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12 Articles in Volume 17, Issue #2
Chronic Pain and Bipolar Disorders: A Bridge Between Depression and Schizophrenia Spectrum
Differences in Pain Management of Peripheral Vascular Disease and Peripheral Artery Disease
Duloxetine and Liver Function Tests
How Well Do You Know Your Patient?
Insurers End Policies Requiring Prior Authorization for Opioid Use Disorder
Letters to the Editor: Initiating Hormones
Managing Opioid Use Disorders and Chronic Pain
Opportunities and Challenges of Pain Management: The Family Physician’s Perspective
Pathways to Recovery From Co-Occurring Chronic Pain and Addiction
Strategies for Weaning Opioids in Patients With an Opioid Use Disorder and Chronic Pain
Treating Multiple Pain Syndromes: A Case Series Using a Functional Medicine Model
Treatment of Chronic Exhaustion and Chronic Fatigue Syndrome

Treatment of Chronic Exhaustion and Chronic Fatigue Syndrome

Cognitive behavioral therapy and an exercise program appear to be the best treatments to improve function and symptoms of fatigue in patients with CFS.

The so-called functional somatic syndromes—such as fibromyalgia (FM) and chronic fatigue syndrome (CFS)—share many characteristics. They are quite common, with population estimates of 2% to 5% for FM, 0.26% to 0.78% for CFS (1% to 3% using older definitions), and 10% to 30% for irritable bowel syndrome (IBS).1,2

These syndromes have similar symptoms, notably chronic pain, exhaustion, headaches, and bowel and bladder complaints, as well as mood and sleep disturbances. None of these common disorders are well understood, and no causative agent has ever been identified. Therefore, they have been controversial disorders, especially in regard to their “mind or body” underpinnings.

Pain management in patients with for chronic exhaustion and chronic fatigue syndrome

CFS is the most perplexing of these chronic illnesses, especially for patients. Even the diagnostic term CFS has been a source of frustration for health care providers and patients. In the United Kingdom in the 1800s, the term neurasthenia was coined for patients with chronic exhaustion and neurocognitive symptoms. Subsequently, the term myalgic encephalomyelitis (ME) became popular.3 Then, following a cluster of cases of unexplained exhaustion in Lake Tahoe, Nevada, the term CFS became widely used, especially in the United States.4

In 2015, a committee organized by the Institute of Medicine (IOM) concluded that the terms CFS/ME did not reflect the main symptoms or the serious nature of the condition.5 The committee concluded that the terms fostered a psychogenic focus to CFS and recommended a new term, systemic exertion intolerance disease (SEID). Based on this new definition, it was estimated that 836,000 to 2.5 million Americans have CFS/SEID, with direct and indirect economic costs between $17 billion and $24 billion annually (Table 1).5

The IOM committee hoped that the new diagnostic term SEID would foster the notion that this is a discrete and legitimate physical disorder. However, the new terminology does not change CFS/SEID’s poorly understood nature or overlap with other common functional illnesses. A number of investigators have concluded that the new term and diagnostic criteria of SEID have not strengthened the understanding or acceptance of CFS.6 Therefore, for this article, I will refer to this illness as CFS and focus on its overlap with FM.

The Road to Diagnosis

Both CFS and FM often take years to diagnose. Only recently have physicians understood that these are not diagnoses of exclusion but can and should be diagnosed primarily by a complete history and physical examination. The cardinal symptom of CFS is profound exhaustion—for FM, the main symptom is generalized body pain. These symptoms must be present for 6 months and be unrelieved by rest. Exhaustion is present in 60% to 90% of subjects with FM. Furthermore, 60% to 90% of subjects diagnosed with CFS have widespread body pain, and pain was a part of all previous definitions of CFS/ME. Yet the IOM committee concluded that the pain of CFS is not specific for this disorder and elected not to include pain as a required element for the newly recommended diagnostic criteria for CFS/ME.

Much of the controversy in CFS may relate to the long-held notion, popularized in the United States in the 1980s, that CFS was caused by the Epstein-Barr virus (EBV).4 However, more extensive research failed to find a causal association of chronic fatigue with the EBV. The IOM report concluded that EBV may trigger CFS, but CFS is not sustained by ongoing EBV infection.5 Other potential viral associations with CFS have been proposed, but none have held up to careful scrutiny. In a prospective, multisite study, researchers were unable to confirm an association between murine retroviral DNA signature and CFS.7 The results showed low frequency in both CFS and control subjects (5/72; 6.7% vs 2/37; 5.4%, respectively).

Management of CFS

CFS has been one of the most controversial and challenging functional somatic syndromes to treat. In the 1980s and early 1990s, most treatments for CFS were based on a possible infectious or immune pathogenesis. When such efforts failed, more holistic therapies were pursued, with approaches similar to the treatment of FM and IBS. CFS patient organizations, however, have been critical of many of these trials and have interpreted these studies differently than physicians.

In addition, physicians and patients score various CFS therapies very differently.8 In a recent survey conducted in the United Kingdom, 75% of patients and 16% of health care providers supported alternative and complementary treatments; 71% of patients and 42% of providers supported medication management; 91% of patients and 50% of providers supported pacing exercise; and 28% of patients and 94% of providers supported rehabilitative therapy (Figure 1).8

To help understand the literature, this review begins with a look at nonpharmaceutical treatments that have been shown to be effective.

Cognitive Behavioral Therapy

There is evidence that cognitive behavioral therapy (CBT) is effective in the management of CFS. There are a number of reports demonstrating the efficacy of CBT for CFS.

  • In a randomized clinical trial (RCT), patients who underwent a group-based CBT program achieved significant benefit compared to controls (wait-list for treatment) with respect to symptoms of fatigue (effect size = 1.1) and function (effect size = 0.5).9 The authors noted that “group size did not seem to affect the general efficacy of the intervention, which is of importance for settings in which large treatment groups are not feasible due to limited referral.”
  • In another study, investigators looked at the cost-effectiveness of CBT. They found that a 2-session CBT self-management program was more cost-effective than usual care in CFS patients treated in the primary care setting.10
  • A prospective study from 6 CFS specialist centers in the UK found modest improvement in fatigue and mood with CBT and graded exercise but less improvement in physical function.11 Outcomes correlated with levels of fatigue, disability, and pain at initial evaluation.
  • At 6-months follow-up of CFS patients treated with CBT, 40% no longer met criteria for CFS, and 20% were completely recovered.12 Poor outcome correlated with worse scores on the work and social adjustment scale, unhelpful beliefs about emotions, high levels of depression, and older age.
  • In a cost-analysis study, CBT was the most cost-effective treatment, followed by gradual exercise (GET), compared to standard medical care.13 Adaptive pacing was the least cost-effective therapy.
  • Treatment expectations have strongly influenced the outcome of CFS treatment. For example, in a study of 120 patients with CFS, half received CBT and half received multidisciplinary rehabilitation therapy (MRT).14 Patient expectation had a significant effect on outcome from MRT but not from CBT.
  • As with other somatic syndromes, there is growing evidence that hypothalamic-pituitary-adrenal (HPA) axis dysregulation is common in CFS. Hypocortisolism has been noted in some studies of adolescents and adults with CFS.15 In 1 study, adolescents with CFS had reduced early-morning cortisol levels, but these levels normalized after a CBT guided self-help program—almost doubling the odds of recovery.15,16

However, there is some evidence that does not support the efficacy of CBT. CFS patients undergoing 8 biweekly CBT sessions demonstrated no improvement compared to patients receiving usual care in a recent study.17 In addition, a meta-analysis review of various treatments found that the results often were inconsistent and no conclusions could be drawn regarding what type of counseling or behavioral intervention worked best.18

Exercise and Multidisciplinary Therapy

Most clinicians understand the benefits of exercise, even for patients with chronic pain. But what are the benefits of exercise for patients with CFS? What type, duration, and intensity level is recommended? To answer some of these questions, a Cochrane review evaluated 8 RCTs of exercise in 1,518 CFS subjects.19 The authors concluded that “patients with CFS may generally benefit and feel less fatigued following exercise therapy.” There was no evidence that exercise therapy worsened outcomes.

The most common intervention used structured, incremental increase in aerobic exercise over time (graded exercise therapy, GET). Seven of these trials showed a positive effect on fatigue. A variety of land- (walking, cycling) and water-based exercise programs of varying time and intensity were used. In general, exercise also improved sleep, physical function, and self-perceived general health. The retrospective review was unable to look at what effect exercise had on pain, quality of life, mood, or health service resources. The authors concluded that the efficacy of exercise therapy was greater than that of pacing and similar to that of CBT. There were no significant adverse effects from exercise.

The largest trial of CFS patients, the PACE trial, evaluated the outcome in more than 600 patients with CFS who were randomly assigned to adaptive pacing therapy, CBT, GET, or specialist medical care. Both CBT and GET, but not pacing, improved outcomes over specialist medical care alone.20 The results of other forms of exercise, including qigong, were inconsistent.18 The PACE study results, however, were considered by CFS support groups to be erroneous (patients groups prefer pacing), resulting in a petition, signed by 10,000 people, asking for study retraction.21

A combination of CBT and exercise may help both fatigue and neurocognition.22,23 A 12-week graded activity program combined with CBT resulted in objective neurocognitive performance improvement.23

Pharmaceutical Management

Immune Modulators

The inability to identify a specific infectious agent has not dissuaded some CFS investigators from postulating that transient exposure to an unknown agent may trigger an aberrant immune reaction in genetically susceptible people. Some reports have noted increased levels of proinflammatory cytokines, including interleukin (IL)-1 and tumor necrosis factor (TNF)-α, as well as increased levels of nuclear factor (NF)-KB predisposed to autoimmune abnormalities.24 Therefore, many of the earlier therapeutic trials in CFS used techniques designed to boost a defective immune response.

An early RCT of 28 CFS subjects found no benefit of intravenous (IV) IgG (1 g/kg) treatment every 30 days for 6 months compared to placebo.25 Another small RCT of 30 CFS subjects with elevated EBV titers found slight improvement in fatigue scale scores after valganciclovir therapy—900 mg twice daily for 3 weeks, followed by 900 mg daily for 6 months.26 There was no change in function or other measures.

There have been 2 RCTs using rintatolimod (Ampligen), an investigational IV immune modulator and antiviral drug, in severely affected CFS patients. In the first study by Strayer et al, 92 CFS subjects were treated for 6 months, with some improvement noted in their ability to exercise and a reduction in medication use.27 A second study by the same investigators enrolled 234 CFS subjects and noted similar results, including some improved function.28 The Food and Drug Administration (FDA) has not approved the agent for CFS based on these results.

A few RCTs with a variety of other immune-acting medications reported no efficacy in CFS subjects. Galantamine (Razadyne), a centrally acting acetylcholinesterase inhibitor that is approved to treat Alzheimer’s dementia, was not found to be helpful in a large RCT of CFS.29 However, a subset of CFS patients had a substantial and long-lasting improvement in CFS symptoms following treatment with the B-cell inhibitor rituximab (Rituxan).30 In the open-label study, rituximab was given as 2 infusions 2 weeks apart (500 mg/m2), followed by maintenance rituximab infusions after 3, 6, 10, and 15 months; follow-up was for 36 months. The authors reported major or moderate responses, predefined as lasting improvements in self-reported fatigue score, in 18 out of 29 patients (intention to treat). Clinically significant responses also were seen in 18 out of 28 patients (64%) receiving rituximab during the maintenance phase. Improvement, however, did not correlate with B-cell depletion in most patients.


Neurostimulants that increase dopamine and norepinephrine activity have been studied in small trials in CFS. Methylphenidate (Ritalin, others), 10 mg twice daily, was found to be better than placebo at relieving fatigue and concentration disturbances in CSF patients.31 A clinically significant effect of > 33% improvement in fatigue occurred in 17% of the patients, and improvement in concentration in 22%. Another study evaluated a combination of methylphenidate and mitochondrial support nutrients in 15 patients with CFS. The researchers reported an improvement in fatigue and concentration, but the study lacked a placebo comparison group, making it hard to judge overall effectiveness.32


Many patients with functional somatic syndromes also have comorbid depression. In 1 RCT, 20 mg per day of the selective serotonin reuptake inhibitor (SSRI) fluoxetine (Prozac) had no efficacy in reducing CFS symptoms, including depression.33 A small open-label study, however, did find the SSRI escitalopram (Lexapro) to benefit both mood and fatigue in CFS patients.34

In a study by Li et al, various SSRIs were combined with the Chinese medicine Dengzhanshengmai, which contains erigeron breviscapus, ginseng, schisandra, and Ophiopogon japonicus. Dengzhanshengmai may “augment the immune function and promote blood circulation,” noted the authors.35 The combination improved fatigue, activity, and motivation of CFS patients compared to monotherapy with an SSRI in an open-label trial.35

The serotonin and norepinephrine reuptake inhibitor (SNRI) duloxetine (Cymbalta), which is FDA approved for the treatment of FM, also has been studied in patients with CFS. However, in a 3-month RCT, the investigators found no significant improvement in fatigue in patients given 60 mg to 120 mg of duloxetine per day.36 There were significant improvements in secondary measures of mental fatigue, pain, and global measure of severity, and the authors concluded that larger controlled trials were needed to confirm these results.

Looking at morbidity and mortality, there was no increase in all-cause mortality in a population study of more than 2,000 subjects with CFS.37 However, there was an increased mortality rate from suicide. These findings are similar to most reports in FM patients and remind physicians to assess suicidality adequately in patients with CFS.

Treatment of Neurally Mediated Hypotension

Orthostatic intolerance has been observed frequently in patients with CFS. It is 1 of the symptoms included in the new IOM SEID diagnostic criteria. These specific criteria include more than 6 months of debilitating fatigue, post-exertional malaise, and unrefreshing sleep, as well as cognitive impairment and/or orthostatic intolerance.5

Evidence for orthostatic intolerance has included abnormal cardiac response to standardized laboratory stimuli, particularly rapid standing and exercise.38 However, such abnormalities are inversely related to the subject’s overall fitness. The heart rate dynamic response during the head-up tilt test has been especially helpful to distinguish patients with CFS from healthy controls.

In an earlier, uncontrolled trial, 22 of 23 CFS patients had abnormal tilt testing and were treated with increasing doses of the corticosteroid fludrocortisone, the beta-blocker atenolol, and the antiarrhythmic disopyramide.39 Most of the patients reported marked relief of symptoms following treatment. The same investigators found similar positive outcomes in a follow-up trial of subjects with CFS and FM, but neither of these trials was controlled.40

In contrast, most controlled studies have not found benefit in treating neurally mediated hypotension in CFS. In 100 CFS patients, 0.1 mg of fludrocortisone daily resulted in no improvement in symptoms or in post-treatment tilt table testing compared to placebo.41 In a controlled trial of 176 adolescents with CFS, low-dose clonidine did not improve symptoms.42 In another trial of 120 adolescents with CFS, catecholamine levels dropped with low-dose clonidine, but there was no improvement in fatigue or orthostatic hypotension.43

Despite the new IOM recommendations, there is conflicting evidence whether orthostatic intolerance or postural orthostatic tachycardia syndrome (POTS) distinguishes subjects with CFS from controls. The largest study evaluating the potential role of POTS compared 419 patients with CFS to 341 patients who had fatigue but did not meet CFS criteria. POTS was present in 6% of CFS patients and 7% of non-CFS subjects—in adolescents, prevalence rates were 18.2% and 17.4%, respectively.44 In patients with CFS, criteria for SEID were met in 76% of adults and 67% of adolescents. In patients with CFS fulfilling the SEID criteria, the prevalence of POTS was not different from that in the overall CFS population, the researchers noted.

Complementary and Alternative Therapy

There is no good evidence that diets, supplements, homeopathy, and phototherapy are effective in treating CFS. Despite their lack of proven benefit, complementary and alternative (CAM) treatments are used by the majority of CFS patients. In a large RCT of paced exercise in patients with CFS, 70% of subjects were using some form of CAM, 31% were seeing a CAM practitioner, and 64% were taking a CAM medication.45 CAM use did not correlate with any clinically important trial outcomes.

A systematic review of 26 RCTS involving 3,273 CFS subjects included trials of mind-body medicine, massage, tui na (therapeutic message) and tai chi, homeopathy, and dietary supplements, including ginseng and nicotinamide adenine dinucleotide (NADH).46 Studies of qigong with meditation, massage, and tui na and tai chi showed these therapies had modest positive effects on CFS symptoms such as fatigue. There was no evidence for benefit from homeopathy. There was no efficacy of dietary approaches, including a low-sugar and low-yeast diet, pollen extract, or supplements, with the possible exception of NADH and magnesium.

A large, controlled report found some benefit from acupuncture in CFS.47 Patients who benefited from acupuncture were treated for 4 weeks and were able to continue their “usual care.”

A small, uncontrolled report suggested that high-frequency transcranial magnetic stimulation may be beneficial for CFS, as has been suggested in FM.48 Five of 7 patients completed the 3-day protocol without any adverse events—most of the patients had improvement in fatigue symptoms, the authors noted.


CFS is a controversial and challenging condition to treat. Although absence of a causative agent or well-understood disease mechanisms plagues FM, chronic headaches, chronic pelvic and bladder pain, and IBS, CFS, especially, has been caught between outdated mind-body dualism treatment paradigms.

Currently, no medication can be strongly recommended for the treatment of CFS.18,49 Rintatolimod may be promising, but more RCTs are needed. CBT and other forms of counseling and GET over time are recommended with low to moderate strength of evidence. The presence of orthostatic hypotension should be evaluated and treated when if present.

Update 7/5/19: See latest updates on the pathophysiology of CFS here.

Last updated on: July 25, 2019
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Differences in Pain Management of Peripheral Vascular Disease and Peripheral Artery Disease

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