Chronic Fatigue Syndrome:

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(Drug information on amitriptyline), desipramine, and nortriptyline; the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, paroxetine, and sertraline; the serotonin norepinephrine(Drug information on norepinephrine) reuptake inhibitors (SNRIs) venlafaxine and duloxetine(Drug information on duloxetine); and other antidepressants, such as trazodone, mirtazapine(Drug information on 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(Drug information on temazepam) or flurazepam(Drug information on 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(Drug information on ibuprofen), may be helpful in reducing pain and fever. The antiepileptics phenytoin, gabapentin(Drug information on gabapentin), and divalproex sodium(Drug information on divalproex sodium) may be useful, especially in patients who have neuropathic pain. Pregabalin can also be used in this setting. Muscle relaxants (eg, cyclobenzaprine(Drug information on cyclobenzaprine)) and antispasmodics (eg, baclofen(Drug information on baclofen)) or naproxen(Drug information on 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(Drug information on 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(Drug information on fludrocortisone) and midodrine(Drug information on midodrine) may be useful for the treatment of neurally mediated hypotension in patients with CFS.¹⁹

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(Drug information on 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(Drug information on 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(Drug information on 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(Drug information on 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(Drug information on folic acid), magnesium sulfate(Drug information on 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(Drug information on 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