Pharmaceutical Interventions in the Treatment of Chronic Fatigue Syndrome: A Literature-based Commentary

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disorder characterized by prolonged periods of fatigue, chronic pain, depression, and a complex constellation of other symptoms. Currently, ME/CFS has no known cause, nor are the mechanisms of illness well understood. Therefore, with few exceptions, attempts at treating ME/CFS have been directed mainly towards symptom management. These treatments include antivirals, pain relievers, antidepressants, and oncologic agents as well as other single-intervention treatments. Results of these trials have been largely inconclusive and, in some cases, contradictory. Contributing factors include a lack of well-designed and executed studies and the highly heterogeneous nature of ME/CFS, which has made a single etiology difficult to define. Because the majority of single-intervention treatments have shown little efficacy, it may instead be beneficial to explore broader-acting combination therapies where a more focused precision medicine approach is supported by a systems-level analysis of endocrine and immune co-regulation.

Introduction

The management of complex multi-factorial chronic diseases is often marred by a confluence of partially or entirely ineffectual treatments. Due to the many symptoms displayed by those affected, there is very often no single clear path to treatment or symptom management. Myalgic encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/CFS), is a disease characterized by an inability to exert oneself physically, often coupled with a combination of other symptoms, including sleep disorders, severe unpredictable pain, and compromised cognitive abilities. Those suffering from ME/CFS experience prolonged (six months or greater) periods of exhaustion that is not relieved by rest¹. The exact etiology of ME/CFS is currently unknown² though multiple hypotheses exist regarding potential triggers and mechanisms of illness, including viral infection^3,4, mitochondrial dysfunction⁵, and neurological abnormalities^6–8. Ultimately, there may be no single underlying cause for this illness and it is not improbable that ME/CFS may serve as an umbrella term for multiple different diseases associated with overlapping symptoms⁹. The diversity in symptom profiles and potential etiologies associated with ME/CFS make treatment and management of this illness extremely challenging and a treatment that may be effective for one subset of individuals may not be effective for another.

As a result of this uncertainty regarding the underlying mechanisms of illness in ME/CFS, most attempts at pharmacological treatment have focused on reduction in the severity of specific subsets of symptoms. This summary overview delineates a number of the more prominent treatments for ME/CFS into different categories, and evaluates the methods and results of corresponding drug trials (Figure 1). Drugs including pain relievers (both specific and non-specific non-steroidal anti-inflammatory drugs or NSAIDS), antidepressants (MAO inhibitors, SNRIs, and SSRIs), antivirals, and antihistamines have been identified as possibly beneficial in treating ME/CFS. Though other non-pharmacological approaches to treatment have been considered for ME/CFS such as Cognitive Behavioral Therapy (CBT) and Graded Exercise Therapy (GET)¹⁰, we have focused in this overview on pharmaceutical agents only.

Figure 1.

A summary overview of existing pharmacological interventions for ME/CFS. For the most part, clinical trials have studied antiviral agents, analgesics, and antidepressants, with some additional drugs falling outside these categories.

Antivirals

A viral cause for ME/CFS has been long-hypothesized, and there is evidence that both enteroviruses and herpesviruses may be responsible for ME/CFS, at least in some cases^11,12. There has been a significant amount of research over the past three decades into the efficacy of antiviral drugs in the treatment of ME/CFS. These treatments generally include two different classes of antivirals, guanosine analogs such as Acyclovir and Valacyclovir, and the immunomodulator Rintatolimod (trade name Ampligen). Such treatments have met with varying levels of success in clinical trials on ME/CFS patients.

The first study attempting to treat ME/CFS with acyclovir was published in 1988. A placebo-controlled study of twenty-four ME/CFS patients, each given first rapid doses of intravenous acyclovir for one week, followed by one month of oral administration, found no significant difference in the improvement of individuals between the control and test groups. The study ultimately concluded that acyclovir had no noticeable effect on ME/CFS patients¹³. However, a 2007 study on valacyclovir, which is metabolized into acyclovir upon administration, found significant improvements in physical activity among 27 ME/CFS patients with elevated Epstein Barr virus (EBV) antibodies¹⁴. However, treatment methods were altered significantly in those that were not responding to valacyclovir treatment alone, complicating the interpretation of results. Additional drugs, including cimetidine and probenecid, were added to the treatment course in patients not responding within three months of treatment. Furthermore, three patients who suffered side-effects of valacyclovir were placed on a different guanosine analog, famciclovir¹⁴. In addition administration of these drugs was also not performed at consistent intervals, as treatment was withheld when symptoms appeared to improve over a month and only re-administered if patients began to relapse¹⁴. These confounding variables leave the effectiveness of valacyclovir/acyclovir in question. A 2013 study by Montoya et al conducted at Stanford University examined another guanosine analog, valganciclovir, in 30 ME/CFS patients who also had elevated serum IgG titers for EBV and human herpesvirus 6 (HHV-6)¹⁵. This study found statistically significant improvements in cognitive function and reduced mental fatigue in patients receiving valganciclovir as compared to the placebo, further supporting similar conclusions drawn earlier by the same group in which 75% (9 of 12) patients suffering from viral central nervous system dysfunction found “near-resolution of their symptoms” following treatment with valganciclovir¹⁶. This study was limited by its small size but provided evidence for continued research by these and other investigators.

Rintatolimod, a double-stranded RNA drug designed to increase antiviral immune response via toll-like receptor 3 (TLR3) activation, is one of the only drugs to have been developed with the specific goal of treating ME/CFS^17,18. A 1995 study by Strayer, et al. found significant improvements in cognitive function and memory, as well as a reduction in HHV-6 mRNA expression, in 15 ME/CFS patients undergoing long-term treatment with rintatolimod¹⁹. In a second, larger clinical trial of 234 severe ME/CFS patients, results were consistent with the earlier trial, though improvements were somewhat reduced in magnitude²⁰. Rintatolimod treatment has been associated with improvements in symptom burden in multiple clinical trials¹⁷, but has generally not been found to produce stable remission, suggesting that further studies are required.

Overall, evidence so far suggests that antiviral drugs appear to show limited efficacy in treating ME/CFS over a broad demographic. Trials of existing antiviral medications either fail outright or tend to be plagued by imperfect study design and/ or low statistical power. Once again, it should be noted that the causes for ME/CFS are likely heterogeneous, meaning that treatments may work in some, but not broadly in all patients. Future trials of antiviral drugs may benefit greatly from careful selection of inclusion criteria for patients, especially with respect to seropositivity for specific viruses.

Analgesics

Pain relievers, both over-the-counter and prescription-only, are often used to treat the generalized body pains and aches associated with ME/CFS. A 2009 review by Boneva, et al. on medication use by ME/CFS patients in Georgia found that pain relievers were the most commonly used drugs in the ME/CFS group²¹. Sixty-five percent of ME/CFS patients reported use of NSAID and narcotic pain relievers, which was significantly greater than the use of pain relievers by subjects designated as having insufficient symptoms to diagnose as ME/CFS and control subjects²¹. The drugs surveyed by Boneva included NSAIDs such as ibuprofen, aspirin, acetaminophen, while specific drugs in the narcotic category were not specified²¹. Opiates and opioids sometimes prescribed to treat the hyperalgesia and chronic pain associated with CFS/fibromyalgia have been found to be only minimally effective²², though large-scale studies specific to ME/CFS have not yet been performed.

NSAIDs are classified as either general or specific inhibitors of cyclooxygenase-2 (COX-2)²³. Nonspecific NSAIDs are commonly available over the counter, and include pain relievers such as aspirin and ibuprofen. Though acetaminophen is not an NSAID, it is included in this category because its mode of action, the inhibition of the COX-1 and COX-2 enzymes, is the same as that of nonspecific NSAIDs²⁴. While NSAIDs do target the mechanisms by which oxidative stress-inducing prostaglandin derivatives form, these same derivatives have been shown to form independent of the function of COX enzymes^25,26. Therefore, non-specific NSAIDs are most useful as symptomatic relief agents.

On the other hand, the sub-class of NSAIDs consisting of COX-2 specific inhibitors are of potential interest in treating ME/CFS because it has been demonstrated that COX-2 plays a central role in the replication of viruses, and is upregulated during viral infection^27,28. If ME/CFS does in fact have a viral origin, selective COX-2 inhibitors may be useful in treating latent infections. Selective COX-2 inhibitors such as celecoxib, have been demonstrated to be effective in the treatment of fibromyalgia (FM)²⁸. Though fibromyalgia is believed to be a distinct condition, symptoms often overlap with ME/CFS²⁹. If further research demonstrates a link between the etiologies of the two conditions, there may be cause for the use of drugs such as celecoxib in a subset of ME/CFS patients. Furthermore, these specific inhibitors target COX-2, an enzyme driving inflammation and pain, without targeting COX-1, the inhibition of which often associates with gastrointestinal distress³⁰. While the reduction of off-target effects is a goal for most drug-development efforts, minimizing side-effects is especially important for ME/CFS patients who already suffer from a wide variety of comorbidities, often including gastrointestinal disorders such as irritable bowel syndrome³¹.

Currently, there is a lack of clinical research focusing on the use of specific COX-2 inhibitors to treat ME/CFS. While it is apparent and expected that NSAIDs are being used to mediate pain in patients with ME/CFS, it may be warranted to further expand research into the efficacy of COX-2 specific inhibitors in particular. First, however, it may be necessary to establish a viral etiology for ME/CFS and, if such a cause exists, identify biomarkers of the corresponding sub-population. Unfortunately, at this point in time research supporting a broader use of antivirals and a viral etiology remains inconclusive.

Antidepressants

The use of antidepressants in the treatment of ME/CFS has a multifaceted basis. In many cases, it is unclear whether depressive symptoms associated with ME/CFS are a direct symptom of the disease or if they are a side-effect, brought on by the psychological pressure of living with a debilitating illness^6,32,33. Due to the heterogeneous nature of the disease, it is entirely possible that either or both of these may be the cause for the onset of depressive symptoms. Though arguments regarding depression’s role in ME/CFS persist, treatment of these symptoms is still a necessary priority. Furthermore, energy production and mitochondrial dysfunction are believed to possibly play a role in ME/CFS. Some antidepressants, such as monoamine oxidase (MAO) inhibitors, operate by targeting mitochondrial enzymes³⁴. Therefore, in addition to providing direct symptomatic relief for ME/CFS patients, antidepressants may also address the underlying molecular mechanisms of illness.

Though there have been a limited number of studies on the efficacy of antidepressants in treating ME/CFS, the findings have again been largely inconclusive and contradictory. A study on the effectiveness of the tricyclic MAO inhibitor fluoxetine, which was performed in a randomized, double-blind manner with 96 participants, found that a daily dosage of fluoxetine had no beneficial effect on symptoms of ME/CFS³⁵. Neither depressed nor non-depressed ME/CFS patients showed significant improvement, leading the authors to conclude that depressive symptoms seen in ME/CFS may arise from unique mechanisms not shared by other depressive disorders³⁵. An open-label study of moclobemide, another MAO inhibitor, in 49 ME/CFS patients found “significant but small reductions in fatigue, depression, anxiety and somatic amplification, as well as a modest overall improvement” in patients³⁶, indicating that this class of drugs may be of interest. However, the authors note that further, double-blind, placebo-controlled studies are necessary to confirm these findings. A 2003 study of the selective serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine in fibromyalgia found significant improvements in pain, fatigue, and depressive symptoms³⁷. However, the relevance of the study is questionable, as fibromyalgia and ME/CFS are distinct clinical entities despite sharing similar symptom profiles, and only a total of 15 participants were enrolled. A 2008 study on the effectiveness of Escitalopram, a selective serotonin reuptake inhibitor (SSRI), found significant reductions in the symptomatic presentation of both ME/CFS and depressive symptoms³⁸. However, this study was neither double-blinded nor placebo controlled, and the study population comprised only 16 individuals in total.

As with antiviral drug trials, studies of antidepressant treatments in ME/CFS patients suffer from a lack of statistical power and rigorous study design. While some of these trials appear to show promise, there has thus far been either insufficient ability or interest to further explore these antidepressant treatments in double-blinded, placebo-controlled studies. However, if true depressive disorders can be diagnosed comorbidly with ME/CFS, antidepressants may be of use in delivering improvements in the quality of life. Until such studies are undertaken, it is difficult to judge the true effectiveness of antidepressants in patients suffering from ME/CFS.

Other Treatments

There is a growing body of literature on treatments for ME/CFS that do not fall into either of the above categories and that are not well-developed enough to garner their own category. A 1998 randomized controlled study by McKenzie et al. tested the effect of hydrocortisone application on a cohort of 70 ME/CFS patients³⁹. The basis for this study being that researchers have found dysregulation of the hypothalamic–pituitary adrenal (HPA) axis in some patients with ME/CFS, and thus hormone supplementation may be beneficial⁴⁰. However, the results did not show a statistically significant improvement in ME/CFS patients receiving hydrocortisone compared to control subjects. Another study, conducted by Steinberg et al. in 1996, tested oral dosages of terfenadine, an antihistamine, on 30 ME/CFS patients in a placebo-controlled manner, but found no evidence of improvement in any patients⁴¹. A 2014 study of coenzyme Q and NADH supplementation in 73 ME/CFS patients was attempted based on evidence of decreased energy production via depleted coenzyme Q and ATP levels, and decreased mitochondrial function in ME/CFS^42,43. This study found significantly increased levels of the supplemented coenzymes post-treatment, as well as increased ATP and citrate-synthase levels and a decrease in lipid peroxidation. However, this corresponded to only a small improvement in patient symptom presentation versus placebo in one of four categories assessed, this being the Fatigue Impact Scale total score⁴³. Since various studies have found evidence of B cell dysfunction in ME/CFS^44–46, the B cell-depleting anti-CD20 antibody rituximab has also attracted interest. While a 2015 trial found positive responses in approximately two thirds of 28 patients⁴⁷, this finding has not been replicated by other groups⁴⁸, and the mechanism of action for rituximab in this context is unclear⁴⁹. Thus, none of these treatments targeting anecdotally dysregulated pathways individually in ME/CFS patients have so far shown significant and broad benefit. This reaffirms that the heterogeneous nature of ME/CFS presents important challenges to both the identification of illness mechanisms and the development of treatments that will reliably benefit a significant number of these patients. Moreover, it also raises the issue of robustness in biological networks and of regulatory stability. Theoretical work by our group has suggested that recalibration of endocrine-immune regulation may be involved in supporting the persistence of ME/CFS and may be responsible at least in part for its resistance to single agent interventions⁵⁰.

Discussion

The current literature on treatment of ME/CFS leans strongly towards a single conclusion - that there is no single solution. The assumption that a single drug can successfully treat ME/CFS is likely incorrect. The multifaceted, complex nature of ME/CFS may instead be more effectively treated with combination therapies, tailored to the specific causes and symptoms present in an individual patient. These potential therapies will be supported by advancements in two fields. Firstly, advancements in systems biology and systems-level analysis of the biological drivers behind ME/CFS will more clearly inform researchers as to which illness mechanisms are viable targets for treatment^3,51. Systems biology approaches have already been undertaken to analyze gene co-expression networks, perform pathway analysis, and explore metabolic pathway perturbations in ME/CFS^52–54. Generating robust tools for system-wide analysis of ME/CFS, at all of the conventional -omics levels, may prove invaluable for the discovery of a treatment or cure.

While systems biology approaches are needed to conduct basic research into the underlying causes ME/CFS, personalized and translational medicine are the necessary complement to such research. Personalized or precision medicine is a field which seeks to tailor treatments to individuals or narrow groups of individuals based on genetic or epigenetic makeup as well as a variety of other non-generalizable patient characteristics⁵⁵. It has been promoted by some as the future of medicine, and it may prove invaluable in treating patients with ME/CFS, who abound with non-generalizable characteristics. Though it is currently difficult to conduct focused such research in ME/CFS, due primarily to the scarcity of promising pharmaceutical agents and poorly understood disease underpinnings, advances in personalized strategies will no doubt play a role in the future of ME/CFS treatment. Since, with the possible exception of rintatolimod, existing drugs have largely failed, research into new treatment paradigms is called for, and must be developed with an eye for translation. As researchers gain a greater understanding of the etiology and progression of ME/CFS, modern approaches using multi-drug, tailored interventions may take the place of conventional single-drug approaches when combined with targeted research into new pharmacological targets and compounds. The combination of treatment responsive sub-typing together with the design of combination therapies could well prove to be at least one solution to the current stalemate and may help turn the tables on the suffering of ME/CFS patients and an illness that has for so long been considered largely incurable.

Conclusions

The heterogeneous nature of ME/CFS in symptom profiles and perhaps in etiology remains a significant challenge in the search for effective drugs and the design of insightful clinical trials supported by optimal inclusion criteria. Clinical trials conducted so far have suffered from generally poor design hampered by a lack of statistical power and a confluence of confounding factors. There is a great need for larger, longitudinal studies focused on a more clearly defined subset of ME/CFS as well as a greater consideration of potential synergies between interventions and the suitability of combination therapies. Without such studies, many promising treatments will remain just that – promising - but lacking enough evidence to support their widespread adoption.