Sleep and circadian rhythm disorders in fibromyalgia

Fibromyalgia (FM) is a syndrome of generalized muscle pain that is also associated with equally distressing symptoms of sleep disturbance and fatigue. FM shows clinical overlap with other stress-associated disorders, including chronic fatigue syndrome (CFS) and depression. All of these conditions have the features of disrupted sleep patterns and dysregulated biologic circadian rhythms, such as stress hormone secretion. This review focuses on the role of sleep and circadian rhythm disorders in FM and, in the absence of any specific treatment for FM, presents a pragmatic therapeutic approach aimed at identifying and treating comorbid sleep and depressive disorders, optimizing sleep habits, and judicious use of pharmacologic agents.     

The Prevalence of Psychiatric and Chronic Pain Comorbidities in Fibromyalgia: an ACTTION systematic review

Fibromyalgia (FM) is a chronic widespread pain condition that overlaps with multiple comorbid health conditions and contributes to considerable patient distress. The aim of this review was to provide a systematic overview of psychiatric and chronic pain comorbidities among patients diagnosed with FM and to inform the development of recommendations for the design of clinical trials. Thirty-one, cross-sectional, clinical epidemiology studies that evaluated patients diagnosed with FM were included for review. None of the reviewed studies reported on the incidence of these comorbidities. Sample size-weighted prevalence estimates were calculated when prevalence data were reported in 2 or more studies for the same comorbid condition. The most prevalent comorbidity across all studies reviewed was depression/major depressive disorder (MDD) with over half of the patients included having this diagnosis in their lifetime (weighted prevalence up to 63%). In addition, nearly one-third of FM patients examined had current or lifetime bipolar disorder, panic disorder, or post-traumatic stress disorder. Less common psychiatric disorders reported included generalized anxiety disorder, obsessive compulsive disorder, and specific phobias (agoraphobia, social phobia). There were fewer studies that examined chronic pain comorbidities among FM patients, but when evaluated, prevalence was also high ranging from 39% to 76% (i.e., chronic tension-type or migraine headache, irritable bowel syndrome, myofascial pain syndrome, and temporomandibular disorders). The results of the review suggest that depression and chronic pain conditions involving head/jaw pain and IBS were elevated among FM patients compared to other conditions in the clinic-based studies. In contrast, anxiety-related disorders were much less common. Addressing the presence of these comorbid health conditions in clinical trials of treatments for FM would increase the generalizability and real-world applicability of FM research.     

Symptoms and signs in fibromyalgia syndrome

Fibromyalgia syndrome (FM) is a common chronic pain condition that affects at least 2% of the adult population. Chronic widespread pain is the defining feature of FM, but patients may also exhibit a range of other symptoms, including sleep disturbance, fatigue, irritable bowel syndrome, headaches, and mood disorders. The etiology of FM is not completely understood and the syndrome is influenced by factors such as stress, medical illness, and a variety of pain conditions. Establishing diagnosis may be difficult because of the multifaceted nature of the syndrome and overlap with other chronically painful conditions. A unifying hypothesis is that FM results from sensitization of the central nervous system; this new concept could justify the variety of characteristics of the syndrome. FM symptoms can be musculoskeletal, non-musculoskeletal, or a combination of both; and many patients will also experience a host of associated symptoms or conditions. The ACR classification criteria focus only on pain and disregard other important symptoms; but three key features, pain, fatigue and sleep disturbance, are present in virtually every patient with FM. Several other associated syndromes, including circulatory, nervous, digestive, urinary and reproductive systems are probably a part of the so called central sensitivity or sensitization syndrome. A minority subgroup of patients (30-40%) has a significant psychological disturbance. Psychological factors are an important determinant of any type of pain, and psychological comorbidity is frequent in FM. Psychiatric disorders most commonly described are mood disorders, but psychiatric illness is not a necessary factor in the etiopathogenesis of FM.     

The rational management of fibromyalgia patients

The exponential increase in pain research over the last 10 years has established fibromyalgia (FM) as a common chronic pain syndrome with similar neurophysiologic aberrations to other chronic pain states. As such, the pathogenesis is considered to involve an interaction of augmented sensory processing (central sensitization) and peripheral pain generators. The notion, that FM symptomatology results from an amplification of incoming sensory impulses, has revolutionized the contemporary understanding of this enigmatic problem and provided a more rational approach to treatment. To date, the management of FM has been mainly palliative, with the aims of reducing pain, improving sleep, maintaining function, treating psychologic distress and diminishing the impact of associated syndromes. The rapidly evolving neurophysiologic, psychophysiologic and molecular biologic basis for chronic pain states has already opened up new avenues for management which should be applicable to this difficult group of patients. Indeed, it is now possible to think about a "rational" approach to managing FM patients that was unthinkable just a few years ago.     

Sleep disorders over the full range of chronic kidney disease

Sleep disorders are common and underrecognized in patients at all stages of chronic kidney disease. They include sleep apnea, insomnia, excessive sleepiness, restless legs syndrome and periodic limb movement disorder. They can be related to underlying uremia or comorbidities. Sleep disorders can affect the quality of life, and some are associated with increased morbidity and mortality. Clinical assessment, polysomnography and other standardized assessments are required for diagnosis. Therapeutic approaches include improvement in uremia management, treatment of comorbidities or specific interventions directed at individual sleep disorders. Diagnosis and treatment of sleep disorders in this population may improve quality of life and patient survival.     

Pharmacotherapy of fibromyalgia

There have been substantial advances in the pharmacotherapy of fibromyalgia (FM), which have occurred in parallel with advances in our understanding of the pathophysiology of FM in the past several years. Consortia of researchers have established a core set of symptom domains, which constitute the condition of FM, including pain, fatigue, sleep and mood disturbance and cognitive dysfunction, which significantly impact a patient's overall well-being and ability to function. Outcome measures, which assess these domains, both singly and in composite format, are showing increasing reliability to discriminate between the treatment and placebo arms in clinical trials of emerging therapies, which are targeting the pathophysiologic mechanisms of FM. Several different medications, including the serotonin and norepinephrine reuptake inhibitors, duloxetine and milnacipran, and the α(2)δ modulator, pregabalin, have been approved by the Food and Drug Administration (FDA) for the management of FM, based on their clinically meaningful and durable effect on pain in monotherapy trials. They also have been shown to beneficially effect patient global impression of change, function and variably other key symptom domains, such as fatigue, sleep disturbance and cognition. Other medicines, although they have not gone through the formal approval process, have also shown efficacy in multiple domains of FM. Although combination trials have generally not yet been performed, the combined use of medicines with complementary mechanisms of action is rational, and, when done with appropriate caution, will likely be shown to be safe and well tolerated. Adjunctive therapy with medicines targeted at specific symptom domains, such as sleep, as well as treatments aimed at common co-morbid conditions, such as irritable bowel syndrome, or disease states, such as rheumatoid arthritis, should be considered for the purpose of reducing the patient's overall symptom burden. Current therapies neither completely treat FM symptoms nor benefit all patients; thus, further research on new therapies with different mechanisms and side-effect profiles is needed.     

Complementary and alternative therapies for fibromyalgia

Fibromyalgia (FM) is a syndrome of chronic widespread musculoskeletal pain that is accompanied by sleep disturbance and fatigue. Clinical treatment usually includes lifestyle modifications and pharmacologic interventions meant to relieve pain, improve sleep quality, and treat mood disorders. These therapies are often ineffective or have been shown in clinical studies to have only short-term effectiveness. Pharmacologic treatments have considerable side effects. Patients may have difficulty complying with exercise-based treatments. Thus, patients seek alternative therapeutic approaches and physicians are routinely asked for advice about these treatments. This article reviews nontraditional treatment alternatives, from use of nutritional and herbal supplements to acupuncture and mindbody therapy. Little is known about efficacy and tolerance of complementary and alternative therapies in FM and other chronic musculoskeletal pain syndromes. Most studies on these treatments have been performed for osteoarthritis, rheumatoid arthritis, or focal musculoskeletal conditions. Clinical trials are scarce; the quality of these trials is often criticized because of small study population size, lack of appropriate control interventions, poor compliance, or short duration of follow-up. However, because of widespread and growing use of alternative medicine, especially by persons with chronic illnesses, it is essential to review efficacy and adverse effects of complementary and alternative therapies.     

Fibromyalgia and obesity: A comprehensive systematic review and meta-analysis

IntroductionObesity has been associated with several complications, including musculoskeletal disorders. Aim of the present systematic review was to identify all available evidence on the relationship between fibromyalgia (FM) and obesity, including epidemiological association, impact of obesity on FM severity and effect of weight loss strategies on FM symptoms.MethodsMedLine, Cochrane Central Register of Controlled Trials and Web of Science databases were searched up to September 2020 to identify eligible articles. Data from studies reporting the prevalence of obesity in FM patients were pooled using a random-effects model.ResultsAfter removal of duplicate records, 393 studies proceeded to review. A total of 41 articles were deemed eligible for inclusion in final synthesis. Quality assessment revealed that the overall risk of bias was high.The overall prevalence of obesity in FM was 35.7% (95% CI: 31.8 – 39.9%), with higher figures reported for USA.The majority of studies included demonstrated that obesity is associated with different domains of the disorder, including composite measures of activity, pain severity, tender point count, stiffness, fatigue, physical functioning/disability, sleep, cognitive dysfunction, and quality of life; the strength of correlation was weak on average. Inconsistent data were available regarding the correlation with depression and anxiety.Only few studies addressed the effect of therapeutic weight loss in FM, either by bariatric surgery, diet/exercise combination or behavioral weight loss, providing preliminary evidence for a potential benefit of weight loss in ameliorating FM symptoms.ConclusionsAvailable data support a potential interplay between obesity and FM-related symptoms. Weight management should be encouraged in patients with FM.     

A randomized, double-blind, placebo-controlled, phase III trial of pregabalin in the treatment of patients with fibromyalgia

OBJECTIVE: To evaluate the efficacy and safety of pregabalin for symptomatic relief of pain associated with fibromyalgia (FM) and for management of FM. METHODS: This multicenter, double-blind, placebo-controlled trial randomly assigned 748 patients with FM to receive placebo or pregabalin 300, 450, or 600 mg/day (dosed twice daily) for 13 weeks. The primary outcome variable for study objective 1, symptomatic relief of pain associated with FM, was comparison of endpoint mean pain scores between each pregabalin group and placebo. The outcome variable for study objective 2, management of FM, included endpoint mean pain scores, Patient Global Impression of Change (PGIC), and Fibromyalgia Impact Questionnaire (FIQ)-Total Score. Secondary outcomes included assessments of sleep, fatigue, and mood disturbance. RESULTS: Patients in all pregabalin groups showed statistically significant improvement in endpoint mean pain score and in PGIC response compared with placebo. Improvements in FIQ-Total Score for the pregabalin groups were numerically but not significantly greater than those for the placebo group. Compared with placebo, all pregabalin treatment groups showed statistically significant improvement in assessments of sleep and in patients' impressions of their global improvement. Dizziness and somnolence were the most frequently reported adverse events. CONCLUSION: Pregabalin at 300, 450, and 600 mg/day was efficacious and safe for treatment of pain associated with FM. Pregabalin monotherapy provides clinically meaningful benefit to patients with FM.     

Fibromyalgia in patients with irritable bowel syndrome. An association with the severity of the intestinal disorder

Fibromyalgia (FM) syndrome and irritable bowel syndrome (IBS) are functional disorders in which altered somatic and or visceral perception thresholds have been found. The aim of this study was to evaluate the prevalence of FM in a group of patients with IBS and the possible association of FM with patterns and severity of the intestinal disorder. One hundred thirty consecutive IBS patients were studied. The IBS was divided into four different patterns according to the predominant bowel symptom and into three levels of severity using a functional severity index. All patients underwent rheumatological evaluation for number of positive tender points, number of tender and swollen joints, markers of inflammation, and presence of headache and weakness. Moreover, patients' assessments of diffuse pain, mood and sleep disturbance, anxiety, and fatigue were also measured on a visual analogue scale. The diagnosis of FM was made based on American College of Rheumatology classification criteria. Nonparametric tests were used for statistical analysis. Fibromyalgia was found in 20% of IBS patients. No statistical association was found between the presence of FM and the type of IBS but a significant association was found between the presence of FM and severity of the intestinal disorder. The presence of FM in IBS patients seems to be associated only with the severity of IBS. This result confirms previous studies on the association between the two syndromes.     

Office management of fibromyalgia

The office management of fibromyalgia (FM) is best determined by two variables: (1) the severity and complexity of each patient's symptoms, and (2) the specialization and interest of the treating physician. Because there are 6 to 10 million Americans with FM, most patient visits will be to the primary care physician. Rheumatologists, physiatrists, and other musculoskeletal specialists must work with primary care physicians to foster the early diagnosis and appropriate treatment of FM. Primary care physicians are faced with enormous challenges in caring for patients with chronic pain disorders like FM. Our managed health care system insists that patient encounters be brief. Specialty referrals are often discouraged. There is little if any reimbursement for patient education. FM treatment is labor-intensive. Therefore, optimal planning and use of precious office time and resources are most important. Rheumatologists should train our primary care colleagues to recognize FM. Many patients still go months or years before this common syndrome is diagnosed. Rheumatologists should also spearhead teaching primary care physicians the basic treatment principles of FM. If the diagnosis is made early, patients with FM in community practice do very well with simple management techniques. As consultants, rheumatologists should confirm the diagnosis of FM and suggest basic FM management. Some primary care providers or other specialists will be fully capable of bypassing this consultation, especially if the patient responds to simple management suggestions. Manpower surveys have not studied the cost-effectiveness of specialty care in FM. Rheumatologists should also assume the responsibility for the management of FM patients who have not responded to basic FM management. Additionally, some rheumatologists may wish to subspecialize in FM, a major career commitment to this perplexing disorder. These situations constitute advanced FM management.     

The effects of sodium oxybate on clinical symptoms and sleep patterns in patients with fibromyalgia

OBJECTIVE: Fibromyalgia (FM) is associated with the sleep phenomenon of alpha intrusion, and with low growth hormone secretion. Sodium oxybate has been shown to increase both slow-wave sleep and growth hormone levels. This double blind, randomized, placebo controlled crossover trial was conducted to evaluate the effects of sodium oxybate on the subjective symptoms of pain, fatigue, and sleep quality and the objective polysomnographic (PSG) sleep variables of alpha intrusion, slow-wave (stage 3/4) sleep, and sleep efficiency in patients with FM. METHODS: Patients received either 6.0 g/day sodium oxybate or placebo for 1 month, with an intervening 2 week washout period. Efficacy measures included PSG evaluations, tender point index (TPI), and subjective measurements from daily diary entries. Safety measures included clinical laboratory values, vital signs, and adverse events. RESULTS: Twenty-four female patients were included in the study; 18 completed the trial. TPI was decreased from baseline by 8.5, compared with an increase of 0.4 for placebo (p = 0.0079). Six of the 7 pain/fatigue scores (overall pain, pain at rest, pain during movement, end of day fatigue, overall fatigue, and morning fatigue) were relieved by 29% to 33% with sodium oxybate, compared with 6% to 10% relief with placebo (p < 0.005). Alpha intrusion, sleep latency, and rapid-eye-movement sleep were significantly decreased, while slow-wave (stage 3/4) sleep was significantly increased, compared with placebo (p < 0.005). Two of the 5 subjective sleep related variables were significantly different from placebo: morning alertness (improved by 18% with sodium oxybate, compared with 2% for placebo; p = 0.0033) and quality of sleep (improved by 33% and 10%, respectively; p = 0.0003). CONCLUSION: Sodium oxybate effectively reduced the symptoms of pain and fatigue in patients with FM, and dramatically reduced the sleep abnormalities (alpha intrusion and decreased slow-wave sleep) associated with the nonrestorative sleep characteristic of this disorder.     

Sleep disorders in adolescents and young adults: Insights into types,relationship to obesity and high altitude and possible lines of management

A sleep disorder is a medical disorder of the sleep pattern of a person that may be serious enough to interfere with normal physical, mental and emotional functioning. Disruptions in sleep can be caused by a variety of causes, from teeth grinding to night terrors. Sleep disorders are usually prevalent among adolescents and young adults, possibly due to factors related to life style, dietary habits, hormonal and emotional disturbances. Other factors that may precipitate sleep disorders include environmental, psychological and genetic factors. Sleep disorders may lead to serious psychological and mood disorders and may even affect the immune system. Management of sleep disorders depends on amelioration of the precipitating factors and the use of certain drugs that may help to restore the normal sleep-wake cycle. This review sheds light on sleep disorders in adolescents and young adults regarding their types, etiology, dangers and possible lines of management.     

Understanding sleep in persons with diabetes

Restorative sleep is as essential for well-being as proper diet or exercise in persons with type 2 diabetes. However, sleep disorders such as insomnia, restless leg syndrome/periodic leg movements, and obstructive sleep apnea increase in prevalence with age and are very common in persons with type 2 diabetes. Disrupted sleep may result in weight gain, increased insulin resistance, and decreased daytime functioning. Although sleep disturbances have a major influence on health and quality of life, diagnosis and treatment can reduce their negative effects. Diabetes educators are pivotal in patient assessment, management, teaching, and collaborating with the primary health care provider to deliver holistic management of the patient with diabetes. This article will provide diabetes educators with various strategies for assessing sleep, including an easy 8-item questionnaire that can be used in the clinical setting. In addition, interventions to improve sleep hygiene that can be easily implemented by diabetes educators will be described.     

Sleep and fibrositis syndrome

Chronic diffuse myalgia, localized areas of tenderness, fatigue, and unrefreshing sleep are related to a physiologic arousal disorder within sleep, that is, the alpha EEG NREM sleep anomaly. This sleep physiologic disorder, nonrestorative sleep, and symptoms of fibrositis syndrome are shown to occur with psychologic, environmental, and physiologic distress conditions. Pathogenic mechanisms that link nonrestorative sleep physiology to pain and fatigue may involve metabolic dysfunction of the brain with sleep-related alteration in immunologic and neurotransmitter functions (serotonin, substance P, endorphins). These sleep-related mechanisms have important implications for the understanding and treatment of fibrositis/fibromyalgia syndrome.     

Regional musculoskeletal pain. The elbow, forearm, wrist and hand.

Two main groups of soft-tissue disorders are identified: specific soft tissue syndromes and a non-specific disorder as yet not fully characterized. Specific soft tissue syndromes occur in joint, muscle or nerve and are associated with characteristic symptoms and physical signs. These include epicondylitis at the elbow, tendon disorders at the wrist and nerve entrapments such as carpal tunnel syndrome. The non-specific soft tissue syndrome is primarily described by symptoms of pain but may include muscular symptoms (such as weakness and cramp) or nerve symptoms (such as numbness, pins and needles, and burning). Agreed, validated diagnostic criteria for use in surveillance are urgently required. Biological markers are still sought; both muscle and nerve seem promising for future studies. The multifactorial aetiology of these disorders will be discussed, and guidelines to management will embrace the principles of this model. Treatments aimed at the pain in isolation are most often studied. Psychosocial and environmental influences on the presentation and persistence of pain need further evaluation.     

Metabolic disturbances in obesity versus sleep apnoea: the importance of visceral obesity and insulin resistance

Obstructive sleep apnoea (OSA) is a very prevalent disorder particularly amongst middle-aged, obese men, although its existence in women as well as in lean individuals is increasingly recognized. Despite the early recognition of the strong association between OSA and obesity, and OSA and cardiovascular problems, sleep apnoea has been treated as a 'local abnormality' of the respiratory track rather than as a 'systemic illness'. In 1997, we first reported that the pro-inflammatory cytokines interleukin (IL)-6 and tumour necrosis factor-alpha (TNF alpha) were elevated in patients with disorders of excessive daytime sleepiness (EDS) and proposed that these cytokines were mediators of daytime sleepiness. Also, we reported a positive correlation between IL-6 or TNF alpha plasma levels and the body mass index (BMI). In subsequent studies, we showed that IL-6, TNF alpha, leptin and insulin levels were elevated in sleep apnoea independently of obesity and that visceral fat, was the primary parameter linked with sleep apnoea. The association of OSA with insulin resistance and diabetes type 2 has been confirmed since then in several epidemiological and clinical studies. Furthermore, our findings that women with polycystic ovary syndrome (PCOS, a condition associated with hyperandrogenism and insulin resistance) were much more likely than controls to have sleep disordered breathing (SDB) and daytime sleepiness support the pathogenetic role of insulin resistance in OSA. Other findings that support the view that sleep apnoea and sleepiness may be manifestations of a serious metabolic disorder, namely the Metabolic or Visceral Obesity Syndrome, include: obesity without sleep apnoea is associated with daytime sleepiness; PCOS and diabetes type 2 are independently associated with EDS after controlling for SDB, obesity and age; and increased prevalence of sleep apnoea in postmenopausal women, with hormonal replacement therapy associated with a significantly reduced risk for OSA. In conclusion, accumulating evidence provides support to our model of the bi-directional, feedforward, pernicious association between sleep apnoea, sleepiness, inflammation and insulin resistance, all promoting atherosclerosis and cardiovascular disease.     

Pharmacological treatment of fibromyalgia

Fibromyalgia syndrome (FM) is a condition of chronic and diffuse muscular pain affecting particularly middle aged women. The aetiology of FM is not completely understood and it is currently considered a disorder of pain regulation. The most efficacious compounds include the tricyclic drugs and mixed reuptake inhibitors. Recent works suggest that the anticonvulsant medications pregabalin and gabapentin are also effective. Moreover, two serotonin and norepinephrine-reuptake inhibitors-duloxetine and milnacipran show encouraging results in treating FM symptoms. The results of clinical trials of anti-inflammatory medications have been generally disappointing, but three RCTs have found that tramadol (with or without acetaminophen) is effective in FM.     

Multidisciplinary approach to fibromyalgia: what is the teaching?

Fibromyalgia (FM) is a rheumatic disease that is characterised by chronic musculoskeletal pain, stiffness, fatigue, sleep and mood disorder. FM patients demonstrate dysregulation of pain neurotransmitter function and experience a neurohormone-mediated association with sleep irregularities. There are currently no instrumental tests or specific diagnostic markers for FM, and many of the existing indicators are only significant for research purposes. Anti-depressants, non-steroidal anti-inflammatory drugs (NSAIDS), opioids, sedatives, muscle relaxants and antiepileptics have all been used to treat FM with varying results. It has been shown that interdisciplinary treatment programmes lead to greater improvements in subjective pain and function than monotherapies. Physical exercise and multimodal cognitive behavioural therapy are the most widely accepted and beneficial forms of non-pharmacological therapy.     

Sexual and physical abuse in women with fibromyalgia: Association with outpatient health care utilization and pain medication usage

Objective. To evaluate the relationship between sexual and/or physical abuse and health care usage in patients with fibromyalgia (FM) and identify variables that may influence this relationship. Methods. We assessed history of sexuall physical abuse, health care utilization, and medication usage, as well as related variables in 75 women with FM using standardized questionnaires, structured interviews, and laboratory pain perception tasks. Results. Fifty-seven percent of FM patients reported a history of sexuall physical abuse. Compared to non-abused patients, abused patients reported significantly greater utilization of outpatient health care services for problems other than FM and greater use of medications for pain (P ≤ 0.025). Consistent with our expectations, abused patients also were characterized by significantly greater pain, fatigue, functional disability, and stress, as well as by a tendency to label dolorimeter stimuli as painful regardless of their intensities (P ≤ 0.05). Additional analyses suggested that the high frequency of sexuall physical abuse in our patients was associated primarily with seeking health care for chronic pain rather than the FM syndrome itself or genetic factors. Conclusion. There is an association in FM patients between sexuall physical abuse and increased use of outpatient health care services and medications for pain. This association may be influenced by clinical symptoms, functional disability, psychiatric disorders, stress, and abnormal pain perception. The relationships among these variables should be further tested in prospective, population-based studies.