Treatment of chronic fatigue syndrome (CFS) is variable and uncertain, and the condition is primarily managed rather than cured.[1] Only two treatments, cognitive behavioral therapy and graded exercise therapy, have demonstrated reproducible evidence for their efficacy in ambulant (non-severely affected) patients. Other proposed treatments include medications, medical treatments, and complementary and alternative medicine. Even when treated, the prognosis of CFS is often poor.[2] In one study, poor early management was reported to be a main risk factor for severe CFS (delayed diagnosis, poor response to analgesics, physiotherapy, or complementary therapy), with associated variables including a poor relationship with the GP before and after diagnosis, and the involvement of a psychiatrist in initial treatment.[3]
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CFS management techniques include behavioral interventions such as cognitive behavioral therapy (CBT, a form of psychological therapy), and graded exercise therapy (GET). Based on evidence from multiple randomized clinical trials (RCTs), a systematic review published in the Journal of the Royal Society of Medicine (October 2006) stated that CBT and GET interventions showed promising results, appearing to reduce symptoms and improve function. The review stated that the evidence of effectiveness was inconclusive for most other interventions, with some reporting significant adverse effects. The wide variety of outcome measures used in CFS research was found to be a "fundamental problem" for assessing the effectiveness of interventions in general, and no intervention has proven to be effective in restoring the ability to work.[4]
According to the cognitive-behavioural model of illness, the patient's interpretation of symptoms plays an important role in perpetuating the illness. CBT aims to help the patient change these negative beliefs with the goal being either to reduce the symptoms, help the patient cope with the illness, or to fully recover.[5]
A systematic review of RCTs found that there is moderate evidence of benefit for CBT in CFS, but that the effectiveness of CBT for CFS outside of specialist settings has been questioned and the quality of the evidence is low.[6] A 2008 Cochrane review of CBT concluded, "CBT is more effective than usual care for reducing fatigue symptoms in adults with CFS, with 40% of participants assigned to CBT showing clinical response at post-treatment, in comparison with 26% assigned to usual care control.", however, it also stated that the benefits of CBT in sustaining clinical response at follow up are inconclusive, and there were no conclusive improvements to physical functioning, depression, anxiety or psychological distress at either post treatment or later follow-up. Data on adverse effects were not systematically presented by any included study. The review also concluded that while the quantity and quality of the evidence has grown in recent years "there is a surprising lack of high quality evidence on the effectiveness of CBT alone or in combination with other treatments to inform the development of clinical management programmes for people with CFS".[7] One uncontrolled study with no follow-up found that CBT could facilitate full recovery in some patients, with 69% of the patient cohort no longer meeting the CDC criteria for CFS and "full recovery" occurring in 23% of CFS patients after CBT using the most comprehensive definition of recovery.[8]
Another systematic review on CBT[4] finds that "CBT was associated with a significant positive effect on fatigue, symptoms, physical functioning and school attendance.", but had not proved to be effective in restoring the ability to work. The reviewers state that the quality of many recent trials on CBT are lower quality randomized controlled trials or trials that did not involve random allocation. The reviewers also state that one recent, good quality trial of CBT in children and adolescence supports the effectiveness of CBT. The reviewers state that reasons for withdrawals typically remain unreported, and that a degree of publication bias seems to be present in CFS/ME literature as a whole. In one study, the effect of CBT has been demonstrated up to five years after therapy.[9]
A 2007 meta-analysis found that the effectiveness of CBT depends on the diagnostic criteria used, with studies using the Oxford criteria having a trend towards significantly higher effect sizes that those using the CDC criteria. The review also notes that CBT for chronic fatigue disorders has about the same efficacy as diverse psychological treatments for a variety of psychological disorders.[10]
A 2010 meta-analysis of trials that measured physical activity before and after CBT showed that although CBT effectively reduced fatigue, activity levels were not improved by CBT and changes in physical activity were not related to changes in fatigue. They conclude that the effect of CBT on fatigue is not mediated by a change in physical activity.[11]
According to a 2006 systematic review, "very few studies have assessed the effectiveness of interventions for children and young people and for severely affected patients. The effectiveness of CBT for adolescents is supported by a recent high-quality RCT, although this had only 69 participants." Currently there is no research into the effectiveness of CBT for the severely affected, and these patients may be effectively excluded from trials due to the need to attend a clinic.[4] Some CBT trials suffer from large dropout rates, up to 42% in one study, with a mean dropout rate of 16%. This compares to a 17% dropout rate in a trial of 432 patients receiving CBT for anxiety, "so is not unusually high" according to a 2007 meta-analysis.[10]
CBT has been criticised by patients' organisations because of negative reports from some of their members[12] which have indicated that CBT can sometimes make people worse,[13] a common result across multiple patient surveys.[14] One such survey conducted by Action for ME in 2001 found that out of the 285 participants who reported using CBT, 7% reported it to be helpful, 67% reported no change, and 26% reported that it made their condition worse.[15] A subsequent survey in 2008 reported that 50% of patients found CBT helpful, 38% reported no change, and 12% felt that it made their illness worse, though it remained among the lowest-rated treatments in the survey despite the significant increase.[16]
A 2008 Cochrane systematic review included 4 studies which used group CBT and concluded that it was less effective than individual CBT at reducing fatigue at post-treatment.[7] A 2007 meta-analysis stated that the one included study which tested group CBT had produced a similar effect to the other studies using individual CBT.[10] In a more recent study of a multidisciplinary intervention which combined group CBT and GET with pharmacological treatment, at 12 months after completion this intervention was "slightly inferior" to usual care alone, resulting in no improvements to fatigue or health related quality of life, and worse physical function and bodily pain scores.[17]
A study which included 45 CFS patients found that psychodynamic counselling has comparable effectiveness to cognitive behavioral therapy (CBT) in the treatment of chronic fatigue.[18]
Some CFS patients have comorbid depression and/or anxiety.[19] Children have been successfully treated using antidepressants and therapy.[20] A 2009 survey of two Norwegian patient organizations (ME-association and MENiN) had found that out of 828 participants with CFS, 57% of those who had received help to "identify and challenge negative thought patterns" regarded this as useful.[21]
Two systematic reviews cautiously conclude that some patients may benefit from graded exercise therapy (GET), although there are some limitations with the evidence and the generalizability of the findings.[4][22]
A 2004 Cochrane systematic review included 5 eligible studies on GET and found statistically significant improvements to self-reported fatigue severity and physical functioning. This benefit was sustained after 6 months but became non-significant compared to the control group who did not receive GET. Functional work capacity was not significantly improved. GET had a tendency towards higher dropout rates, and although there was no evidence that exercise therapy worsened outcomes on average, no data was reported for adverse effects. The authors state that the evidence base and the precision of the results are limited, and encourage higher quality studies "that involve different patient groups and settings, and that measure additional outcomes such as adverse effects, quality of life and cost effectiveness over longer periods of time".[22]
A 2006 systematic review published in the Journal of the Royal Society of Medicine included 5 eligible studies on GET and found an overall effect in the reduction of symptoms and improvement to physical functioning. GET had not been proven to restore the ability to work. Withdrawals were noted in some GET studies but difficult to interpret due to the poor reporting of adverse effects. The protocols for many clinical studies may have biased the sample towards those with less severe symptoms, and severely affected patients were not included in the studies of GET. The authors state the need for research to "define the characteristics of patients who would benefit from specific interventions and to develop clinically relevant objective outcome measures."[4]
A New Zealand study suggests that GET may result in self-reported improvement in part by "reducing the degree to which patients focus on their symptoms."[23] To avoid detrimental effects from GET, care must be taken to avoid the exacerbation of symptoms while catering the program to individual capabilities and the fluctuating nature of symptoms.[24]
Patient organisations' surveys commonly report adverse effects[12][13][14][15] with a survey of two Norwegian patient organizations (ME-association and MENiN) reporting that 79% of those with experience with graded training regarded this to worsen their health status.[21]
Pragmatic rehabilitation is "a programme of gradually increasing activity designed collaboratively by the patient and the therapist". In response to an earlier successful trial, a larger trial was conducted, known as Fatigue Intervention by Nurses Evaluation. In the FINE trial, patients fulfilling Oxford 1991 CFS criteria who were allocated to pragmatic rehabilitation reported a statistically significant but "clinically modest" improvement in fatigue when compared to patients allocated to either "supportive listening" or "treatment as usual", but after 12 months follow-up there were no statistically significant differences. There was no significant improvement to physical functioning at any time. About 10% of the trial participants were non-ambulatory and about 30% met London ME criteria, but separate results for these groups were not published.[25] In an accompanying editorial, possible reasons are given for why the earlier success was not replicated in this trial, and further research is encouraged; the patients in this trial had higher comorbidity and disability than patients in the earlier trial or most other trials, and received less sessions than most successful trials of CBT and GET. The question was also raised whether generalists are as successful as specialists in offering behavioural interventions.[26]
Pacing techniques encourage behavioral change, but unlike cognitive behavioural therapy, acknowledges the typical patient fluctuations in symptom severity and delayed exercise recovery.[27] Patients are advised to set manageable daily activity/exercise goals and balance their activity and rest to avoid possible over-doing which may worsen their symptoms. Those that are able to function within their individual limits may then try to gradually increase activity and exercise levels (GET) while maintaining pacing methods. The goal is to increase over time the level of routine functioning of the individual.[24] A small randomised controlled trial concluded pacing with GET had statistically better results than relaxation/flexibility therapy.[28][27] A 2008 patient survey by Action for ME found pacing to be the most helpful treatment[16] and a 2009 survey of two Norwegian patient organizations (ME-association and MENiN) had found that 96% evaluated pacing as useful.[21]
The PACE trial was a large-scale five-year trial funded by the UK government which compared the efficacy and safety of four treatments: specialist medical care (SMC), SMC with CBT, SMC with GET, and SMC with adaptive pacing therapy (APT). The results were published in February 2011 and showed that CBT and GET were, when combined with SMC, each "moderately" effective compared to SMC alone. APT was not found to be effective when added to SMC.[29][30]
Out of 3158 potential participants screened for eligibility, about 80% of candidates were excluded and 641 patients meeting the Oxford criteria for CFS were recruited. 160 were assigned to the APT group, 161 to the CBT group, 160 to the GET group and 160 to the SMC group. SMC alone reduced mean fatigue scores by 4.5, SMC with CBT reduced scores by 7.4 and SMC with GET reduced scores by 7.6. The addition of APT made no statistical difference. Physical functioning scores were also improved by CBT and GET compared to APT or SMC alone.
All patients met Oxford criteria, and when further stratified into groups of patients that also met the international CDC criteria and/or the London criteria for ME, a subgroup analysis found no significant differences in outcomes between the groups - in all cases CBT and GET resulted in statistically significant moderate improvements compared to SMC alone or APT.
CBT was done on the basis of the fear avoidance theory of chronic fatigue syndrome. This theory regards chronic fatigue syndrome as being reversible and that cognitive responses(fear of engaging in activity) and behavioural responses (avoidance of activity) are linked and interact with physiological processes to perpetuate fatigue. The aim of treatment was to change the behavioural and cognitive factors assumed to be responsible for perpetuation of the participant’s symptoms and disability.[30]
Graded exercise therapy (GET) was done on the basis of deconditioning and exercise intolerance theories of chronic fatigue syndrome. These theories assume that the syndrome is perpetuated by reversible physiological changes of deconditioning and avoidance of activity. These changes result in the deconditioning being maintained and an increased perception of effort, leading to further inactivity. The aim of treatment was to help the participant gradually return to appropriate physical activities, reverse the deconditioning, and thereby reduce fatigue and disability.[30]
The trial reported that CBT and GET were "safe". A serious adverse event was defined as either: death, life-threatening, hospitalisation, increased severe disability for at least 4 weeks duration, any episode of deliberate self-harm. Serious adverse reactions to the therapies were recorded in two (1%) of the 159 patients in the APT group, three (2%) of the 161 patients in the CBT group, 2 (1%) of the 160 patients in the GET group and two (1%) of the 160 patients in the SMC group.
Limitations of the trial included the fact that patients younger than 18 years of age and those not able to attend hospital were excluded.
The trial generated a furious response from patient groups and campaigners. Letters to the editor critiqued the definitions of secondary outcomes, questioned protocol changes, and expressed concern over generalisability of the results. Professor Malcolm Hooper branded the results "unethical and unscientific" and submitted a 442 page response to the Medical Research Council and a shorter 43-page complaint to the Lancet. The MRC and the Lancet have considered the submissions and rejected them. A Lancet editorial conjectured that the strong negative response might be due to the dismay over the debilitating illness, "but also from an active campaign to discredit the research."[31][32]
In subsets of patients, various viruses have been reported as the causative agents of CFS, see Pathophysiology of chronic fatigue syndrome although so far consistent and compelling supportive evidence is still lacking.[33] Others consider that treatment studies of subtypes may reduce the inconsistencies [34] A number of antiviral treatment studies have been conducted with inconsistent results.
Nucleic acid (double-stranded RNA) compounds represent a potential new class of pharmaceutical products that are designed to act at the molecular level, it is an inducer of interferon and is considered to be antiviral and immunomodulatory.
One RCT evaluated Ampligen and found an overall beneficial effect.[35] In December 2009 the U.S. Food and Drug Administration (FDA) refused to approve a New Drug Application to market and sell Ampligen for treatment of CFS. The FDA concluded that the two RCTs submitted "did not provide credible evidence of efficacy."[36]
Nucleosidic class drugs such as acyclovir, valacyclovir and ganciclovir are inhibitors of viral replication during DNA (for DNA- and retroviruses) or RNA (for RNA viruses) multiplication.[37]
A small 1988 RCT compared acyclovir against placebo and found that an equal proportion of patients improved from placebo and with active treatment. The authors concluded that the improvement reflected either spontaneous remission or the placebo effect.[38] Three people withdrew from acyclovir treatment due to reversible renal failure.[35]
A systematic review found two small RCTs that evaluated interferon.[35] One RCT found an overall beneficial effect and the other showed some positive effects in relation to immunological outcomes only. The quality of both of these studies was considered poor.[35] A 2007 review of research needs for CFS concluded that trials for interferon beta are an important priority.[39]
A systematic review found five RCTs to have assessed the effects of immunoglobulin treatment for CFS;[35] of these, two RCTs showed an overall beneficial effect and two RCTs showed some positive results, although in one of the studies this was for physiological effects only. The largest of the RCTs found no effect for the treatment. Another review concluded that "Given the weak evidence of benefit for immunotherapy, the potential harms indicate that it should not be offered as a treatment for CFS."[6]
There is a striking paucity of RCTs evaluating pharmacological treatments in CFS.[40] No pharmacological treatments have been established as a cure for CFS, but various drugs are used to manage the symptoms of CFS.
Antidepressants are often prescribed to CFS patients. Their purpose can be to treat secondary depression or mood swings, but low dosage tricyclic antidepressants are sometimes prescribed to improve sleep quality and reduce pain.[41]
The evidence for antidepressants is mixed[42] and their use remains controversial.[43] In a review of pharmacological treatments for CFS, 5 trials of antidepressants were included but only one of these reported a statistically significant improvement in symptoms and this effect was only observed in patients who received 12 weeks of CBT before starting treatment with mirtazapine.[40]
Treatment with steroids such as cortisol and thyroid hormones has been studied.
There have been 7 RCT’s, four trialling hydrocortisone, 2 with fludrocortisone and one with hydrocortisone plus fludrocortisone . Two RCT’s have found overall benefit for hydrocortisone, but it has not been recommended for clinical use.
A 2006 systematic review found one low-quality RCT of hydrocortisone which found a significant difference between groups for fatigue, but two other RCTs found no benefit for steroid treatment.[44]
A randomized, placebo-controlled, double-blind therapeutic trial, conducted between 1992 and 1996 in a tertiary care research institution. 70 patients met the CDC criteria many comorbid with psychiatric diagnosis but who withheld concomitant treatment with other medications. Although hydrocortisone treatment (at a higher dose of 20–30 mg) was associated with some statistical improvement in symptoms of CFS, the authors concluded a degree of adrenal suppression precludes its practical use for CFS.[45]
A poor quality randomized, double-blind, placebo-controlled crossover study in 26 patients with CFS of reduced nicotinamide adenine dinucleotide NADH reported positive results in 1999. No severe adverse effects were observed related to the study drug.[46]
The RCT had several problems with its methods and a review concluded that there is no good evidence that NADH is of benefit for CFS patients.[6]
An October 2011 study from Norway suggests that the cancer chemotherapy rituximab can help patients with chronic fatigue syndrome.[47] A clinical trial has been completed and a new open-label trial has begun.[48][49][50]
There have been 2 RCT’s with staphylococcal toxoid vaccine. A small RCT showed considerable benefit[51] and a large follow up RCT showed overall benefit. However the quality of the follow-up RCT was low and there were relatively high levels of adverse effects. A review concluded that there is insufficient evidence for treatments of this type.[44]
People with CFS may use more alternative medicine treatments than people without CFS.[52] In a twin study, 91% of twins with CFS and 71% without CFS used at least one alternative treatment. A large proportion of the study participants said alternative treatments were helpful.[53]
A 2006 updated systematic review concluded that the supplements essential fatty acids and magnesium, have shown beneficial effects but only in one or two trials and further rigorous trials of these interventions would be helpful.[44] A 2008 review found insufficient evidence to recommend dietary supplements as a treatment in chronic fatigue syndrome. One RCT compared a polynutrient supplement (containing several vitamins, minerals, and coenzymes, taken twice daily) with a placebo for 10 weeks, but found no difference in fatigue scores.[6]
L-Carnitine is an amino acid which includes ALC, a group of natural compounds that have an important role in cellular function. It is required for the transport of fatty acids into the mitochondria during the breakdown of lipids(or fats) for the generation of metabolic energy including in muscles and in the brain.[54] Two RCTs found benefit from dietary supplementation with L-carnitine or its esters. A 2006 systematic review reported one RCT with overall benefit, although there was no placebo control.[44]
In 2008 a randomised double blind placebo controlled 6 months trial on 96 aged subjects with CFS symptoms administering Acetyl L Carnitine was reported. By the end of the treatment, significant differences between the two groups were found for both physical and mental fatigue and improvements in both the cognitive status and physical functions.[55]
A randomized controlled trial on patients diagnosed with post viral fatigue syndrome (PVFS) and deficient RBC levels, using essential fatty acids consisting of evening primrose oil containing n-6 GLA together with fishoil concentrate containing n-3 EPA and DHA showed significant overall improvement in symptoms and RBC essential fatty acid levels.[56] However a subsequent RCT trying to replicate this study found no significant differences between the treatment and placebo group after treatment, and no significant differences in pre-treatment red-cell membrane lipids between the two groups.[57] The different results may be explained by the patient selection: the first trial tested people with PVFS, whereas the second used the Oxford criteria for CFS. Also, the first trial used paraffin while the second trial used sunflower oil which is better tolerated and less likely to adversely affect the placebo group. [6]
Positive results from a trial of magnesium delivered by injection to magnesium-deficient CFS patients were published in 1991,[58] but three subsequent studies did not find magnesium deficiency as a general problem in CFS patients. A 2008 review concluded that there is no good evidence that intramuscular magnesium is of benefit in CFS.[6]
Both oral and injected Vitamin B12 have been suggested as treatments for generalized fatigue since the 1950s, however recent studies do not suggest any benefit from it, either for generalized fatigue or CFS specifically. Further research is needed, however, as studies to date have been small and used inconsistent dosing regimens.[59]
It was previously assumed that placebo response rates in patients with chronic fatigue syndrome (CFS) are unusually high, "at least 30% to 50%", because of the subjective reporting of symptoms and the fluctuating nature of the condition. However, a meta-analysis found that the pooled response rate in the placebo group was 19.6%, lower than the usually reported one third response in other medical conditions. The authors offer possible explanations for this result: CFS is widely understood to be difficult to treat, which could reduce expectations of improvement. In context of evidence showing placebos do not have powerful clinical effects when compared to no treatment, a low rate of spontaneous remission in CFS could contribute to reduced improvement rates in the placebo group. Intervention type also contributed to the heterogeneity of the response, low patient and provider expectations regarding psychological treatment may explain particularly low placebo responses to psychiatric treatments.[60]
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