New Drug ReviewA Systematic Review of Drug Therapies for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis
Introduction
Chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a complex and debilitating disorder with an unknown etiology. Patients experience a substantial loss in quality of life, with severe disruption to daily activities.1 This disorder is heterogeneous in nature, with patients experiencing varied symptoms, at different severities, frequencies, and duration. Patients also report relapse and remission of their symptoms.2 Consequently, there are no universally acceptable approaches to treating and managing the syndrome, and patients are often prone to self-adjusting their medication regimens to try and enhance the treatment response.3
The unknown etiology and inconsistent presentation have hindered the formation and implementation of standardized diagnostic criteria.4, 5 The lack of standardization has resulted in CFS/ME becoming an umbrella term.6 Patients who experience general chronic fatigue but do not meet the other criteria, or experience fatigue as a result of an underlying condition, can be misdiagnosed with CFS/ME. Alternatively, those who may have CFS/ME are often misdiagnosed as having another illness due to lack of recognition.7 Progress toward establishing a well-defined diagnostic criterion was made in 1994 with the publication of the Fukuda criteria.8, 9 To meet these criteria, debilitating fatigue must be present for at least 6 months that substantially interferes with daily activities. In addition, ≥4 of the following symptoms must be present: postexertional malaise, difficulties with short-term memory or concentration, unrefreshing sleep, sore throat, muscle pain, joint pain, headaches, and tender lymph nodes. Although widely applied, the Fukuda criteria have been considered too broad,1 capturing a widely heterogeneous patient population.
In 2003, the Canadian Consensus1 definition was released that included the core requirements of the Fukuda criteria (chronic fatigue and postexertional malaise), with the additional requirements of symptoms specific to the neurologic, autonomic, endocrine, and immune body systems. The 2011 revision included renaming the definitions as the International Consensus Criteria (ICC) and emphasized the role of postexertional fatigue, which was labeled as postexertional neuroimmune exhaustion (PENE).10 PENE outlines the pathologic inability of patients with CFS/ME to produce sufficient energy on demand. This scenario includes a marked, rapid physical and/or cognitive fatigability in response to exertion; postexertional symptom exacerbation; postexertional exhaustion that may be immediate or delayed; a recovery period that is prolonged, usually taking ≥24 hours; and a low threshold of physical and mental fatigability. This more specific criteria may identify a homogeneous sample compared with the Fukuda criteria.1
The lack of a gold standard diagnostic criteria has prevented clinical trials from being conducted in consistent CFS/ME populations, and it has also prevented the application of results in different settings. Additional complications arise when factors such as ethnicity, age, and socioeconomic demographic factors are taken into account. In many cases, trials have suffered from poor external validity. Thus, universally applicable evidence-based research and practices are limited. Pharmacologic treatment of CFS/ME and management of symptoms is a research area that has proven to be inconsistent and inconclusive.11 Despite a lack of strong supporting evidence, however, patients with CFS/ME report using a great number and variety of medications.12
The aim of the present systematic review was to summarize and examine available clinical research on drug therapies in patients with CFS/ME, provide a comprehensive assessment of the effectiveness of these therapies, and identify how outcomes are being measured and whether these outcomes are appropriate.
Section snippets
Materials and Methods
Ovid MEDLINE, EMBASE, and PubMed databases were searched. The Medical Subject Headings used included the following: fatigue syndrome, chronic; myalgic encephalomyelitis; therapeutics; treatment; medication; complementary therapies; pharmaceutical preparations; drug therapy; vitamins; minerals; enzymes and coenzymes; anti-depressive agents; gastrointestinal agents or anti-inflammatory agents, non-steroidal; analgesic; anti-bacterial agents; non-prescription drugs; melatonin; symptom management;
Results
The search terms yielded a total of 1039 publications. Publications were assessed to determine if inclusion criteria were met. Twenty-six studies were identified,7, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 and 13 reported statistically significant results (Appendix A1 presents, in greater depth, the key findings from these included trials). Twenty drug therapies were trialed in these studies (Table II) and, of the 26 studies, 18 applied the
Discussion
To the best of our knowledge, this article is the first systematic review solely investigating therapeutic trials in patients with CFS/ME meeting specific diagnostic criteria. Eleven of the 20 medications identified in this review reported slight to moderate effectiveness according to different outcome measures. The most frequently used study outcomes to examine drug therapy effectiveness were fatigue, cognitive disability, and functional status. When examining pharmaceutical therapies, it is
Conclusions
This systematic review found that there is no clear recommended pharmaceutical therapy for CFS/ME, and the findings reinforce the need for standardized diagnostic criteria and outcome measurements. From the results, it is evident that despite some studies reporting significant outcomes, interpreting and applying those results in a different setting or to a different CFS/ME cohort will not necessarily yield the same findings. The results from these studies are limited to their respective
Conflicts of Interest
The authors have indicated that they have no conflicts of interest regarding the content of this article.
Acknowledgments
This study was conducted with support from the Alison Hunter Memorial Foundation, Change for ME, Mason Foundation, the Stafford Medical Research Foundation, the Edward P Evans Foundation, and Queensland Smart State funds.
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2019, Clinical TherapeuticsCitation Excerpt :The classification of patients into subgroups would facilitate research.8–10 However, the heterogeneity of patients with ME/CSF also interferes in studies, at 2 levels: (1) it might hinder the understanding of the molecular basis of the disease; and (2) treatments will be effective only if they target the effects of the disease, and treatments that act in intermediate or initial steps will be discarded.11 In addition, research on ME/CFS presents another challenge: how to obtain patient samples.
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2019, Journal of Contextual Behavioral ScienceCitation Excerpt :Results from recent studies indicate that low-grade inflammation could play a role, nevertheless, further studies are needed (Blundell, Ray, Buckland, & White, 2015; Lacourt, Vichaya, Chiu, Dantzer, & Heijnen, 2018; Montoya et al., 2017). Pharmacological and biological treatments have shown none or very weak evidence of efficacy in improving symptoms, functioning or quality of life (Collatz, Johnston, Staines, & Marshall-Gradisnik, 2016). As with many other longstanding somatic conditions, psychological factors are of importance for the illness impact on functioning and quality of life (Hall et al., 2014; Lattie et al., 2013).
Relationship Between Exercise-induced Oxidative Stress Changes and Parasympathetic Activity in Chronic Fatigue Syndrome: An Observational Study in Patients and Healthy Subjects
2019, Clinical TherapeuticsCitation Excerpt :While exercise normally induces hypoalgesic effects in healthy subjects, quickly increasing pain thresholds and improving subjective reports of pain symptoms,15–17 people with ME/CFS actually show a decrease in pain thresholds following exercise.18,19 The exact mechanisms underlying this lack of exercise-induced hypoalgesia in ME/CFS are largely unknown, as ME/CFS is heterogeneous in nature and several mechanisms co-occur.20–22 However, oxidative stress may reasonably be proposed as one of the underlying mechanisms.