Chronic Fatigue Syndrome:

ABSTRACT: Because there is no specific therapy yet for chronic fatigue syndrome (CFS), management focuses on symptomatic relief and on treatment of coexisting conditions. Antidepressants and anxiolytics are effective in treating co-occurring psychiatric disorders. First-line management of sleep disturbances consists of sleep hygiene techniques. If these strategies are not effective, consider the possibility of an underlying sleep disorder. An important aspect of managing CFS is to help the patient achieve an appropriate balance between rest and daily physical and mental activities. Useful nonpharmacological approaches include graded exercise therapy, relaxation techniques, participation in self-help groups, cognitive-behavioral therapy, and mindfulness-based cognitive-behavioral therapy.

Key words: chronic fatigue syndrome, management, treatment

The treatment of chronic fatigue syndrome (CFS) is mainly supportive. The key to effective management is to establish a therapeutic alliance with patients and to convey a consistent message that their complaints are taken seriously. Although spontaneous recovery is rare, it does occur in some patients with CFS.

In the second part of this 2-part series, the various treatments are described, with emphasis on those that are most commonly used in the primary care setting. In part 1 (CONSULTANT, February 2011, page 73), the diagnostic criteria for CFS and the differential diagnosis were described and discussed.

GENERAL MANAGEMENT PRINCIPLES

In patients with CFS, treatment goals are based on the stage and severity of the disability, as well as the type of symptom complex that is present.^1-7 In most cases, primary care practitioners are best equipped to initiate and coordinate treatment. Referral to subspecialists-such as infectious disease specialists, dietitians, occupational therapists, physiotherapists, and psychiatrists-is based on patients’ needs; the type, duration, complexity, and severity of their symptoms; and the presence of co-occurring medical and psychiatric conditions. The decision to refer to a subspecialist should be made jointly with the patient. An individualized, patient-centered treatment plan with specific objectives should be offered in order to:

• Sustain or gradually extend, if possible, the level of physical, emotional, and cognitive functioning.
• Manage the physical and psychosocial impact of the symptoms.
• Provide the evidence-based interventions that have the clearest benefit.

Because there is no specific therapy for CFS, management focuses on symptomatic relief and on treatment of co-occurring conditions.

Patient education is an essential element of treatment. It is important to reassure patients that CFS is a non–life-threatening condition and that extensive medical workups and diagnostic testing are unnecessary and could cause increased stress as a result of their financial impact. A frank discussion that encompasses the nature and prognosis of CFS as well as available therapies enables patients to become active participants in selecting an acceptable treatment plan.

NONPHARMACOLOGICAL MANAGEMENT

An important aspect of managing CFS is to help the patient achieve an appropriate balance between rest and daily physical and mental activities.^1,7-9 This balance depends on the stage and severity of the illness as well as the degree of variability of the symptoms.

Pacing approach. Several reports found the pacing approach to be the most helpful.⁹ Despite patients’ resistance to physical activity because of their ongoing fatigue, exercise is a helpful treatment modality. Although the absolute advantages of exercise are still unclear, the key is to encourage inactive patients to follow a simple, regular, and not overly aggressive program that does not exacerbate their feelings of tiredness and frustration. Graded exercise therapy that is supervised by a physical therapist or physiatrist has demonstrated benefits in mobile patients.⁹ A balance between exercise and rest may be an essential component of gradually increasing physical activity as tolerated.

Pacing is based on finding a level of activity at which patients feel comfortable. Physical and mental activity can then be gradually increased and interspaced with periods of rest-but always within individual limitations.

Relaxation techniques. These can be used to manage pain, sleep problems, and co-occurring stress or anxiety. Various relaxation techniques (such as guided imagery and breathing exercises) can be incorporated during periods of rest.

Diet. Educating patients about the value of a well-balanced diet is important. A dietary plan should address the complications associated with the CFS symptoms of nausea, dysphagia, and sore throat as well as the difficulties patients may have in buying and preparing food. The importance of eating regularly also needs to be emphasized.

Self-help groups. Patients with CFS have benefited from self-help groups that instill hope, offer an opportunity to share experiences and exchange information and, most of all, enable patients to identify with others who face the same difficulties. Because many patients with CFS often feel that they are not taken seriously by their physicians, the cohesiveness among self-help group members rebuilds the self-esteem that is usually impaired in these patients.¹⁰ Self-help groups also provide social support to patients with CFS, because many of their family members and friends do not believe that they are ill.

Cognitive-behavioral therapy (CBT). In this form of therapy, patients perform a cognitive assignment that entails gathering background details and identifying automatic thoughts and cognitive errors. The patients then engage in homework assignments and propose experiments that challenge their perception of illness and generate alternative ways to view their problems with chronic fatigue and to cope with their symptoms.

Although some studies show that CBT improves functioning in patients with CFS, other studies found CBT to be no more beneficial than regular follow-up appointments. These different outcomes may reflect differences in study design rather than ineffectiveness of CBT.^7,11,12

Various CBT techniques can improve coping skills and psychosocial functioning. The central components of CBT that lead to reduction in fatigue and improvement of mood are associated with enhancing motivation, challenging and changing fatigue-related cognitions, achieving and maintaining an appropriate level of physical activity, gradually increasing physical activity, and achieving work rehabilitation. Factors that reduce the effectiveness of CBT are the receipt of medical leave or disability-related benefits, a low sense of control, a strong focus on symptoms, and a pervasively passive activity pattern.^11,12

Mindfulness-based cognitive-behavioral therapy (MCBT). This therapy is based on the mind-body interaction and on practicing mindfulness meditation. Mindfulness meditation teaches how to focus on the present moment and act with purpose rather than letting judgments about past events or fears about what may happen in the future affect current feelings. Being focused only on the present in this way helps patients respond positively to situations rather than react in a negative way. As a result, the use of mindfulness may better prepare patients with CFS to implement the changes in thought. The combination of CBT and MCBT can be a powerful tool in certain CFS patients in whom CBT alone could not achieve its intended goals.¹³

Education and employment. The inability to pursue education or to maintain employment is generally detrimental to the health and overall well-being of patients with CFS.¹⁴ Advise patients about their fitness for work and education, and recommend referral to occupational health services, disability services, home education services, and disability advisers in schools and colleges. The goal is to initiate flexible adjustments to work or studies to help patients resume their employment or education whenever possible.

TREATMENT OF CO-OCCURRING CONDITIONS

Co-occurring medical or psychiatric conditions can contribute to a poor prognosis. Thus, it is important to diagnose and treat conditions that could aggravate symptoms of CFS. Although patients with CFS are often reluctant to consider a psychiatric cause of their symptoms, co-occurring psychiatric conditions need to be treated.^7,10,15

Depression. For patients with mild to moderate depression, the options include CBT, antidepressant medication, or both.¹⁵ The choice of an antidepressant depends on the type of depression, the presence of symptoms such as pain or sleep disturbance, and any adverse effects of the medication that may exacerbate existing CFS symptoms. Psychiatric consultation is indicated for patients who have severe or chronic depression; suicidal intentions, especially when these coexist with social isolation; poor symptom control; or financial, interpersonal, and social difficulties.

Among the antidepressants that have been used in this setting are tricyclic antidepressants (TCAs), such as amitriptyline, desipramine, and nortriptyline; the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, paroxetine, and sertraline; the serotonin norepinephrine reuptake inhibitors (SNRIs) venlafaxine and duloxetine; and other antidepressants, such as trazodone, mirtazapine, and bupropion. The SNRIs duloxetine and milnacipran, which have an FDA-approved indication for treatment of fibromyalgia, may ameliorate CFS symptoms of fatigue, body achiness, and pain.¹⁶

The enhanced sense of well-being that results from alleviation of the depressed mood may decrease the degree of fatigue in patients with CFS. Certain antidepressants, especially trazodone and mirtazapine, may also play a role in improving sleep. The TCAs may also relieve associated pain.

Anxiety. A common practice has been to prescribe antianxiety medications, especially the benzodiazepines, to treat the co-occurrence of anxiety disorders in patients with CFS. Because most SSRIs and SNRIs can alleviate anxiety symptoms associated with CFS, it is advisable to use these agents instead of the benzodiazepines. If benzodiazepines are prescribed, discussion and education about the benefits of these agents versus their potential for dependence and possible addiction would be warranted.

Sleep disturbances. The first line of treatment consists of sleep hygiene techniques, such as regulating times of going to bed and getting up; relaxing rather than sleeping during the day; and controlling noise, light, and temperature in the sleeping environment. If these strategies are not effective, the possibility of an underlying sleep disorder should be considered. A low dose of an antidepressant such as amitriptyline, trazodone, or mirtazapine may be indicated.¹⁷

Difficulty in initiating sleep can be temporarily managed with a short course of a hypnotic medication, such as the benzodiazepine temazepam or flurazepam, or a nonbenzodiazepine sedative-hypnotic, such as zolpidem, zaleplon, or eszopiclone. The nonbenzodiazepine sedative-hypnotics pose less risk of daytime confusion and morning hangover and may be safer than benzodiazepines, although they can cause other problems, including dissociative phenomenon and addiction. Even short-acting hypnotic agents may increase the risk of nighttime falling, cognitive difficulties, and confusion. In some patients with CFS who have severe and persistent sleep disturbances, the melatonin agent ramelteon has been helpful in initiating and maintaining sleep. Frequent monitoring of the adverse effects and duration of use of hypnotic medications is necessary to prevent the development of dependence and addiction.

Pain. Acetaminophen and NSAIDs, such as aspirin and ibuprofen, may be helpful in reducing pain and fever. The antiepileptics phenytoin, gabapentin, and divalproex sodium may be useful, especially in patients who have neuropathic pain. Pregabalin can also be used in this setting. Muscle relaxants (eg, cyclobenzaprine) and antispasmodics (eg, baclofen) or naproxen may be helpful in patients who have painful muscle spasms. Because all these medications can have adverse effects, careful monitoring is warranted.

The use of opiates for pain associated with CFS is not recommended in a primary care setting; if these agents are indicated, refer the patient to a pain management specialist. Transcutaneous electrical nerve stimulation could be considered as an additional intervention for pain relief in some patients with CFS.^7,15,17

Allergy-like symptoms. Antihistamines and decongestants that contain pseudoephedrine may relieve allergy-like symptoms. However, the adverse effects associated with these medications warrant their cautious use, especially because they may contribute to increased fatigue.^14,17,18

Hypotension. Medications such as fludrocortisone and midodrine may be useful for the treatment of neurally mediated hypotension in patients with CFS.¹⁹

Additional Resources
for Primary Care Practitioners

Books

• Firestein GS, Budd RC, Harris ED Jr, et al, eds. Kelley’s Textbook of Rheumatology. 8th ed. Philadelphia: Saunders Elsevier; 2008.

• Jason LA, Fennell PA, Taylor RR, eds. Handbook of Chronic Fatigue Syndrome. Hoboken, NJ: John Wiley and Sons, Inc; 2003.

• Khouzam HR, Tan DT, Gill TS, eds. Handbook of Emergency Psychiatry. Philadelphia: Mosby Elsevier; 2007.

• Rakel P, ed. Conn’s Current Therapy. 58th ed. Philadelphia: WB Saunders; 2006.

Other publications

• Recognition and Management of Chronic Fatigue Syndrome:
Resource Guide for Health Care Professionals. 2006. Centers for Disease
Control and Prevention; 1600 Clifton Rd, Atlanta, GA 30333, USA
Tel: 404-639-3311, CDC Contact Center: 800-CDC-INFO , 888-232-6348 (TTY).

Associations

• American Association for Chronic Fatigue Syndrome, c/o Harborview Medical Center, 325 Ninth Avenue, Box 359780, Seattle, WA 98104

• The Chronic Fatigue Immune Dysfunction Syndrome Association of America, PO Box 220397, Charlotte, NC 28222-0398; Phone: 800-442-3437;
Fax: 704-365-2343; E-mail: cfids@cfids.org

• The National ME/FM Action Network, 3836 Carling Avenue,
Nepean, Ontario, Canada K2K 2Y6; Phone/Fax: 613-829-6667;
E-mail: ag922@freenet.carleton.ca

Internet resources

• Chronic Fatigue Immune Dysfunction Syndrome (CFIDS) Association of America  http://www.cfids.org

• The ME and CFS Information Page  http://www.cfids-me.org

• National ME/FM Action Network  http://www3.sympatico.ca/me-fm.action/main.html

CONTROVERSIAL AND EXPERIMENTAL THERAPIES

The following interventions should not be used to treat CFS unless co-occurring conditions exist to warrant their use.

CNS stimulants. These medications, such as methylphenidate, which are commonly used to treat attention-deficit/hyperactivity disorder (ADHD), could reduce fatigue and improve mental concentration in some patients with ADHD and CFS; however, CNS stimulants are not recommended for those who do not have ADHD.^15,20 Modafinil-which is FDA-approved for treatment of narcolepsy, obstructive sleep apnea, and shift work sleep disorder-can increase wakefulness in patients with excessive daytime sleepiness and secondary fatigue, but it does not decrease fatigue in patients with CFS.²¹

D-Ribose. Although some trials found that natural D-ribose supplements may significantly ameliorate symptoms of CFS-with particular benefit in participants’ energy level and overall sense of well-being-the use of D-ribose is not recommended in a primary care setting.²²

Hormonal treatment. Some studies have found that glucocorticoids, such as hydrocortisone, and mineralocorticoids, such as fludrocortisone, may improve symptoms of CFS. In contrast, other studies found no benefit and showed only that hydrocortisone was effective in correcting underlying hypocortisolemia. Estradiol patches and cyclical progestogens did decrease fatigue in CFS patients who had estrogen deficiency.²³ Thyroid hormones, such as thyroxine, have no effect on the symptoms of CFS. Patients with comorbid hypothyroidism who received thyroid hormone experienced improvement in their daily functioning, which indirectly enhanced their ability to cope with fatigue related to CFS.

Cholinesterase inhibitors. These agents, such as donepezil, galantamine, and rivastigmine, which slow the progression of cognitive decline in Alzheimer disease, are not effective for the treatment of CFS.^15,24

ALTERNATIVE AND COMPLEMENTARY THERAPIES

Acupuncture. This modality, which has been studied as a treatment for fatigue associated with fibromyalgia, has been reported to relieve coexisting pain and headache in some patients with CFS. Whether to recommend acupuncture for CFS patients in a primary care setting remains a controversial issue.²⁵

Supplemental agents. Numerous self-help books and Web sites provide confusing and conflicting information to patients about the value of dietary changes and the use of various vitamin and mineral supplements and other products. There is little evidence to support most of these claims, and further lifestyle restrictions may impose greater financial and social burdens on patients.

Lentinan, beta carotene, high-dose vitamin B12, liver extract, folic acid, magnesium sulfate, essential fatty acids (eg, primrose oil and fish oil), and eicosapentaenoic acid (an omega-3 fatty acid supplement) have all been reported as effective treatments for CFS; however, none of these agents have undergone rigorous scientific testing.²⁶ Despite limited data that suggest supplements such as carnitine and nicotinamide adenine dinucleotide may have some value in reducing physical fatigue, expensive vitamin and mineral supplements are generally not recommended and megadose products should be avoided.^10,26

Looking to the future. Recent evidence of and controversies on the role of xenotropic murine leukemia virus-related virus (XMRV) in the blood of persons with CFS has attracted considerable interest in the possibility of finding treatment or possibly discovering a vaccine to prevent CFS. However, the relevance and significance of XMRV to CFS still remain unclear.²⁷

References:

REFERENCES:1. Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121:953-959.
2. Carruthers BM, Jain AK, De Meirleir KL, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. J Chron Fatigue Syndrome. 2003;11:7-36.
3. Matsuda Y, Matsui T, Kataoka K, et al. A two-year follow-up study of chronic fatigue syndrome comorbid with psychiatric disorders. Psychiatry Clin Neurosci. 2009;63:365-373.
4. Gunn WJ, Connell DB, Randall B. Epidemiology of chronic fatigue syndrome: the Centers for Disease Control Study. Ciba Found Symp. 1993;173:83-93; discussion 93-101.
5. Cho HJ, Menezes PR, Hotopf M, et al. Comparative epidemiology of chronic fatigue syndrome in Brazilian and British primary care: prevalence and recognition. Br J Psychiatry. 2009;194:117-122.
6. Harvey SB, Wadsworth M, Wessely S, Hotopf M. Etiology of chronic fatigue syndrome: testing popular hypotheses using a national birth cohort study. Psychosom Med. 2008;70:488-495.
7. Shepherd C. The debate: myalgic encephalomyelitis and chronic fatigue syndrome. Br J Nurs. 2006;15:662-669.
8. Scheeres K, Wensing M, Severens H, et al. Determinants of health care use in chronic fatigue syndrome patients: a cross-sectional study. J Psychosom Res. 2008;65:39-46.
9. Shepherd C. Pacing and exercise in chronic fatigue syndrome. Physiotherapy. 2001;87:395-396.
10. Afari N, Buchwald D. Chronic fatigue syndrome: a review. Am J Psychiatry. 2003;160:221-236.
11. Deale A, Husain K, Chalder T, Wessely S. Long-term outcome of cognitive behavior therapy versus relaxation therapy for chronic fatigue syndrome: a 5-year follow-up study. Am J Psychiatry. 2001;158:2038-2042.
12. Prins JB, Bleijenberg G, Bazelmans E, et al. Cognitive behaviour therapy for chronic fatigue syndrome: a multicentre randomised controlled trial. Lancet. 2001;357:841-847.
13. Roth AD, Pilling S, Turner J. Therapist training and supervision in clinical trials: implications for clinical practice. Behav Cogn Psychother. 2010;38:291-302.
14. Chambers D, Bagnall AM, Hempel S, Forbes C. Interventions for the treatment, management and rehabilitation of patients with chronic fatigue syndrome/myalgic encephalomyelitis: an updated systematic review. J R Soc Med. 2006;99:506-520.
15. Pae CU, Marks DM, Patkar AA, et al. Pharmacological treatment of chronic fatigue syndrome: focusing on the role of antidepressants. Expert Opin Pharmacother. 2009;10:1561-1570.
16. Kranzler JD, Gendreau RM. Role and rationale for the use of milnacipran in the management of fibromyalgia. Neuropsychiatr Dis Treat. 2010;25:197-208.
17. Neu D, Cappeliez B, Hoffmann G, et al. High slow-wave sleep and low-light sleep: chronic fatigue syndrome is not likely to be a primary sleep disorder. J Clin Neurophysiol. 2009;26:207-212.
18. Lyall M, Peakman M, Wessely S. A systematic review and critical evaluation of the immunology of chronic fatigue syndrome. J Psychosom Res. 2003;55:79-90.
19. Wyller VB, Thaulow E, Amlie JP. Treatment of chronic fatigue and orthostatic intolerance with propranolol. J Pediatr. 2007;150:654-655.
20. Blockmans D, Persoons P, Van Houdenhove B, Bobbaers H. Does methylphenidate reduce the symptoms of chronic fatigue syndrome? Am J Med. 2006;119:167.e23-e30.
21. Kumar R. Approved and investigational uses of modafinil: an evidence-based review. Drugs. 2008;68:1803-1839.
22. Teitelbaum JE, Johnson C, St Cyr J. The use of D-ribose in chronic fatigue syndrome and fibromyalgia: a pilot study. J Altern Complement Med. 2006;12:857-862.
23. Veldman J, Van Houdenhove B, Verguts J. Chronic fatigue syndrome: a hormonal origin? A rare case of dysmenorrhea membranacea. Arch Gynecol Obstet. 2009;279:717-720.
24. Madill PV. Chronic fatigue syndrome and the cholinergic hypothesis. JAMA. 2004;292:2723; author reply 2723.
25. Lijue Z. Acupuncture and Chinese patent drugs for treatment of chronic fatigue syndrome. J Tradit Chin Med. 2005;25:99-101.
26. Vermeulen RC, Scholte HR. Exploratory open label, randomized study of acetyl- and propionylcarnitine in chronic fatigue syndrome. Psychosom Med. 2004;66:276-282.
27. Menéndez-Arias L. Evidence and controversies on the role of XMRV in prostate cancer and chronic fatigue syndrome. Rev Med Virol. 2011;21:3-17.

Acknowledgments: The author thanks the VA Medical Center director, Mr Al Perry, FACHE, for his leadership and the chief of staff, Dr Wessel Meyer, for his support; Drs Robert Hierholzer, Nestor Manzano, Scott Ahles, and Craig C. Campbell, for their clinical guidance; Dr Avak A. Howsepian for his constructive criticism; Matthew Battista, PhD, and Leonard Williams, PA, for their encouragement; and Ms Ruth A. Cowell for her secretarial assistance.