Significant use of non-evidence-based therapeutics in a cohort of Australian fibromyalgia patients.

BACKGROUND: Fibromyalgia is a common condition characterised by chronic widespread musculoskeletal pain and central sensitivity features. Appropriate management requires a multidisciplinary approach prioritising non-pharmacological strategies. Evidence-based fibromyalgia medications are not always easily available, effective or tolerated. AIM: To characterise actual medication usage in Australian fibromyalgia patients. METHODS: Demographic and clinical data, including medication use information, were gathered by chart review from patients attending the Monash Fibromyalgia Clinic between January 2019 and June 2022. Eligible patients were invited to complete an anonymous questionnaire between June and August 2022 to assess current therapeutic use. The questionnaire assessed fibromyalgia clinical features by using the Revised Fibromyalgia Impact Questionnaire and the 2016 modified American College of Rheumatology Fibromyalgia criteria. RESULTS: The chart review included 474 patients, and 108 participants completed the questionnaire. Most chart review (78.7%) and questionnaire participants (85.2%) reported using at least one medication for their fibromyalgia. 48.5% of chart review patients and 58.3% of questionnaire participants reported using at least one evidence-based medication, usually amitriptyline, duloxetine or pregabalin. However, the most common individual medications for questionnaire participants were non-steroidal anti-inflammatory drugs (48.2%), paracetamol (59.3%) and opioids (34.3%), with most opioids being typical opioids. Among questionnaire participants, 14.8% reported using cannabinoids, and 70.4% reported using at least one supplement, vitamin or herbal/naturopathic preparation. Not all medication or substance use was recorded during clinic appointments. CONCLUSION: Fibromyalgia patients engage in various pharmacotherapeutic strategies that are not always evidence-based or disclosed to their treating clinicians.

Fibromyalgia, mood disorders, cognitive test results, cognitive symptoms and quality of life in systemic lupus erythematosus.

OBJECTIVES: Cognitive dysfunction, and comorbidities such as mood disorder and fibromyalgia, are common in SLE. This study aims to explore the associations between fibromyalgia, mood disorders, cognitive symptoms and cognitive dysfunction in SLE patients, and their impact on quality of life. METHODS: We tested cognition in SLE patients and healthy controls, and evaluated cognitive symptoms, mood disorder, fibromyalgia, fatigue and quality of life using patient-reported outcome measures. We examined associations of these comorbidities with both patient-reported cognitive symptoms and cognitive test performance. RESULTS: High fibromyalgia symptom score and history of depression or anxiety were associated with cognitive dysfunction. There were no significant associations between current depression, anxiety symptoms or fatigue score and objective cognitive dysfunction. In contrast, mood disorder symptoms, history of mood disorder, fibromyalgia symptoms and fatigue all had significant associations with patient-reported cognitive symptoms. There were no significant associations between patient-reported cognitive symptoms and objective cognitive dysfunction. Objective cognitive dysfunction, patient-reported cognitive symptoms, history of mood disorder and fibromyalgia symptoms all had significant associations with poorer quality of life; fibromyalgia had the biggest impact. CONCLUSIONS: Cognitive symptoms are common in SLE, but there were no associations between cognitive symptoms and objective cognitive dysfunction. Depression, anxiety and fibromyalgia were more consistently associated with patient-reported cognitive symptoms than with objective cognitive dysfunction. These factors all have a significant impact on quality of life. Understanding the discrepancy between patient-reported cognitive symptoms and cognitive test performance is essential to advance care in this area of unmet need.

Central sensitivity and fibromyalgia.

Fibromyalgia presents with symptoms of widespread pain, fatigue, sleeping and cognitive disturbances as well as other somatic symptoms. It often overlaps with other conditions termed 'central sensitivity syndromes', such as irritable bowel syndrome, chronic fatigue syndrome and temporomandibular disorder. Central sensitisation, mediated by amplified processing in the central nervous system, has been identified as the key pathogenic mechanism in these disorders. The term 'central sensitivity' can be used to describe collectively the clinical presentation of these disorders. Fibromyalgia is highly prevalent in most rheumatic diseases as well as non-rheumatic chronic diseases and if unrecognised results in high morbidity. It is diagnosed clinically after excluding important differential diagnoses. Diagnostic criteria have been developed as tools to help identify and diagnose fibromyalgia. Such tools can fulfil an important need when managing patients with rheumatic disease and other chronic diseases as a way to identify fibromyalgia and improve patient outcomes. Treatment involves an integrated approach including education, exercise, stress reduction and pharmacological therapies targeting the central nervous system. This approach is suitable for all presentations of central sensitivity and some central sensitivity syndromes have additional treatment options specific to the clinical presentation.

Fibromylagia.

BACKGROUND: Fibromyalgia is a common and debilitating condition. The cardinal feature of fibromyalgia is musculoskeletal pain, usually accompanied by other problems, such as fatigue, sleep disturbance and cognitive difficulties. Fibromyalgia commonly coexists with other chronic illnesses and can result in poorer outcomes if untreated. OBJECTIVE: The objective of this review is to discuss when fibromyalgia should be considered as a diagnosis, how it is diagnosed, the current understanding of the pathophysiology of fibromyalgia and the management strategies available. DISCUSSION: The features of fibromyalgia are similar to those of many other chronic illnesses, sometimes resulting in diagnostic confusion. Fibromyalgia can co-exist with other disorders and it is important to consider the possibility of fibromyalgia contributing to symptoms in any chronically ill patient.

Outcomes of Percutaneous Coronary Intervention in Patients With Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is the most common inflammatory arthritis and is associated with increased risk of cardiovascular events and mortality. Evidence regarding outcomes following PCI is limited. This study aimed to assess differences in outcomes following percutaneous coronary intervention (PCI) between patients with and without RA. The Melbourne Interventional Group PCI registry (2005 to 2018) was used to identify 756 patients with RA. Outcomes were compared with the remaining cohort (n = 38,579). Patients with RA were older, more often female, with higher rates of hypertension, previous stroke, peripheral vascular disease, obstructive sleep apnea, chronic lung disease, myocardial infarction, and renal impairment, whereas rates of dyslipidemia and current smoking were lower, all p <0.05. Lesions in patients with RA were more frequently complex (ACC/AHA type B2/C), requiring longer stents, with higher rates of no reflow, all p <0.05. Risk of long-term mortality, adjusted for potential confounders, was higher for patients with RA (hazard ratio 1.53, 95% confidence interval 1.30 to 1.80; median follow-up 5.0 years), whereas 30-day outcomes including mortality, major adverse cardiovascular events, bleeding, stroke, myocardial infarction, coronary artery bypass surgery, and target vessel revascularization were similar. In subgroup analysis, patients with RA and lower BMI (Pfor interaction < 0.001) and/or acute coronary syndromes (Pfor interaction = 0.05) had disproportionately higher risk of long-term mortality compared with patients without RA. In conclusion, patients with RA who underwent PCI had more co-morbidities and longer, complex coronary lesions. Risk of short-term adverse outcomes was similar, whereas risk of long-term mortality was higher, especially among patients with acute coronary syndromes and lower body mass index.

Key Milestones Contributing to the Understanding of the Mechanisms Underlying Fibromyalgia.

The promulgation of the American College of Rheumatology (ACR) 1990 criteria for fibromyalgia (FM) classification has significantly contributed to an era of increased research into mechanisms that underlie the disorder. The previous emphasis on putative peripheral nociceptive mechanisms has advanced to identifying of changes in central neural networks that modulate pain and other sensory processes. The influences of psychosocial factors on the dynamic and complex neurobiological mechanisms involved in the fibromyalgia clinical phenotype are now better defined. This review highlights key milestones that have directed knowledge concerning the fundamental mechanisms contributing to fibromyalgia.

The Relation of Physical Comorbidity and Multimorbidity to Fibromyalgia, Widespread Pain, and Fibromyalgia-related Variables.

OBJECTIVE: To investigate the relation of physical (non-psychological) comorbidity and multimorbidity to quantitative measures of fibromyalgia (FM) and musculoskeletal pain. METHODS: We studied 12,215 patients in a research databank with quantitative measures of FM-related variables (FMV) that included binary determinations of FM and widespread pain (WSP), and constituent variables of FM diagnosis that included the WSP index (WPI), the symptom severity score (SSS), and the polysymptomatic distress scale (PSD). We assessed self-reported comorbid conditions and covariates that included age, sex, body mass index, hypertension, smoking history, and total household income. We used nearest-neighbor matching and regression adjustment treatment effects models to measure the effect of comorbidities on FMV. RESULTS: We found a positive association between FMV and the probability of having each comorbid condition. Patients with ≥ 1 comorbidities had PSD, WPI, and SSS increases of 3.0 (95% CI 2.7-3.3), 1.8 (95% CI 1.6-2.0), and 1.2 (95% CI 1.1-1.3) units, respectively, and an increase in FM prevalence from 20.4% to 32.6%. As the number of comorbid conditions present increased from 1 to 4 or more, PSD, WPI, SSS, and FM percent increased stepwise. For patients with ≥ 4 conditions, the predicted prevalence of FM was 55.2%. CONCLUSION: FM and FMV are associated with an increase in the number of comorbidities, and the association can be measured quantitatively. However, the association of WSP and FM may be an effect of definitions of WSP and FM, because comorbidity increases are also present with subsyndromal levels of both conditions.

All-cause and cause-specific mortality in persons with fibromyalgia and widespread pain: An observational study in 35,248 persons with rheumatoid arthritis, non-inflammatory rheumatic disorders and clinical fibromyalgia.

PURPOSE: Studies of the relation of fibromyalgia (FM) and widespread pain (WSP) to mortality have differed as to the presence or absence of an association and the extent of cause-specific mortality. However, no studies have investigated which definitions of FM and WSP associate with mortality, nor of FM mortality in other diseases. We investigated these issues and the meaning of mortality in patients with FM. METHODS: We used Cox regression to study 35,248 rheumatic disease patients with up to 16 years of mortality follow-up in all patients and separately in those with diagnoses of rheumatoid arthritis (RA) (N = 26,458), non-inflammatory rheumatic disorders (NIRMD) (N = 5,167) and clinically diagnosed FM (N = 3,659). We applied 2016 FM criteria and other FM and WSP criteria to models adjusted for age and sex as well as to models that included a full range of covariates, including comorbid disease and functional status. We estimated the degree of explained of variance (R2) as a measure of predictive ability. RESULTS: We found positive associations between al`l definitions of FM and WSP and all-cause mortality, with relative risks (RR)s ranging from 1.19 (95%CI 1.15-1.24) for American College of Rheumatology (ACR) 1990 WSP to 1.38 (1.31-1.46) in age and sex adjusted revised 2016 criteria (FM 2016). However, in full covariate models the FM 2016 RR reduced further to 1.15 (1.09-1.22). The association with mortality was noted with RA (1.52 (1.43-1.61)), NIRMD (1.43 (1.24-1.66)) and clinical FM (1.41 (1.14-1.75) - where 37% of FM diagnosed patients did not satisfy FM 2016 criteria. In the all-patient analyses, the age and sex explained variation (R2) was 0.255, increasing to 0.264 (4.4%) when FM 2016 criteria were added, and to 0.378 in a full covariate model. Death causes related to FM 2016 status included accidents, 1.45 (1.11-1.91); diabetes 1.78 (1.16-2,71); suicide, 3.01 (1.55-5.84) and hypertensive related disorders, 3.01 (1.55-5.84). Cancer deaths were less common 0.77 (0.68-0.88). CONCLUSIONS: FM is weakly associated with mortality within all criteria definitions of FM and WSP examined (3.4% of explained variance), and across all diseases (RA, NIRMD, clinical FM) equally. Clinical and criteria-defined FM had different mortality outcomes. We found no evidence for a positive association of cancer and FM or WSP.

Chronic pain syndromes: overlapping phenotypes with common mechanisms.

The common chronic pain syndromes of fibromyalgia, regional pain syndrome, and complex regional pain syndrome have been made to appear separate because they have been historically described by different groups and with different criteria, but they are really phenotypically accented expressions of the same processes triggered by emotional distress and filtered or modified by genetics, psychology, and local physical factors.

Neurogenic inflammation in fibromyalgia.

Fibromyalgia is a high impact chronic pain disorder with a well-defined and robust clinical phenotype. Key features include widespread pain and tenderness, high levels of sleep disturbance, fatigue, cognitive dysfunction and emotional distress. Abnormal processing of pain and other sensory input occurs in the brain, spinal cord and periphery and is related to the processes of central and peripheral sensitization. As such, fibromyalgia is deemed to be one of the central sensitivity syndromes. There is increasing evidence of neurogenically derived inflammatory mechanisms occurring in the peripheral tissues, spinal cord and brain in fibromyalgia. These involve a variety of neuropeptides, chemokines and cytokines with activation of both the innate and adaptive immune systems. This process results in several of the peripheral clinical features of fibromyalgia, such as swelling and dysesthesia, and may influence central symptoms, such as fatigue and changes in cognition. In turn, emotional and stress-related physiological mechanisms are seen as upstream drivers of neurogenic inflammation in fibromyalgia.

Fibromyalgia remains a significant burden in rheumatoid arthritis patients in Australia.

AIM: High rates of fibromyalgia (FM) are reported in rheumatoid arthritis (RA) patients. Advances in RA management have occurred, but information regarding current significance of FM in RA is limited. This investigation estimated the prevalence and health effects of concomitant FM in Australian RA patients. METHODS: Participants were recruited from Australian rheumatology clinics. Subjects were assessed using the 1990 and 2011 American College of Rheumatology (ACR) FM criteria and the polysymptomatic distress score (PDS) was calculated. A medical history and a clinical examination were recorded. RA Disease Activity Score of 28 joints - erythrocyte sedimentation rate (DAS-28 ESR), and the Short Form-36 survey (SF-36) were completed. RESULTS: Of 117 RA patients, 33.3% (n = 39) met 1990 ACR FM criteria and 41.9% (n = 49) met 2011 ACR FM criteria. RA patients with comorbid FM had worse outcomes across all domains of health as defined by the SF-36 (P < 0.05). There was correlation between both physical and mental health outcomes and the PDS (P < 0.001). RA patients with FM on average took 1.18 extra ongoing prescribed medications (P < 0.05), despite comparable RA disease activity (DAS-28: 3.09 vs. 3.27, P = NS). Comorbid central sensitivity conditions were more common in patients with FM (P < 0.001). CONCLUSION: FM continues to demonstrate a high prevalence in a population of RA patients. RA patients with FM have more symptoms of other chronic sensitivity syndromes in addition to FM. They have a lower quality of life outcome and higher medication use. This has important clinical implications in terms of diagnosis, response to therapy, prescribing choices and clinical outcomes.

Modulation of NMDA Receptor Activity in Fibromyalgia.

Activation of the N-methyl-d-aspartate receptor (NMDAR) results in increased sensitivity of spinal cord and brain pathways that process sensory information, particularly those which relate to pain. The NMDAR shows increased activity in fibromyalgia and hence modulation of the NMDAR is a target for therapeutic intervention. A literature review of interventions impacting on the NMDAR shows a number of drugs to be active on the NMDAR mechanism in fibromyalgia patients, with variable clinical effects. Low-dose intravenous ketamine and oral memantine both show clinically useful benefit in fibromyalgia. However, consideration of side-effects, logistics and cost need to be factored into management decisions regarding use of these drugs in this clinical setting. Overall benefits with current NMDAR antagonists appear modest and there is a need for better strategy trials to clarify optimal dose schedules and to delineate potential longer-term adverse events. Further investigation of the role of the NMDAR in fibromyalgia and the effect of other molecules that modulate this receptor appear important to enhance treatment targets in fibromyalgia.

Fibromyalgia has a high prevalence and impact in cardiac failure patients.

OBJECTIVE: Chronic cardiac failure (CCF) shares several clinical features with fibromyalgia (FM), a syndrome of increased central sensitivity and musculoskeletal pain. FM frequently coexists with other chronic illness. Musculoskeletal pain is reported in patients with CCF; however, the prevalence and impact of FM in patients with CCF is not known. This research aims to assess the prevalence and effects of concurrent FM in patients with CCF and to identify other coexisting central sensitivity syndromes. MATERIAL AND METHODS: In a cross-sectional study, demographic, clinical, and functional information was gathered from participants with CCF from public and private clinics. Cardiac failure severity was rated using the New York Heart Association (NYHA) scale. FM diagnosis was determined using 2011 American College of Rheumatology (ACR) criteria. The short-form 36 (SF-36) assessed overall health function. RESULTS: Of the 57 CCF participants (63.2% male, mean age 70.3 years), 22.8% (n=13) met FM diagnostic criteria. CCF patients with FM had poorer outcomes across multiple SF-36 domains (p<0.05), compared to those without, despite having comparable CCF severity. Those with FM were more likely to report other central sensitivity syndromes, especially temporomandibular joint dysfunction (mean Δ=23%, p<0.05), headache (mean Δ=28.8%, p<0.05), and irritable bladder (mean Δ=14%, p<0.05). CONCLUSION: High prevalence of FM was found in patients with CCF. This was associated with increased likelihood of other comorbid central sensitivity syndromes and with poorer clinical outcomes. The recognition of coexisting FM in patients with CCF provides an important opportunity to improve health outcomes by managing FM-related symptoms, in addition to symptoms that relate specifically to CCF.

Fibromyalgia syndrome: which antidepressant drug should we choose.

Fibromyalgia syndrome [FM] has core clinical features of widespread pain and widespread abnormal tenderness. The specific cause of the altered neurophysiology that underpins these clinical manifestations remains unclear. However, increased sensitisation of neural networks that relates to pain, as well as interacting mechanoreceptors, appear important targets for modulation by pharmacological agents. Further, many FM patients have emotional distress and some are depressed. Antidepressant agents have therapeutic benefits in FM. If depression is present antidepressant drugs will provide typical benefits to mood but not always to other key outcome measures, such as pain or tenderness. Selective serotonin receptor reuptake blockers are not as effective for overall FM improvement as drugs that block both serotonin and norepinephrine in a relatively balanced way. Thus tricyclic antidepressants will improve many important FM outcomes but are effective in only about 40 percent of individuals. Newer agents of this class, such as duloxetine and milnacipran, show improvement in key FM outcomes in about 60 percent of patients. Longer term studies will indicate the durability of these responses and the overall tolerance of the drugs. Any drug therapy will need to be integrated with appropriate education, exercise and attention to psychological modulatory factors to achieve best results.

Is there a role for opioids in the treatment of fibromyalgia?

The use of opioids for chronic pain has increased significantly due to a combination of the high patient burden of pain and the more widespread availability of a range of long-acting opioid preparations. This increased opioid use has translated into the care of many patients with fibromyalgia. The pain mechanism in fibromyalgia is complex but does not seem to involve disturbance of opioid analgesic functions. Hence, there is general concern about the harms in the absence of benefits of opioids in this setting. There is no evidence that pure opioids are effective in fibromyalgia but there is some evidence that opioids with additional actions on the norepinephrine-related pain modulatory pathways, such as tramadol, can be clinically useful in some patients. Novel actions of low-dose opioid antagonists may lead to better understanding of the role of opioid function in fibromyalgia.

Treatment of fatigue in fibromyalgia.

Clearly, fatigue is a large and challenging problem for those suffering from fibromyalgia. It adds greatly to the morbidity and disability associated with the disease. In the management of this specific symptom in fibromyalgia, attention should first be focused on identifying comorbidities that may be present and contribute to fatigue. As with other symptoms of fibromyalgia, education is a critical component of management. This can be done by the practitioner, with available free resources, or with specialized cognitive behavioral programs. This education process can be augmented with a variety of other nonpharmacologic therapies, especially very gradually increasing, low-impact, aerobic exercise programs. Numerous pharmacologic therapies may also be helpful as an adjunct to treatment. Classes of compounds that raise central levels of norepinephrine or dopamine appear to be the most specific for management of fatigue. There are also many medications used to combat fatigue in other disorders that have not yet been adequately explored as to the possible benefits in alleviating the fatigue of fibromyalgia. Advances in the management of fatigue in fibromyalgia are likely to come from a variety of directions. Easier access to well designed nonpharmacologic therapies is essential, because these treatments are underutilized in clinical practice at present. Improvements in pharmacologic therapies will come from new insights into mechanisms, especially those that might only be present in subsets of patients and would respond to more targeted therapies.

GILZ: Glitzing up our understanding of the glucocorticoid receptor in psychopathology.

Dysfunction of the hypothalamic-pituitary-adrenal axis, particularly the glucocorticoid receptor, is a commonly implicated link between stress and psychopathology. GR abnormalities are frequently reported in depression, and these anomalies must be resolved before depressive symptoms remit. This biological finding is rendered clinically relevant by the knowledge that only select antidepressants alter GR function. The relationship between GR dysfunction and other diseases associated with psychiatric stress, such as post-traumatic stress disorder (PTSD) and fibromyalgia, is also documented. However, as laboratory constraints limit the utility of GR testing, other measures of GR activity, such as levels of GR-induced genes, may have greater clinical value. In this review, glucocorticoid-induced leucine zipper (GILZ), a product of GR-initiated gene transcription, will be discussed in the context of GR dysfunction in psychopathology.

Clinical characteristics of 150 consecutive fibromyalgia patients attending an Australian public hospital clinic.

AIM: To describe clinical characteristics of fibromyalgia in an Australian population. METHOD: Data was collected from 150 consecutive patients with clinical features of fibromyalgia seen in an Australian public hospital clinic. Demographic information and clinical characteristics were recorded. Significant correlations between clinical characteristics were identified, then used in multiple regression analyses to identify factors influencing outcome in physical function, pain, fatigue and sleep disturbance. Clinical features in groups who were or were not using different treatment strategies were compared. RESULTS: Most patients were female and Caucasian. The majority reported a recognizable trigger factor and many had associated conditions, most commonly headache and irritable bowel syndrome. Physical function was significantly accounted for by pain levels (P = 0.001); pain score was significantly predicted by tenderness (P = 0.002) and physical function level (P = 0.001); fatigue levels were significantly influenced by age (P = 0.007) and sleep disturbance (P < 0.001), and sleep disturbance was significantly predicted by fatigue (P < 0.001). Just over one-third (34%) of patients were using fibromyalgia medications (low-dose tricyclic antidepressant, pregabalin or duloxetine); however, they had less anxiety (P = 0.006) and better reported physical function (P = 0.04) than those who were not. Less than half (43.6%) of the patients were regularly exercising; however, they had reduced overall illness impact scores (P = 0.004), better physical function (P = 0.01) and less fatigue (P = 0.03), anxiety (P = 0.02) and depressive features (P = 0.008) than non-exercisers. CONCLUSION: Baseline clinical characteristics in this group were comparable to other study populations. The use of management modalities with proven benefit in fibromyalgia was limited; however, those patients who were engaged in regular exercise or using medication had better self-reported outcome measures than those who were not.

The use of opioids in fibromyalgia.

Fibromyalgia syndrome (FMS) is a chronic disorder of widespread pain with high personal and societal burdens. Although targeted pharmacotherapies have become available in recent years, it remains a challenging condition to treat. Despite no randomized controlled trials addressing the short- or long-term use of opioids in FMS, their use remains prevalent. In this article we discuss the role of opioids and other analgesics in the management of FMS, with particular focus on problems associated with their use. We review aspects of the pathophysiology of FMS and consider how specific factors may contribute to the lack of efficacy of opioids in this condition. Finally, we discuss drugs with combined opioid and anti-opioid action and their roles in FMS. There is insufficient evidence to recommend the routine use of opioids in FMS. As well as having a significant adverse effect profile, their inefficacy may be due to their inability to target the pathophysiologic processes involved in this central sensitization syndrome.