• Highlights
• Introduction
• Risk Factors
• Causes
• Diagnosis
• Prognosis
• Treatment
• Medications
• Resources
• References

Chronic fatigue syndrome

Description

An in-depth report on the causes, diagnosis, and treatment of chronic fatigue syndrome.

Medications

No medications are specifically approved for the treatment of CFS. However, some may be useful for specific symptoms or in cases where CFS may have a specific cause. Doctors generally use combinations of drugs to accomplish specific goals, such as medication at night to improve sleep and medication in the morning to improve cognition and energy. Treatment is very individualized.

Mild Pain Relievers

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). Patients with CFS may find relief using NSAIDs. They are common pain relievers that reduce pain and swelling. Types include aspirin, ibuprofen (Motrin, Advil, Nuprin), and naproxen (Aleve, Naprosyn, Naprelan, Anaprox).

Although NSAIDs work well, long-term use can cause stomach problems, such as ulcers and bleeding. In April 2005, the FDA asked drug manufacturers of NSAIDs to include a warning label on their product that alerts users of an increased risk for cardiovascular events and gastrointestinal bleeding. Due to its proven cardiovascular benefits, aspirin was excluded from these labeling revisions.

NSAIDs can also increase blood pressure, particularly among people already being treated for hypertension. About 12 - 15% of elderly people take both an NSAID and an antihypertensive drug. Piroxicam, naproxen, and indomethacin appear to pose the greatest risk of high blood pressure. Sulindac has the smallest effect.

Other side effects of NSAIDs include dizziness, ringing in the ears, headaches, skin rashes, and possibly depression. Studies have appeared suggesting that high doses of NSAIDs can damage cartilage, and there have also been reports that NSAIDs can cause kidney damage. (The damage resolves once the patient stops using the drug. People with high blood pressure, severe circulation disorders, or kidney or liver problems, as well as people taking diuretics or oral hypoglycemics, must be closely monitored if they need to use NSAIDs on a long-term basis. Because NSAIDs reduce blood clotting, NSAID users scheduled for surgery should stop taking those drugs a week before the operation.

COX-2 Inhibitors (Coxibs). Coxibs block an inflammation-promoting enzyme called COX-2. This class of drugs was initially believed to work as well as traditional NSAIDs, but with less stomach problems. However, numerous reports of cardiovascular events, skin rashes, and other adverse effects prompted the FDA to re-evaluate the risks and benefits of the COX-2 drugs. Rofecoxib (Vioxx) and valdecoxib (Bextra) have been withdrawn from the U.S. market following reports of heart attacks in patients taking the drugs. Celecoxib (Celebrex) was still available at the time of this report, but labeled with strong warnings and a recommendation that it be prescribed at the lowest possible dose for the shortest duration possible. Patients should ask their doctor whether the drug is appropriate and safe for them.

Antidepressants

Because of the association between depression and CFS, antidepressants are often tried with varying degrees of success, depending on the type. Common side effects of many antidepressants include dry mouth, restlessness, reduced sexual drive, a slightly increased heart rate, and constipation. Virtually all antidepressants have complicated interactions with other drugs, and some are very serious.

Tricyclic Antidepressants. Antidepressants known as tricyclics may be particularly helpful for CFS patients. For example, the tricyclic amitriptyline (Elavil) is known to relieve many of the symptoms of CFS, including sleeplessness and low energy levels. They may provide benefits by promoting deep sleep and inhibiting pain pathways in the nervous system. Improvement in symptoms can take 3 - 4 weeks. Other tricyclics include doxepin (Sinequan), desipramine (Norpramin), nortriptyline (Pamelor), clomipramine (Anafranil), and imipramine (Tofranil, Janimine). These agents can have severe side effects, although patients with CFS normally respond to much lower doses than those used to treat people with depression. In fact, many CFS patients cannot tolerate the higher doses commonly used to treat the psychiatric disorder. Like all medications, tricyclics must be taken as directed. Overdose can be life-threatening.

Monoamine Oxidase Inhibitors (MAOIs). Monoamine oxidase inhibitors (MAOIs) block the enzyme monoamine oxidase, which has negative effects on many of the neurotransmitters that are important for well-being. In one study moclobemide, a newer MAOI, was associated with improved energy levels in CFS patients regardless of whether they are depressed or not. Other MAOIs are likely to have similar effects. The most serious side effect of MAOIs is severe hypertension, which can be brought on by eating certain foods having a high tyramine content. Such foods include aged cheeses, most red wines, sauerkraut, vermouth, chicken livers, dried meats and fish, canned figs, fava beans, and concentrated yeast products. They also have serious interactions with a number of medications and should not be taken by pregnant women.

Designer Antidepressants. Newer, so-called designer SSRIs, including bupropion (Wellbutrin), nefazodone (Serzone), or mirtazapine (Remeron), affect combinations of different neurotransmitters, and some may have moderate benefits for CFS patients. For example, in one study, nefazodone improved mood, fatigue, and sleep disturbances.

SSRIs. The popular antidepressants known as selective serotonin-reuptake inhibitors (SSRIs) may be helpful for the subgroup of CFS patients who experience significant depression. They include fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil). Cymbalta (duloxetine) is a new antidepressant that is classified as a selective serotonin and norepinephrine reuptake inhibitor (SSNRI). Doctors are hopeful that it will be more effective because the drug targets two key neurotransmitters, serotonin and norepinephrine, in contrast to the SSRIs, which target only serotonin.

In a 2006 UK study of 275 CFS patients, those treated with antidepressants recovered faster than those who did not receive the medication. SSRIs were found to be more effective than tricyclic antidepressants, producing improvements that included a reduction in fatigue that were maintained at the 3-year followup.

Treatment of Neurally Mediated Hypotension

Treating NMH may be appropriate in the subgroup of CFS patients with this condition. In one study, 76% of patients diagnosed with and specifically treated for neurally mediated hypotension (NMH) experienced improvement within a month, and in 40% of these patients, chronic fatigue symptoms completely or nearly completely resolved. It should be stressed that increasing blood pressure can be very dangerous in individuals with existing normal or high blood pressure. No one should take measures to raise blood pressure without a clear diagnosis of NMH or without a doctor's approval.

Life Style Changes. For treating NHM, the doctor might first recommend non-medicinal measures:

• Increasing salt content in the diet may be warranted in patients with demonstrated low blood pressure.
• Caffeinated beverages may be helpful.
• Before getting out of bed, perform exercises that flex the feet so that the blood moves up toward the head.
• Avoid excessive activity after meals.
• Special support garments may help to prevent circulating blood from pooling in the lower part of the body and to return it to the heart.

Medications. If NMH does not improve with lifestyle measures, certain medications may be tried in combination or alone. A wide range of drugs normally used for other disorders have been used to treat NMH, but doctors have had difficulty adjusting them so that they would be effective for NMH without causing distressing side effects. Such medications include:

• Drugs that narrow blood vessels
• NSAIDs
• Anti-arrhythmic drugs (such as disopyramide)
• Beta-blockers (such as propranolol)
• Stimulants (such as methylphenidate)

Other Drugs Being Investigated for CFS

Galantamine . Galantamine (Razadyne) is a cholinesterase inhibitor used to treat Alzheimer’s disease. A multicenter placebo-controlled trial of 434 patients with CFS tested various doses of galantamine during a 16-week study period. Results published in 2004 in the Journal of the American Medical Association clearly demonstrated that galantamine had no effect. This study was the largest CFS trial to date. Although the trial’s results were disappointing, its rigorous study design may serve as a model for future CFS trials.

Corticosteroids. Some evidence exists that patients with CFS may be deficient in cortisol, a steroid hormone. Studies testing the steroid drug hydrocortisone have reported increased energy and less fatigue in patients taking it. However, side effects, including insomnia, increased appetite, weight gain, and, more seriously, suppression of the adrenal gland, make this therapy unacceptable. One study reporting improvement with very low doses (5 - 10 mg daily) with only minor side effects may make this therapy feasible for some patients, but longer-term and larger studies are needed. Fludrocortisone (Florinef) is an oral steroid used for low blood pressure. This has been tested specifically on CFS subjects with NMH, but studies reported no benefits and side effects may be serious.

Psychostimulants. Psychostimulants may be helpful for a subgroup of patients with CFS who have cognitive problems such as difficulty concentrating, memory problems, and other attention deficit disorder (ADD)-like characteristics. Imbalances in norepinephrine and dopamine have been demonstrated in imaging studies of CFS patients, and are thought to be responsible for such symptoms. Although such imaging tests are not available to most patients, experts postulate that the benefit of psychostimulants offers proof that some CFS patients in fact have measurable chemical imbalances. It is not clear whether such imbalances may contribute to causing CFS, or whether the disease underlying CFS causes such changes in neurochemical structures in the brain.

Psychostimulants include Dexamphetamine, Adderal, Ritalin and Ritalin-like drugs such as Focalin, Concerta, Ritalin LA, and Metadate, as well as Strattera and Provigil.

Ampligen. The drug Ampligen is a form of genetic material called double-stranded (ds) RNA, which increases the body's defense against disease. In studies, Ampligen has been shown to improve exercise ability by increasing oxygen utilization. No serious adverse effects have been seen to date. Phase 3 studies are now complete, and the developer has applied for a New Drug Application from the FDA. At this time Ampligen must be administered intravenously twice per week.

D-ribose . D-ribose is another drug targeting cellular energy metabolism. It has been shown to increase cellular energy synthesis in heart and skeletal muscle. In a small study of 41 patients with CFS and or fibromyalgia, D-ribose caused significant improvement in energy, sleep, mental clarity, pain intensity, and well-being. Energy increased an average of 45% and well-being an average of 30%.

Antibiotics. Some patients with CFS exhibit a chronic state of immune activation. Azithromycin has been used to modulate the immune system. In one study, azithromycin reduced symptoms in 58 of 99 participants. Blood tests showed lower levels of plasma acetylcarnitine, likely reflecting lower levels of oxidative stress.

Alternative Remedies

Because of the difficulties in treating chronic fatigue syndrome, many patients seek alternative therapies. Some, such as acupuncture, yoga, and relaxation techniques, may be helpful and are not dangerous. No scientific evidence exists that vitamin and mineral supplements will relieve CFS, but taken in moderation, they are usually not harmful.

Herbal and Supplements . Popular herbal and dietary supplement remedies for CFS include coenzyme Q10, DHEA, ginseng, and acetylcarnitine. None have been rigorously tested. Some herbs, such as St. John’s wort, ginkgo, and comfrey, may cause serious side effects and drug interactions. [See Box: Herbs and Supplements .]

Herbs and Supplements Herbal remedies and dietary supplements are not regulated by the FDA. This means that manufacturers and distributors do not need FDA approval to sell their products. In addition, any substance that can affect the body's chemistry can, like any drug, produce side effects that may be harmful. There have been a number of reported cases of serious and even lethal side effects from herbal products. Some so-called natural remedies have been found to contain standard prescription medication. Of specific concern are studies suggesting that up to 30% of herbal patent remedies imported from China having been laced with potent pharmaceuticals, such as phenacetin and steroids. Most reported problems occur in herbal remedies imported from Asia, with one study reporting a significant percentage of such remedies containing toxic metals. CFS patients should be wary of those that promise a cure or urge the purchase of expensive but useless and sometimes potentially dangerous treatments, such as the following: St. John's Wort. One positive study concerned St. John's Wort, which is being investigated for mild depression. In the study, the herbal agent lessened fatigue in CFS patients, even in those who did not consider themselves to be depressed. Still, even St. John's Wort may have some serious side effects. This agent can interact with blood thinning medication. Of note, in a 2002 brand comparison only three products out of eight were within 10% of the active ingredient amounts claimed on their labels. Melatonin. Some patients use melatonin, based on the association between CFS and possible sleep abnormalities. In a 2002 study, however, melatonin had no effect on symptoms. Gingko. Although the risks for gingko appear to be low, there is an increased risk for bleeding at high doses and interaction with high doses of vitamin E anti-clotting medications. Commercial gingko preparations have also been reported to contain colchicine, an agent that can be harmful in pregnant women and people with kidney or liver problems. It should be further noted that some brands have no effect at all. Comfrey. Comfrey is an herbal remedy used for a number of inflammatory problems. Recently, there is evidence that comfrey can be toxic to the liver and animal studies have reported a possible cancer risk. It is banned in Canada and other countries, but is widely available in the U.S. Of particular note for CFS patients are products containing the ingredient Ma Huang, which contains the stimulants ephedrine and kola nut, a caffeine source. Serious adverse reactions, including seizures, psychosis, and several deaths, have been reported in people taking this supplement for increased energy or weight loss. Products that have only one of these ingredients appear not to have the same effect, but people should take so-called energy boosting supplements only with the knowledge and recommendation of their doctor. Other alternative remedies with no proven benefit and possible toxic and dangerous effects include the following: Hydrogen peroxide injection (can cause blood clots or strokes) Megadoses of vitamins (which can be toxic and have shown no benefits) High colonic enemas Bee pollen (which can cause an allergic reaction) Injections of liver extract Superoxide dismutase (SOD)

• Review Date: 1/4/2007
• Reviewed By: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital

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