, Ma Y. A 3-year, open-label, flexible-dosing study of milnacipran for the treatment of fibromyalgia. Clin J Pain. 2013; 29(12):1021-1028.
- FDA approves first drug for treating fibromyalgia [news release]. Silver Spring, MD: US Food and Drug Administration; June 21, 2007. http://www.fda.gov. Accessed March 28, 2016.
- Wiffen PJ, Derry S, Moore RA, et al. Antiepileptic drugs for neuropathic pain and fibromyalgia—an overview of Cochrane reviews. Cochrane Database Syst Rev. 2013;(11):CD010567. doi:10.1002/14651858.CD010567.pub2.
- Üçeyler N, Sommer C, Walitt B, Häuser W. Anticonvulsants for fibromyalgia. Cochrane Database Syst Rev. 2013;(10):CD010782. doi:10.1002/14651858.CD010782.
- Franklin GM. Opioids for chronic noncancer pain: a position paper of the American Academy of Neurology. Neurology. 2014;83(14):1277-1284.
- Chou R, Turner JA, Devine EB, et al. The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015;162(4):276-286.
- Gaskell H, Moore RA, Derry S, Stannard C. Oxycodone for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2014;(6):CD010692. doi: 10.1002/14651858.CD010692.pub2.
- Younger J, Noor N, McCue R, Mackey S. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. 2013;65(2):529-538.
- McIntyre A, Paisley D, Kouassi E, Gendron A. Quetiapine fumarate extended-release for the treatment of major depression with comorbid fibromyalgia syndrome: a double-blind, randomized, placebo-controlled study. Arthritis Rheumatol. 2014;66(2):451-461.
- Olivan-Blázquez B, Herrera-Mercadal P, Puebla-Guedea M, et al. Efficacy of memantine in the treatment of fibromyalgia: a double-blind, randomised, controlled trial with 6-month follow-up. Pain. 2014;155(12):2517-2525.
- Arnold LM, Chatamra K, Hirsch I, Stoker M. Safety and efficacy of esreboxetine in patients with fibromyalgia: an 8-week, multicenter, randomized, double-blind, placebo-controlled study. Clin Ther. 2010;32(9):1618-1632.
- Arnold LM, Hirsch I, Sanders P, Ellis A, Hughes B. Safety and efficacy of esreboxetine in patients with fibromyalgia: a fourteen-week, randomized, double-blind, placebo-controlled, multicenter clinical trial. Arthritis Rheum. 2012;64(7):2387-2397.
- Fuller-Thomson E, Nimigon-Young J, Brennenstuhl S. Individuals with fibromyalgia and depression: findings from a nationally representative Canadian survey. Rheumatol Int. 2012;32(4):853-862.
- Bernardy K, Klose P, Busch AJ, Choy EH, Häuser W. Cognitive behavioural therapies for fibromyalgia. Cochrane Database Syst Rev. 2013;(9):CD009796. doi:10.1002/14651858.CD009796.pub2.
- Lami MJ, Martínez MP, Sánchez AI. Systematic review of psychological treatment in fibromyalgia. Curr Pain Headache Rep. 2013;17(7):345.
- Sañudo B, Carrasco L, de Hoyo M, McVeigh JG. Effects of exercise training and detraining in patients with fibromyalgia syndrome: a 3-yr longitudinal study. Am J Phys Med Rehabil. 2012;91(7):561-569.
- Kaleth AS, Slaven JE, Ang DC. Does increasing steps per day predict improvement in physical function and pain interference in adults with fibromyalgia? Arthritis Care Res (Hoboken). 2014;66(12):1887-1894.
- Busch AJ, Webber SC, Richards RS, et al. Resistance exercise training for fibromyalgia. Cochrane Database Syst Rev. 2013;(12):CD010884. doi:10.1002/14651858.CD010884.
- Hooten WM, Qu W, Townsend CO, Judd JW. Effects of strength vs aerobic exercise on pain severity in adults with fibromyalgia: a randomized equivalence trial. Pain. 2012;153(4):915-923.
- Langhorst J, Klose P, Dobos GJ, Bernardy K, Häuser W. Efficacy and safety of meditative movement therapies in fibromyalgia syndrome: a systematic review and meta-analysis of randomized controlled trials. Rheumatol Int. 2013; 33(1):193-207.
- Jones KD, Sherman CA, Mist SD, Carson JW, Bennett RM, Li F. A randomized controlled trial of 8-form Tai chi improves symptoms and functional mobility in fibromyalgia patients. Clin Rheumatol. 2012;31(8):1205-1214.
- Carson JW, Carson KM, Jones KD, Bennett RM, Wright CL, Mist SD. A pilot randomized controlled trial of the Yoga of Awareness program in the management of fibromyalgia. Pain. 2010; 151(2):530-539.
- Carson JW, Carson KM, Jones KD, Mist SD, Bennett RM. Follow-up of yoga of awareness for fibromyalgia: results at 3 months and replication in the wait-list group. Clin J Pain. 2012;28(9): 804-813.
- Lauche R, Cramer H, Häuser W, Dobos G, Langhorst J. A systematic review and meta-analysis of qigong for the fibromyalgia syndrome. Evid Based Complement Alternat Med. 2013;2013: 635182.
- Li Y-h, Wang F-y, Feng C-q, Yang X-f, Sun Y-h. Massage therapy for fibromyalgia: a systematic review and meta-analysis of randomized controlled trials. PLoS One. 2014;9(2):e89304.
- Yuan SLK, Matsutani LA, Marques AP. Effectiveness of different styles of massage therapy in fibromyalgia: a systematic review and meta-analysis. Man Ther. 2015;20(2):257-264.
- Alves CRR, Santiago BM, Lima FR, et al. Creatine supplementation in fibromyalgia: a randomized, double-blind, placebo-controlled trial. Arthritis Care Res (Hoboken). 2013;65(9):1449-1459.
- Wepner F, Scheuer R, Schuetz-Wieser B, et al. Effects of vitamin D on patients with fibromyalgia syndrome: a randomized placebo-controlled trial. Pain. 2014;155(2):261-268.
- Cuatrecasas G, Alegre C, Fernandez-Solà J, et al. Growth hormone treatment for sustained pain reduction and improvement in quality of life in severe fibromyalgia. Pain. 2012;153(7):1382-1389.
- Hargrove JB, Bennett RM, Simons DG, Smith SJ, Nagpal S, Deering DE. A randomized placebo-controlled study of noninvasive cortical electrostimulation in the treatment of fibromyalgia patients. Pain Med. 2012;13(1):115-124.
- Boyer L, Dousset A, Roussel P, et al. rTMS in fibromyalgia: a randomized trial evaluating QoL and its brain metabolic substrate. Neurology. 2014;82(14):1231-1238.
- Dailey DL, Rakel BA, Vance CG, et al. Transcutaneous electrical nerve stimulation reduces pain, fatigue and hyperalgesia while restoring central inhibition in primary fibromyalgia. Pain. 2013;154(11):2554-2562.
- Naumann J, Sadaghiani C. Therapeutic benefit of balneotherapy and hydrotherapy in the management of fibromyalgia syndrome: a qualitative systematic review and meta-analysis of randomized controlled trials. Arthritis Res Ther. 2014; 16(4):R141.
- Kietrys DM, Palombaro KM, Azzaretto E, et al. Effectiveness of dry needling for upper-quarter myofascial pain: a systematic review and meta-analysis. J Orthop Sports Phys Ther. 2013;43(9):620-634.