Pharmacologic treatment of fibromyalgia

Fibromyalgia is a syndrome of widespread pain, nonrestorative sleep, disturbed mood, and fatigue. Optimal treatment involves a multidisciplinary approach with a team of health care providers using pharmacologic and nonpharmacologic treatment. Because of the heterogeneity of the illness, management should be individualized for the patient. Pharmacologic treatment should address issues of pain control, sleep Nonpharmacologic treatment should include patient education, a regular exercise and stretching program, and cognitive behavioral therapy. All of these are essential to improving functional capacity and quality of life. This review provides general guidelines in initiating a successful pharmacologic treatment program for patients with fibromyalgia.     

Neuropharmacologic targets and agents in fibromyalgia

Chronic widespread pain is a primary feature of fibromyalgia and is a symptom that is poorly managed in many patients. In addition, patients often experience fatigue, sleep disturbances, and anxiety. Its etiology is largely unknown. The successful clinical management of this syndrome relies on a multidisciplinary approach, employing pharmacologic and nonpharmacologic treatments. Clinical evidence on the symptoms and characteristics of fibromyalgia suggests a central mechanism behind the pathogenesis of this syndrome. It is likely that drugs with central actions will prove to be effective against a number of symptoms. This article aims to outline some of the potential spinal pharmacologic targets that may be used to treat this condition.     

Challenges of implementing fibromyalgia treatment guidelines in current clinical practice

The current diagnostic and treatment pathway for patients with fibromyalgia (FM) is lengthy, complex, and characterized by multiple physician visits with an average 2-year wait until diagnosis. It is clear that effective identification and appropriate treatment of FM remain a challenge in current clinical practice. Ideally, FM management involves a multidisciplinary approach with the preferable patient pathway originating in primary care but supported by a range of health care providers, including referral to specialist care when necessary. After the publication of individual clinical studies, high-quality reviews, and meta-analyses, recently published FM treatment guidelines have transitioned from an expert consensus to an evidence-based approach. Evidence-based guidelines provide a framework for ensuring early diagnosis and timely adoption of appropriate treatment. However, for successful outcomes, FM treatments must adopt a more holistic approach, which addresses more than just pain. Impact on the associated symptoms of fatigue and cognitive problems, sleep and mood disturbances, and lowered functional status are also important in judging the success of FM therapy. Recently published guidelines recommend the adoption of a symptom-based approach to guide pharmacologic treatment. Emerging treatment options for FM may be best differentiated on the basis of their effect on comorbid symptoms that are often associated with pain (e.g. sleep disturbance, mood, fatigue). The current review discusses the most recently published Canadian guidelines and the implications of the recent European League Against Rheumatism (EULAR) recommendations, with a focus on the challenges of implementing these guidelines in current clinical practice.     

Fibromyalgia Syndrome

Fibromyalgia is a chronic rheumatologic disorder. The primary symptoms include musculoskeletal pain and aching, disturbed sleep, fatigue, morning stiffness, and local tenderness. It is frequently misdiagnosed, despite being a fairly common, chronic disorder in most primary care clinics. Failure to make this diagnosis often leads to unnecessary medical and surgical treatment. The treatment of fibromyalgia syndrome is multifaceted. Goals include reassurance, education about pain management and modification, and symptom reduction. Exercise may be beneficial. Amitriptyline is effective in reducing certain symptoms of fibromyalgia, such as pain and lack of restful sleep. Narcotics, steroids, and nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided.     

Sleep Disorders and Fibromyalgia

Disordered sleep is such a prominent symptom in fibromyalgia that the American College of Rheumatology included symptoms such as waking unrefreshed, fatigue, tiredness, and insomnia in the 2010 diagnostic criteria for fibromyalgia. Even though sleep recording is not part of the routine evaluation, polysomnography may disclose primary sleep disorders in patients with fibromyalgia, including obstructive sleep apnea and restless leg syndrome. In addition, genetic background and environmental susceptibility link fibromyalgia and further sleep disorders. Among nonpharmacological treatment proposed for sleep disturbance in fibromyalgia, positive results have been obtained with sleep hygiene and cognitive-behavioral therapy. The effect of exercise is contradictory, but overweight or obese patients with fibromyalgia should be encouraged to lose weight. Regarding the approved antidepressants, amitriptyline proved to be superior to duloxetine and milnacipran for sleep disturbances. New perspectives remain on the narcolepsy drug sodium oxybate, which recently was approved for sleep management in fibromyalgia.     

Fibromyalgia: From treatment to rehabilitation

Fibromyalgia is a clinical syndrome of chronic widespread pain and reduced pain thresholds to palpation. The pathophysiology remains unknown, but there is increasing evidence that peripheral and central sensitization cause an amplification of sensory impulses that may alter pain perception in fibromyalgia patients. Interventions to treat fibromyalgia should aim at different targets simultaneously in order to reduce peripheral and central sensitization. There are both pharmacologic and non-pharmacologic approaches with evidence for effectiveness in the treatment of fibromyalgia and its associated symptoms. Evidence from randomized trials and meta-analyses shows that partial and short-term improvements in fibromyalgia symptoms can be achieved with low doses of antidepressants and with physical activity such as aerobic and strengthening exercises. A multidimensional approach which emphasizes education and integration of exercise and cognitive behavior therapy improves quality of life and reduces pain, fatigue and depressive symptoms when measured on a short term basis. More recently, trials have shown the neuromodulators gabapentin and pregabalin to be effective in reducing pain and improving quality of sleep in fibromyalgia. In addition, small trials of noninvasive brain stimulation have also shown benefits in reducing pain in fibromyalgia. It is essential to keep in mind that some important clinical conditions can mimic and overlap with fibromyalgia and should always be ruled out by a complete history, physical examination and appropriate laboratory testing.     

Comparative Efficacy and Harms of Duloxetine,Milnacipran, and Pregabalin in Fibromyalgia Syndrome

Duloxetine (DLX), milnacipran (MLN), and pregabalin (PGB) are the only drugs licensed by the US Food and Drug Administration (FDA) for fibromyalgia syndrome (FMS). Evidence on the comparative benefits and harms is still accruing. The authors searched MEDLINE, SCOPUS, Cochrane Central Register of Controlled Trials, and sought unpublished data from the databases of FDA, US National Institutes for Health, and Industry through May 2009 for randomized controlled trials. Outcomes of interest were symptom reduction (pain, fatigue, sleep disturbance, depressed mood, reduced health-related quality of life), and adverse events. 17 studies with 7,739 patients met the inclusion criteria. The 3 drugs were superior to placebo except DLX for fatigue, MLN for sleep disturbance, and PGB for depressed mood. Adjusted indirect comparisons indicated no significant differences for 30% pain relief and dropout rates due to adverse events between the 3 drugs. Significant differences in average symptom reduction were found: DLX and PGB were superior to MLN in reduction of pain and sleep disturbances. DLX was superior to MLN and PGB in reducing depressed mood. MLN and PGB were superior to DLX in reducing fatigue. The risk of headache and nausea with DLX and MLN was higher compared with PGB. The risk of diarrhea was higher with DLX compared to MLN and PGB. There is evidence for the short-term (up to 6 months) efficacy of DLX, MLN, and PGB. Differences with regard to the occurrence of the key symptoms of FMS and to drug-specific adverse events may be relevant for the choice of medication.PerspectiveThis article presents comparative data on the efficacy and harms of duloxetine, milnacipran, and pregabalin in fibromyalgia syndrome. The results can help clinicians in choosing medication since the 3 drugs have different effects on the key symptoms of fibromyalgia syndrome and differences in side effects, contraindications, and warnings.     

Perspectives on Fatigue from the Study of Chronic Fatigue Syndrome and Related Conditions

Fatigue is a symptom whose causes are protean and whose phenotype includes physical, mood, and behavioral components. Chronic fatigue syndrome (CFS) is an illness that has strong biological underpinnings and no definite etiology. Diagnostic criteria established by the Centers for Disease Control and Prevention have helped classify CFS as an overlap of mood, behavioral, and biological components. These include the presence of fatigue for more than 6 months associated with a diminution of functional activity and somatic symptoms, and pain not attributable to a specific diagnosis or disease. Four of the following criteria need to be present: sore throat, impaired memory or cognition, unrefreshing sleep, postexertional fatigue, tender glands, aching stiff muscles, joint pain, and headaches. Many researchers have observed that CFS shares features in common with other somatic syndromes, including irritable bowel syndrome, fibromyalgia, and temporomandibular joint dysfunction. Correlations between inflammation and infection, augmented sensory processing, abnormalities of neurotransmitters, nerve growth factors, low levels of serotonin and norepinephrine, abnormalities of homeostasis of the stress system, and autonomic dysfunction may be hallmarks of CFS. The relative contributions of each of these abnormalities to the profound fatigue associated with CFS need to be explored further to better evaluate and treat the syndrome.     

Fibromyalgia: helping your patient while maintaining your sanity

In caring for the patient with fibromyalgia, the primary care provider benefits from an understanding of fibromyalgia as a distinct entity. Evidence-based diagnostic criteria for fibromyalgia can be used in all individuals who present with multiple site pain, fatigue, and poor sleep. Planning therapy for individuals with fibromyalgia often involves using both pharmacologic and nonpharmacologic treatment in the primary care setting.     

Peripheral and central sensitization in fibromyalgia: pathogenetic role

Characteristic symptoms of fibromyalgia syndrome include widespread pain, fatigue, sleep abnormalities, and distress. Patients with fibromyalgia show psychophysical evidence of mechanical, thermal, and electrical hyperalgesia. Peripheral and central abnormalities of nociception have been described in fibromyalgia. Important nociceptor systems in the skin and muscles seem to undergo profound changes in patients with fibromyalgia through unknown mechanisms. They include sensitization of vanilloid receptor, acid-sensing ion channel receptors, and purino-receptors. Tissue mediators of inflammation and nerve growth factors can excite these receptors and cause extensive changes in pain sensitivity, but patients with fibromyalgia lack consistent evidence for inflammatory soft tissue abnormalities. Therefore, recent investigations have focused on central nervous system mechanisms of pain in fibromyalgia.     

Violence, stress, and somatic syndromes

Syndromes characterized by pain, fatigue, mood disorder, cognitive dysfunction, and sleep disturbance have been referred to as stress-related somatic disorders by virtue of the observation that onset and exacerbation of symptoms occur with stress. These syndromes include but are not limited to fibromyalgia, chronic fatigue syndrome, temporomandibular disorder, and irritable bowel syndrome. As with most chronic illnesses, genetic susceptibility and lifetime environmental exposures play a role in creating vulnerability to disease. Cumulative lifetime stress has been associated with a number of physiologic changes in the brain and body that reflect dysregulated hormonal and autonomic activity. Exposure to the stressor of violence is likely to create a state of vulnerability for the stress-related somatic syndromes and also to contribute to symptom expression and severity. Understanding the relationship between violence, stress, and somatic syndromes will help in clarifying the consequences of violence exposure to long-term health and health-related quality of life.     

Fibromyalgia syndrome

Fibromyalgia syndrome (FMS) is recognizable syndrome characterized by chronic, diffuse pain, an absence of inflammatory or structural muscloskeletal abnormalities, and a range of symptoms that include fatigue, and sleep and mood disturbances. Physical examination and laboratory testing are unrevealing, except for the presence of pain on palpation of characteristic soft-tissue sites, the tender points. Despite the recognition of FMS by the World Health Organization, it remains a controversial condition and its existence as a distinct entity remains uncertain. However, the concept of FMS is a useful one, allowing many investigations to be avoided and appropriate advice on treatment to be given. FMS may overlap with symptoms of, and the patient further impaired by, anxiety and depression. The term FMS dose not imply causation and merely describes the most common symptoms. Many patients with chronic fatigue syndrome(CFS) fulfill the criteria of FMS and represent one end of a spectrum of presentation. Evidence for triggering viral infection and the lower level of serum acylcarnitine, observed in CFS patients, is lacking in the majority of patients with FMS. These findings are suggestive to be distinctively another disorders between FMS and CFS.     

A framework for fibromyalgia management for primary care providers

Fibromyalgia is a chronic widespread pain disorder commonly associated with comorbid symptoms, including fatigue and nonrestorative sleep. As in the management of other chronic medical disorders, the approach for fibromyalgia management follows core principles of comprehensive assessment, education, goal setting, multimodal treatment including pharmacological (eg, pregabalin, duloxetine, milnacipran) and nonpharmacological therapies (eg, physical activity, behavioral therapy, sleep hygiene, education), and regular education and monitoring of treatment response and progress. Based on these core management principles, this review presents a framework for primary care providers through which they can develop a patient-centered treatment program for patients with fibromyalgia. This proactive and systematic treatment approach encourages ongoing education and patient self-management and is designed for use in the primary care setting.     

Fibromyalgia

Fibromyalgia is an idiopathic, chronic, nonarticular pain syndrome with generalized tender points. It is a multisystem disease characterized by sleep disturbance, fatigue, headache, morning stiffness, paresthesias, and anxiety. Nearly 2 percent of the general population in the United States suffers from fibromyalgia, with females of middle age being at increased risk. The diagnosis is primarily based on the presence of widespread pain for a period of at least three months and the presence of 11 tender points among 18 specific anatomic sites. There are certain comorbid conditions that overlap with, and also may be confused with, fibromyalgia. Recently there has been improved recognition and understanding of fibromyalgia. Although there are no guidelines for treatment, there is evidence that a multidimensional approach with patient education, cognitive behavior therapy, exercise, physical therapy, and pharmacologic therapy can be effective.     

Fibromyalgia Pathogenesis and Treatment Options Update

This review article presents and summarizes up-to-date literature on the clinical manifestations, diagnosis, pathophysiological mechanisms, and treatment options for fibromyalgia patients. First, the most recent diagnostic criteria for fibromyalgia, as put forth by the American College of Rheumatology will be summarized. Clinical features, including chronic widespread pain, hyperalgesia, mood disorders, anxiety, and disturbed sleep patterns will be explored in-depth. The pathogenesis and pathophysiology of fibromyalgia involves alterations in multiple ascending and descending central nervous system pathways, as well as peripheral pathways, leading to heightened pain sensitivity. Risk factors have been studied extensively, and the most recent research focuses on various genetic influences and the contributions of stress and poor sleep. Lastly, the discussion in this article focuses on treatment options for fibromyalgia; some have been mainstay options for many years. Pharmacological agents include tricyclic antidepressants, anti-epileptic drugs, selective serotonin reuptake inhibitors, norepinephrine/serotonin reuptake inhibitors, as well as some investigational agents. The evidence behind non-pharmacologic treatments, including massage therapy, exercise, and acupuncture, are discussed.     

Serotonin mechanisms in pain and functional syndromes: management implications in comorbid fibromyalgia, headache, and irritable bowl syndrome - case study and discussion

A young woman presented with multiple central hypersensitivity disorders, including fibromyalgia, headache, pelvic pain and several smooth muscle spasm disorders, including irritable bowel syndrome, irritable bladder and Raynaud's phenomenon. She also had significant fatigue and sleep problems. Her case illustrates the importance and surprising frequency of atypical bipolar mood disorders in people with multiple central hypersensitivity pain disorders, especially with depression and anxiety resistant to antidepressant treatment. Considering neurological mechanisms common to her overlapping disorders was very helpful in guiding treatment choices. This experience illustrates the value of serotonin receptor type 2 (5HT2) inhibition with atypical neuroleptics, of neural cation channel and glutamate inhibition with anticonvulsants, and the potential usefulness of antidepressants after establishing 5HT2 control to enhance downward inhibitory tracts. Medications with combined usefulness for both bipolar mood and pain disorders were highly effective for her multiple hypersensitivity problems.     

School phobia and childhood chronic fatigue syndrome (CCFS)

Chronic fatigue occurring in previously healthy children and adolescents is a vexing problem encountered by pediatric practitioners and the impact of fatigue in youngsters should not be underestimated. In its severe form, it is often associated with mood disorders. Findings in children and adolescent cases suggest that severe unexplained fatigue might precede the development of fatigue-related illness, such as childhood chronic fatigue syndrome (CCFS). This is a disabling condition characterized by severe disabling fatigue and a combination of symptoms, the prominent features being self-reported impairments in concentration and short-term memory, sleep disturbances and autonomic symptoms that cannot be explained by medical or psychiatric illness. We have encountered such patients with these complaints; their major symptoms include: general fatigue, fever, headache (not migraine), and memory disturbance. From our clinical experience, we have inferred that patients with CCFS might experience changes in brain function levels, which induce an autonomic imbalance and engender symptoms such as general fatigue, higher-order level cognitive dysfunction, and memory disturbance.     

Fibromyalgia and Sleep in Animal Models: A Current Overview and Future Directions

Sleep disorders are highly prevalent in patients with fibromyalgia (FM). Many of the daytime symptoms, such as chronic pain and fatigue, may be related to the non-restorative sleep patterns associated with the disease. Pain influences the sleep process and sleep disturbances decrease the pain threshold in a reciprocal framework. Thus, understanding the link between sleep and FM has become an important research topic in basic science. Therefore, in the current review we connect these topics and provide some insights into the cyclic relationship between sleep and pain, which has been addressed mainly in animal models. Additionally, we highlight the urgent need for sleep studies in FM animal models, which might improve the knowledge base and accelerate advances in this field.     

Behavioral Symptom Clusters,Inflammation, and Quality of Life in Chronic Low Back Pain

BackgroundChronic low back pain is a prevalent condition, often involving an inflammatory process. Behavioral symptoms, including depressed mood, fatigue, and sleep disturbance, intensifies pain and reduces quality of life.AimsThe objectives of this pilot study were to identify behavioral symptom clusters (depressive mood, fatigue, poor sleep) in individuals with chronic low back pain, and to determine whether there are differences in pain, quality of life and inflammation (plasma IL-6) based on cluster membership.Design and SettingsA cross-sectional study was conducted in a pain clinic.Participants/ SubjectsParticipants between ages 21 to 70 years (N=69) were enrolled if they had chronic low back pain for at least six months.MethodsParticipants completed instruments measuring, pain, depressive mood, fatigue, sleep, and demographic form. Blood (10ml) was obtained. Latent class analysis was used to identify clusters.Results and ConclusionsFindings revealed a two-class model, with Class 1 characterized by more depressive mood, fatigue, and sleep disturbance compared to Class 2. Class 1 participants reported worse quality of life than those in Class 2. Pain severity and pain interference were not significantly different between the classes. Levels of IL-6 were significantly greater in Class 1 participants compared to Class 2 with higher levels of IL-6 correlating with greater pain severity and sleep disturbances. Logistic regression revealed higher levels of IL-6 predicted Class 1 membership. Behavioral symptoms cluster exist in chronic low back pain patients and impact quality of life. Inflammation may contribute to relationship between behavioral symptoms and pain severity.     

Operant Learning Versus Energy Conservation Activity Pacing Treatments in a Sample of Patients With Fibromyalgia Syndrome: A Pilot Randomized Controlled Trial

This study's aim was to assess the efficacy of 2 forms of activity pacing in patients with fibromyalgia syndrome (FMS). Treatment-related changes in activity management patterns were also examined. Patients with FMS (n?=?178) were randomly assigned to an operant learning (OL; delayed [n?=?36] or immediate [n?=?54] groups) or an energy conservation (EC; delayed [n?=?35] or immediate [n?=?53] groups) treatment condition. Of these, 32 OL and 37 EC patients completed treatment. Forty-three patients were allocated to the delayed treatment condition (control group). Repeated measures analyses of variance were used to examine the effects of OL and EC treatments on primary (average pain and usual fatigue), secondary (pain and fatigue interference, physical and psychological function, sleep quality, depressive symptoms, and anxiety symptoms), and tertiary (pain-related activity patterns) outcomes. Neither treatment was effective in reducing average pain or usual fatigue symptoms. Relative to EC, OL patients showed greater improvements in depressive symptoms, whereas nonsignificant trends (P values ranging between .05 and .06) were observed for pain interference, fatigue interference, and psychological function. Both treatments were associated with improvements in sleep quality and physical function, increases in pacing, and decreases in overdoing activity patterns. Reductions in activity avoidance were only found in OL. These findings suggest that OL may be more beneficial than EC and that it could potentially be viewed as an effective stand-alone activity pacing treatment for patients with FMS. Research to determine the extent to which these preliminary findings replicate is warranted.