Highly Effective Treatment of Fibromyalgia and Chronic Fatigue Syndrome: Results of a Placebo Controlled Study and How to Apply the Protocol
by Jacob Teitelbaum, MD

(Previously Published: Journal of Chronic Fatigue Syndrome Volume 8, Issue 2 – 2001)

     Background: Hypothalamic dysfunction has been suggested in Fibromyalgia (FMS) and Chronic Fatigue Syndrome (CFS). This dysfunction may result in disordered sleep, subclinical hormonal deficiencies, and immunologic changes. Our previously published open trial showed that patients usually improve by using a protocol which treats all the above processes simultaneously. The current study examines this protocol using a randomized, double-blind design with an intent-to- treat analysis.

     Methods: Seventy-two FMS patients (38 active: 34 placebo; 69 also met CFS criteria) received all active or all placebo therapies as a unified intervention. Patients were treated, as indicated by symptoms and/or lab testing, for: (1) subclinical thyroid, gonadal, and/or adrenal insufficiency, (2) disordered sleep, (3) suspected Neurally Mediated Hypotension (NMH), (4) opportunistic infections, and (5) suspected nutritional deficiencies.

     Results: At the final visit, 16 active patients were "much better," 14 "better," 2 "same," 0 "worse," and 1 "much worse" vs. 3, 9,11, 6, and 4 in the placebo group (p < .0001, Cochran-Mantel-Haenszel trend test). Significant improvement in the FMS Impact Questionnaire (FIQ) scores (decreasing from 54.8 to 33.2 vs. 51.4 to 47.7) and Analog scores (improving from 176.1 to 310.3 vs. 177.1 to 211.9) (both with p < .0001 by random effects regression), and Tender Point Index (TPI) (31.7 to 15.5 vs. 35.0 to 32.3, p < .0001 by baseline adjusted linear model) were seen. Long term follow-up (mean 1.9 years) of the active group showed continuing and increasing improvement over time, despite patients being able to discontinue most treatments.

     Conclusions: Significantly greater benefits were seen in the active group than in the placebo group for all primary outcomes. Using an integrated treatment approach, effective treatment is now available for FMS/CFS.

Introduction
    Effective treatment of chronic fatigue syndrome (CFS) and fibromyalgia (FMS) is, in many ways, fairly straightforward, although the lab testing needs to be interpreted somewhat differently than for other conditions. Detailed information is available in the fully updated edition of From Fatigued to Fantastic! (Avery/Penguin-Putnam August 2001), but the core principles can be learned in this article and by reading our two published studies. The full text of both can be seen at www.endfatigue.com. This will help you understand the rationale behind my approach and will give you a good overview of what occurs in CFS/Fibromyalgia. To aid in caring for these complex CFS/FMS patients in the time you have available, patients can also complete an educational program on our website (www.endfatigue.com). This program will analyze their history and labs and print out a complete medical record for that patient (except, of course, for the physical exam) with a treatment protocol and information sheets tailored to that patient's case. For those who cannot prescribe, most of our protocol can be done naturally and patients can obtain a free prescription to take to their lab for the tests they need on our web site. If you are willing to use a significant part of this protocol, we will also be happy to add your name to the free referral list on our website. We also have workshops for health care practitioners.

Why Have These Diseases Been so Confusing?
     CFIDS/FMS represents a syndrome – a spectrum of processes with a common end point. Because it affects major "control systems” in the body, there are myriad symptoms that initially do not seem to be related. Recent research has implicated hypothalamic and mitochondrial dysfunction.³ These explain the large number of symptoms and why most patients have a similar set of complaints.

How to Make the Diagnosis
     The clinical and research criteria for diagnosing CFIDS and FMS are readily available elsewhere. While these criteria are useful for research and for confirming the diagnosis, and FMS requires a tender point exam that takes a good bit of time to master, these clinically add little and will likely be changed in the future. Instead of focusing on the research definition and tender point exam, you may want to begin by asking this series of questions:

•   Have you had pain that lasted over 6 months that affects your upper and lower body and right and left side without a clear cause? If so, you likely have fibromyalgia.

•   Are you exhausted, have 'brain fog' and can't sleep (with no known cause for over 6 months), the symptoms do not go away with rest, and they limit your activity significantly? If the answer is yes, you likely have CFS unless another cause is found.

Also ask the patient if he or she has the following symptoms:

•   Feeling worse (often described as feeling as if he or she was "hit by a truck”) the day after exercise.

•   Brain fog (difficulty with word finding and substitution, poor short term memory and poor concentration).

•   Bowel dysfunction. Many people diagnosed with irritable bowel syndrome (IBS) or spastic colon have CFIDS/FMS.

•   Recurrent infections including chronic sinusitis, and/or chemical/medication sensitivities.

The Causes of CFIDS/FMS
     It is my belief, and that of many other workers in this area, that (1) CFIDS and FMS represent many different processes and subgroups that have a common outcome, and that (2) FMS and CFIDS are often the same disease.

     Current research and clinical experience show that these patients have a mix of disordered sleep, hormonal deficiencies (often with "normal” laboratory test results), low body temperature, and autonomic dysfunction (for example, low blood pressure, and neurally mediated hypotension [NMH]). This mix makes sense when you recognize that the hypothalamus is the major control center for all four of these functions.

     Although still controversial, a large body of research also strongly suggests mitochondrial dysfunction as a unifying theory in CFIDS/FMS. In several genetic mitochondrial diseases, severe hypothalamic damage is seen (possibly because the hypothalamus has high energy needs).⁴ The mitochondrial dysfunction, combined with secondary hypothalamic suppression, can cause the poor function seen in tissues with high energy needs. This includes dysfunction of the immune system, liver (with medication/chemical sensitivities secondary to decreased ability to detoxify), gastrointestinal tract, muscles, and central nervous system (CNS) (brain fog and decreased neurotransmitters).

Evaluating and Treating CFIDS/FMS
     There are many approaches to evaluating this disease. The diagnosis of CFIDS/FMS itself requires little testing. The evaluation of the symptoms, however, which allow for effective treatment, usually requires extensive testing. Although many tests (for example, immune system testing) are interesting, I adhere to tests that will affect treatment. A thorough and systematic approach works best. Following is a discussion of areas to look at.

Hormonal Dysfunction
     This can have several major sources, including hypothalamic dysfunction and autoimmune processes (for example, thyroiditis), as well as other causes. Our current norms and testing often (and in CFS/FMS routinely) miss important deficiencies. For example, increased hormone binding to carrier proteins is often present in CFIDS/FMS. Because of this, total hormone (for example, testosterone) levels are often normal while the active hormone levels are low. Also, many blood tests use two standard deviations to define blood test norms. This means you have to be in the lowest or highest 2 to 3 percent of the population to be abnormal. Using this definition would result in an income of $8100/year being considered medically "healthy." Normal does not necessarily mean either healthy or optimal! Other tests use late signs of deficiency (for example, anemia or life threatening hypotension) to define an abnormal lab value. These ranges are inadequate in CFIDS/FMS. You should aim for the mid-range of normal.

Thyroid Function
     Suboptimal thyroid function is very common and very important. Because thyroid-binding globulin function and conversion of T4 to T3 may be altered if you have CFIDS/FMS, it is important to check a free (or total) T3 and a free T4 (not T7 or T3RU). I discussed hypothyroidism with Dr. Janet Travell, the world's leading authority on muscle disorders, at her 94th birthday party. Dr. Travell was an emeritus professor of medicine at George Washington Medical School and was the White House physician for Presidents Kennedy and Johnson. She felt that it was important to treat all chronic myalgic patients with thyroid hormone replacement if their T3 or T4 blood levels were below even the fiftieth percentile of normal. She was right. Many CFIDS/FMS patients also have difficulty in converting T4 (which is fairly inactive) to T3 (the active hormone). Blood levels (even a T3 level because of T3 being intracellular and its conversion to reverse T3) can miss this problem. Synthroid has only inactive (storage form) T4. I prefer Armour Thyroid which has both inactive T4 and active T3. Many clinicians will give an empiric trial of Armour Thyroid, 1/2 to 2 grains (30-120 mg) QAM. I am more likely to try an empiric trial of thyroid-hormone therapy if one or more of the following is true:

•   The patient has fibromyalgia, and/or

•   The patient's oral temperatures are generally less than 98.2°F, and/or

•   The patient has symptoms and signs suggestive of hypothyroidism, and/or

•   The patient's TSH test result is less than 0.95 or greater than 3.0, and/or

•   The patient's T3 or T4 are below the fiftieth percentile of normal.

     As physicians, we are trained to interpret a low-normal TSH-that is, 0.5 to 0.95 as a confirmation of euthyroidism. The rules, however, are different with CFIDS/FMS. In this setting, hypothalamic hypothyroidism is common and the patient's TSH can be low, normal, or high.⁵ This is why I recommend an empiric therapeutic trial of thyroid-hormone treatment if the TSH and T4 are both low normal. Also, if sub-clinical hypothyroidism is missed, the patient's fibromyalgia simply will not resolve. The inadequacy of thyroid testing is further suggested by studies that show:

•   That most patients with suspected thyroid problems have normal blood studies.⁶

•   That when these patients with symptoms of hypothyroidism and normal labs were treated with thyroid (Synthroid in an average dose of 120 mcg every day [qd]) a large majority improved significantly.⁷

In addition, I would add the following:

•   If the patient does not respond to Synthroid, switch to Armour Thyroid, and vice versa. For every 50 mcg of Synthroid, have the patient take 1/2 gr (30 mg) of Armour Thyroid. If the free or total T3 result is low or low normal, begin with Armour Thyroid, which has both T3 and T4, instead of Synthroid, which has only T4. I usually recommend beginning with Armour Thyroid.

•   Adjust the thyroid dose according to how the patient feels and also to keep oral temperatures greater than 98°F, as long as the T3 or T4 tests do not show hyperthyroidism. Do not use TSH to monitor thyroid replacement. Because of the hypothalamic suppression, it may be low despite inadequate hormonal dosing.

•   Make sure that the patient does not take any iron supplements within six hours or calcium within two hours of the morning thyroid dose or the thyroid hormone will not be absorbed. Have the patient take the iron between 2:00 and 6:00 p.m. on an empty stomach and away from any hormone treatments.

•   Thyroid supplementation can increase a patient's cortisol metabolism and unmask a case of subclinical adrenal insufficiency. If a patient with symptoms of low thyroid feels worse on low-dose thyroid replacement, the patient may have adrenal (or thiamine) insufficiency. Consider treating the adrenal insufficiency first, and add thiamine 500 mg 2x day and taurine 1000mg 3x day for 4-6 weeks and then retry the thyroid treatment.

     In addition, if the midday temps are under 98.1°F, consider iodine 1500 mg/day for 1-2 months. This will often raise the temperatures and ease symptoms. Dr. Richard Shames has noted that iodine may flare symptoms in patients with Hashimoto's thyroiditis and should be stopped if this occurs.

     Research by John Lowe DC suggests that thyroid receptor resistance occurs in fibromyalgia. Some patients who fail regular thyroid hormone treatment respond dramatically to high dose T3 sustained release. Remember that every patient is an individual and will respond differently to treatment.

Adrenal Insufficiency
     The hypothalamic-pituitary-adrenal (HPA) axis does not function well in CFIDS/FMS.⁸ Dr. William Jefferies, a professor of medicine at the University of Virginia Medical School and previously a professor at Case Western University School of Medicine, is the world's leading clinical expert on subclinical adrenal insufficiency. His book Safe Uses of Cortisol discusses the history of this disease and its treatment.⁹ Because early researchers used massive doses of cortisol (not knowing the physiologic dose), their patients developed severe complications. What is not common knowledge is that these side effects are not seen with physiologic dosing of Cortef (that is, up to 20 milligrams [mg] a day).¹⁰ Twenty mg of hydrocortisone (Cortef) is equal to 4 to 5 mg of prednisone.

     To put it in perspective, if the early thyroid researchers had given ten times the physiologic dose of thyroid hormone (for example, 1,000 to 2,000 mcg qd instead of 100 to 200 mcg), a situation analogous to early adrenal research, many people would have had severe complications. Thyroid hormone would be viewed as very dangerous and we would only be treating hypothyroid patients on the verge of myxedema coma. In adrenal insufficiency, this is what occurs now. Many hypoadrenal patients are only treated when they are ready to go into Addisonian crisis. Research and clinical experience shows that this approach misses most hypoadrenal patients.¹¹

     Symptoms of an underactive adrenal include weakness, hypotension, dizziness, sugar craving, and recurrent infections – all of which are common in CFIDS/FMS. I evaluate CFIDS/FMS patients' adrenal function with a morning cortisol level and, when available, a cortrosyn stimulation test. The test must begin between 7:00 and 9:00 a.m. The patient should not eat anything the morning of the test and also have no caffeine for twenty-four hours before the test. Check a baseline cortisol level and, if convenient, then do the cortrosyn stimulation test by giving ACTH (Cortrosyn) 25 units or 1 unit IM (current data suggests the 1 unit Cortrosyn test is more reliable) and recheck cortisol levels at one-half hour and at one hour. Although a baseline of 6 mcg/dl is often considered "normal,” most healthy people run approximately 16 to 24 mcg/dl at 8:00 a.m.

     My treatment guidelines are that if the baseline cortisol is less than 16 mcg/dl or the cortisol level does not increase by at least 7 mcg/dl at thirty minutes and 11 mcg/dl at one hour, or does not double by one hour and is less than 35 mcg/dl, I treat for adrenal inadequacy. Natural treatments include:

1.  Adrenal Glandulars.

2.  Panax ginseng 100-500 mg 2 x day

3.  Sustained release pantothenic acid (Vitamin B5) 1000 mg 2 x day

4.  Vit C 500-2000 mg/day

5.  Licorice(not DGL)

     If these do not take care of the problem, consider a therapeutic trial of 5 to 15 mg Cortef in the morning, 2.5 to 10 mg at lunch time and 0 to 2.5 mg at 4:00 p.m. (maximum of 20 mg a day). Most patients find 5 to 7 1/2 mg qAM plus 2 1/2 to 5 mg at noon to be optimal (the equivalent of 1 1/2 to 3 mg prednisone daily). Cortef is much more effective than prednisone in CFIDS/FMS.

     After nine to eighteen months, taper the treatments off over a period of one to four months. If the other physiologic stresses, such as infections or fibromyalgia, have been eliminated, the patient's adrenal function may be adequate or normalized. If symptoms recur after the treatments, continue treatment with the lowest optimal dose.

     Improvement is often dramatic and is usually seen within two to four weeks. If using glandulars or Cortef, the dose should be doubled during periods of acute stress and raised even higher during periods of severe stress such as surgery. Consider also giving the patient 1,000 mg of calcium and 400 international units (IU) of vitamin D daily with Cortef.

     There are different approaches to treatment and more is not better. High dose Cortisol taken at night will worsen already disrupted sleep patterns. A recent study by Strauss published in the Journal of the American Medical Association gave too high a dose (about 25 to 35 mg a day) and too much at night – severely disrupting patients' sleep (p<.02). Although he did not treat the sleep disorder, most patients felt somewhat better on treatment. A small percentage of the patients had significantly decreased post treatment Cortrosyn tests, without complications, and he, I believe incorrectly, recommends against using Cortef in CFIDS/FMS.¹² Our study did not show adrenal suppression using lower Cortef dosing.¹³ Dr. Jefferies, with thousands of patient-years' experience in using low-dose Cortef, recommends an empiric trial of Cortef in all patients with severe, unexplained fatigue.¹⁴ Our research and clinical experience suggests this is the best approach.

DHEA
     Dehydroepiandrosterone (DHEA) is a major adrenal hormone that has recently been getting a lot of attention in the press. Although its function has not yet been determined, it plays an important role in people's sense of well-being.¹⁵ Like any hormone, it is best kept near the midrange of optimal. I suspect that too high or too low a level can cause problems. I use the middle of normal range for a 29-year-old, keeping the DHEA-sulfate (DHEA-S) level at 150 to 180 mcg/dl in females and 350 to 480 mcg/dl in males.

     The majority of CFIDS/FMS patients have suboptimal DHEA-S levels, and the benefit of treatment is often dramatic. Most females need 10 to 25 mg a day and most males 25 to 50 mg a day. Adjust to the dose that feels best, as long as the DHEA-S level stays under 200 mcg/dl in females and 480 mcg/dl in males.

     Interestingly, as patients improve, their bodies begin to make DHEA on their own and the DHEA-S level can shoot up. If the level goes too high, the patient can get acne or darkening of the facial hair. Because of this, it is reasonable to initially check the DHEA-S level every 2-4 months in a female or every 3-6 months in a male. Although the body's DHEA-S level is fairly stable throughout the day, which is why I check the DHEA-sulfate level as opposed to the much more variable DHEA level, the DHEA-S level does show significant peaks and troughs when DHEA is taken by mouth. I recommend either prescribing timed-release DHEA (available at General Nutritional Centers) or using two to three times a day (b.i.d-t.i.d.) dosing and check blood levels two to four hours after taking a dose of DHEA. When the DHEA-S level rises over 200 mcg/dl in a female or 450 mcg/dl in a male, start to taper the dose.

     Do not be surprised if a patient's gray hair turns back to its original color in six to eighteen months. This is one reason DHEA got the name "the fountain of youth hormone.”

Low Estrogen and Testosterone
     Although we are trained to diagnose menopause by cessation of menses, hot flashes and elevated FSH and LH, these are late findings. Estrogen deficiency often begins many years before, and may coincide with the onset of fibromyalgia.¹⁶ To compound the problem, research done by Dr. Phillip Sarrel at Yale shows that 60% of women who have a hysterectomy (even with the ovaries left in) will go into menopause within six months to two years.¹⁷ The same may apply to women who have had a tubal ligation. This is not something we were taught in our medical training, and has major implications for younger women who have had hysterectomies or tubal ligations!

     In her book on estrogen and testosterone deficiency, Dr. Elizabeth Vliet gives a well referenced foundation for evaluation and treatment of these problems.¹⁸ To summarize, the initial symptoms of estrogen deficiency are poor sleep, poor libido, brain fog, achiness, PMS, and decreased neurotransmitter function. Dr. Vliet feels that estradiol levels at midcycle should be at least 100 pg/ml. If a woman's CFIDS/FMS symptoms are worse at ovulation and the ten days before her period, or if there is inadequate vaginal lubrication and/or hot flashes, then a trial of estrogen is warranted. It is reasonable to use natural 17-B-estradiol instead (for example, Estrace or Climara patches). Transdermal estrogen has the added benefit of raising growth hormone (which is low in FMS), where oral estrogen does not. Some women feel better with bi-estrogen (developed by Dr. Jonathan Wright) which also contains the estrogen of pregnancy. Interestingly, women with FMS usually feel better during pregnancy.

     The usual dose of Climara is one 0.05 to 0.1-mg patch a week, Estrace is 1/2 to 2 mg a day, and Bi-est is 1 1/4 - 2 1/2 mg 1-2 x day adjusted to what feels best to the patient. In the absence of a hysterectomy, progesterone should be added to prevent uterine cancer. Natural progesterone (available from most pharmacies as Prometrium 100 mg), is better tolerated than Provera. The dose is 100 mg at bedtime (qhs), instead of Provera 2.5 mg, or 200 mg a day for ten to fourteen days a month, instead of Provera 10 mg. Progesterone helps sleep and is best taken at night. It is appropriate to try progesterone even in women who have had a hysterectomy if it helps their symptoms. Many practitioners give only progesterone, an approach popularized by Dr. John Lee.

Testosterone Deficiency
     Testosterone deficiency is important in both males and females. It is important to check a free (not total) testosterone level. If the age-adjusted free testosterone is low or low-normal, a trial of treatment is often very helpful. Seventy percent of my male CFIDS/FMS patients and many of my female patients have low free testosterone levels (and normal total testosterone levels). Be sure the free testosterone normal range is "age-adjusted” using ten-year age groups (for example, twenty to thirty years old). It is meaningless to have a normal range that includes 80-year-olds if the patient is twenty-eight. If the result is below normal, and possibly even in the lowest 20% of the normal range, I would consider a trial of testosterone.

     For men, the standard dose is about 100 to 125 mg by intramuscular injection (IM) every seven to ten days. It can also be given as 200 mg each two weeks, but this can result in peak levels (right after the shot) that are too high, and levels that go too low for a few days before the next shot. Adding the testosterone patches on day nine through fourteen (when getting the shot every fourteen days) can avoid the levels going too low. I feel that giving the shot weekly is much better, however. I use Delatestryl 200 mg/cc and give 1/2 or 6/10 cc every seven to ten days. Unfortunately, the skin patches alone are not adequate for the job. Although I've avoided using testosterone tablets in men, testosterone cream (100 mg/gm in PLO Gel) 25 to 50 mg 1-2 x day (available from most compounding pharmacists) can be very effective. I will sometimes wait until after a patient has been on the shots for eight weeks so he can tell what the optimum effect is. The problem (for men) with taking tablets instead of transdermal creams is that oral testosterone goes to the liver first. The higher dose in men (versus women) can sometimes raise cholesterol levels (cholesterol is produced by the liver). Avoiding other possible side effects by taking the transdermal hormone daily, instead of getting high and low levels by taking it IM every week or two, may be another benefit of the transdermal creams. The benefits of treatment (it takes six to eight weeks to see the effect) are often dramatic. Androderm gel (25 and 50mg/5cc) is also now available in most pharmacies, but is much more expensive than compounded testosterone.

     For women, the treatment is easier. Natural micronized testosterone (and natural estrogen and progesterone) are available through most compounding pharmacies. Belmar pharmacy and Cape Drugs are two of many that do mail-order prescriptions. The usual dose is 2 mg one to two times a day by mouth (po) or transdermally (4mg/gm cream). If the patient needs estrogen or progesterone, these hormones can be combined in the same capsule for a lower cost.

     I check free testosterone blood levels (in men and women) six to eight weeks after starting therapy (in men, before their eight-week shot) and adjust the dosing accordingly. Blood levels are not reliable, however, if the patient is taking synthetic methyl testosterone instead of natural testosterone. In addition, blood levels for oral or transdermal dosing peak at about two to three hours and are back to baseline by five hours, so the blood level should be checked two to three hours after oral or transdermal dosing.

     In women, if acne, intense dreams, or darkening of facial hair occurs (as can occur with DHEA as well), the dose is too high and should be decreased (these are usually reversible). These side effects can also be caused by estrogen being too low, relative to the testosterone level and may be avoided in women by supplementing both together. In men, acne suggests the dose is too high. It is important to monitor levels because (as in body builders who abuse testosterone by taking many times the recommended physiologic dose) elevated levels can cause elevated blood counts, liver inflammation, decreased sperm counts with infertility (also usually reversible) and elevated cholesterol with increased risk of heart disease. Because of this, in men, I would monitor a CBC, cholesterol, and liver enzymes intermittently. Testosterone supplementation can also cause elevated thyroid hormone levels in those taking thyroid supplements. If the patient is on thyroid supplements, I would recheck thyroid hormone levels after six to twelve weeks or sooner if they get palpitations or anxious or hyper feelings. Raising a low testosterone level has been shown repeatedly to lower cholesterol, decrease angina and depression, and improve diabetes. Unfortunately, our training mostly focused on the effects of abusing testosterone with pharmacologic and illicit dosing.

Disordered Sleep
     A foundation of CFIDS/FMS is the sleep disorder.¹⁹ Many patients can only sleep three to five hours a night with multiple wakings. Even more problematic is the loss of deep stage 3 and 4 "restorative” sleep. Using treatments that increase deep restorative sleep, so that the patient gets seven to nine hours of solid sleep without waking or hangover, is critical. Begin with natural remedies, adding the medications if needed.

     I do not recommend most addictive sleeping pills. Most addictive sleep remedies, except for clonazepam (Klonopin) and alprazolam (Xanax), actually decrease the time that is spent in deep sleep and can worsen fibromyalgia.

     The treatments that I do recommend include the following:

Natural remedies:

•   I have designed a wonderful herbal sleep formula containing valerian root, hops, Jamaican Dogwood, Wild Lettuce, L-theanine, and passion flower. It is much more effective than any other sleep formula I've tried and is wonderful. I have a strict policy of not taking money from any company whose products I recommend and all of my royalties are donated to charity (often further helping holistic causes).

     The product "Revitalizing Sleep Formula" can be found in health food stores and practitioner's offices (from Enzymatic Therapies/PhytoPharmica)

•   Melatonin-1/2 mg /night is optimal for most patients, although some benefit from higher doses.

•   5-HTP at 300 mg/ night has been shown to decrease pain and improve sleep.²⁰ but it is expensive. The dose should be lowered to ~150 mg /day in those on anti-depressants.

•   Kava kava is helpful but may cause liver problems.

•   Calcium and Magnesium taken at bed time can improve sleep.

•   Lemon balm is somewhat helpful.

•   Pregnenolone 150 mg/night may also help.

     If the natural remedies do not result in at least 8 hours of deep sleep a night, consider adding these meds:

•   Doxylamine (Unisom for Sleep), 25 mg qhs.

•   Zolpidem (Ambien), 5 or 10 mg. Use 5 to 20 mg qhs.

•   Cyclobenzaprine (Flexeril), 10 mg, and/or carisprodol (Soma), 350 mg. Use 1/2 to 2 tablets qhs.

•   Trazodone (Desyrel), 50 mg. Use 1/2 to 6 tablets qhs.

•   Amitriptyline (Elavil), 10 mg. Use 1/2 to 5 tablets qhs. This drug causes weight gain and can worsen NMH.

     Some patients will sleep well with the natural remedies, and others will require all of the above combined. Because the malfunctioning hypothalamus controls sleep and the muscle pain also interferes with sleep, it is often necessary and appropriate to use multiple sleep aids. Because of next-day sedation and possibly slow liver clearance, CFIDS/FMS patients do better combining low doses of several treatments than with a high dose of one.

     Although less common, two other sleep disturbances must be considered and, if present, treated. The first is sleep apnea. This should especially be suspected if the patient snores and is overweight and hypertensive. Sleep apnea is treated with weight loss and nasal C-pap. Restless leg syndrome (RLS or PLMs), is also more common in fibromyalgia.²¹ (Yunus, 1996). Asking the patient if the bed sheets are scattered about when he or she awakes and/or if the patient kicks his or her spouse during the night will often let you know RLS is present. RLS is treated with iron if the ferritin level is under 40,Vit E 400 units/day, Kava, Ambien, or Klonopin. If these conditions are present and the patient does not improve with our treatment, I would consider a sleep apnea study. I would get pre-approval from the patient's insurance company, as the test usually costs $1,500 to $2,000. Another cheaper option is to have the patient video tape themselves at night to look for apnea or PLMs.

Autonomic Dysfunction
     Low blood pressure and dizziness, increased thirst, polyuria, cold extremities, and night sweats are a few of the symptoms that reflect autonomic dysfunction in CFIDS/FMS. A recent study at John Hopkins Hospital showed that a majority of CFIDS patients had neurally mediated hypotension (NMH) on tilt table testing.²² This means that CFIDS/FMS patients can severely drop their blood pressure with standing or minimal exertion. If the patient has a low BP or dizziness or a positive tilt table test, a treatment trial is appropriate. I predominantly use clinical history and the "poor man's tilt table test” (free instead of $1,800), which consists of having the patient stand and lean against the wall for ten minutes. If this aggravates symptoms, the test is positive. Treatment consists of markedly increasing salt and water intake. Treating adrenal insufficiency as discussed above is also helpful. For those familiar with applied kinesiology, using Autonomic Response Testing (developed by Dr. D Klinghardt) and other protocols can also be helpful. The medications Fluoxetine (Prozac), sertraline (Zoloft), ephedrine (not pseudoephedrine), and dextroamphetamine (Dexedrine) are also effective in treating NMH in CFIDS patients. I rarely use Florinef in anyone over 18 years old.

Immune Dysfunction and Infections
     Although not as severe as AIDS, and not progressive, marked immune dysfunction is part of the process (CFIDS stands for chronic fatigue and immune dysfunction syndrome). Because of this, some of the opportunistic infections seen in AIDS are present in CFIDS/FMS. These include yeast overgrowth with secondary chronic sinusitis, bowel infections (with parasites, fungal, and bacterial overgrowth as in AIDS – often with agents that are nonpathogenic in healthy people), UTIs, and chronic, low-grade prostatitis. These need to be treated.

     In my experience, chronic sinusitis responds well to anti-fungals and poorly to antibiotics. Conservative measures (for example, saline nasal rinsing, avoiding milk products, and so on) are also helpful. These are discussed in my book, and are reviewed at length in the wonderful book Sinus Survival written by Dr. Robert Ivker (Tarcher Putnam, 2000).²³ Avoiding antibiotics also decreases the risk of secondary fungal overgrowth in the sinuses and GI tract. Many patients find that a nose spray containing Bactroban, Xylitol, and sporanox can also be very helpful (compounded by Cape Drug by prescription: 410-757-3522)

     Bowel infections with alterations of normal bacterial flora, fungal overgrowth, and parasitic infections (parasites are seen in one-sixth of my patients) are the norm in this disease. This is reflected by the patient's bowel symptoms. Because of the lack of a definitive test for yeast overgrowth, I treat for yeast empirically based on the patient's history. Stool testing for all infections by Great Smoky Mountain Labs can also be very helpful.

     A history of frequent yeast vaginitis, frequent antibiotic use (especially tetracycline for acne), onchomycosis, chronic sinusitis, or gas, bloating, diarrhea or constipation, in my experience with over 1,000 CFIDS/FMS patients, warrants an empiric therapeutic trial of anti-fungal therapy. Many CFIDS/FMS patients who failed other therapies for spastic colon have responded dramatically to anti-infectious treatments. This was also shown in our 1995 study.²⁴

     Treating for fungal infections is critical in most CFS/FMS patients. Natural remedies include:

1.  Acidophilus and other probiotics. Unfortunately, many have been found to not maintain their potency when tested. The product made by Enzymatic Therapies has, however been proven to have the labeled potency. Take 3-6 billion units (bacteria) daily – preferably on an empty stomach.

2.  Caprylic acid 650 mg 3 x day.

3.  Oregano oil – Must be enteric coated to avoid reflux

4.  Citricidal, Pau D' Arco and lavender oil can also be helpful.

     Prescription treatment consists of nystatin, two 500,000-IU tablets po bid or t.i.d. (start slowly) for five months. The patient's symptoms, especially fibromyalgia pain, may flare initially as the yeast die off. Therefore, begin with one 500,000-unit tablet of nystatin once a day and increase by one tablet every one to three days, as tolerated, up to two tablets t.i.d. After four weeks on the nystatin, add 200 mg of fluconazole (Diflucan) or itraconazole (Sporanox) qd for six weeks. Mild liver enzyme elevations are sometimes seen with Diflucan and Sporanox, but taking lipoic acid, 200 mg/d, seems to markedly decrease this side effect. The other major side effect of both Diflucan and Sporanox is the price – a six-week course can cost more than $600. If symptoms recur after the first six weeks on Diflucan or Sporanox, I recommend repeating the 200 milligrams per day for another six weeks. If no benefit is derived from the first course, I do not recommend repeating it. Have your patient stay on the nystatin for a total of five to eight months. I recommend patients be on nystatin while they are taking Sporanox or Diflucan to avoid development of resistant organisms.

     Parasitic infections, often with "nonpathogenic” or normally self-limiting organisms (again, as seen in AIDS patients) are common. Stool samples can be sent to your local lab for antigenic and chemical testing for giardia, cryptosporidium, and especially clostridium difficile (which was present in approximately 22% of our CFIDS study patients versus approximately 1% of the healthy populace). The only labs I would use for microscopic O&P (parasite) testing, however, are the Great Smokies Diagnostic Laboratory or the Parasitology Center. Sending the O&P to most other labs is a waste of money. Most labs will often report stool O&P's as being negative, even if parasites are present. If the patient has any parasites (even if nonpathogenic) treat them. If he or she uses well water, I would recommend a water filter that eliminates parasites (most do not) such as the Multi-Pure filter.

     In patients with low-grade fevers (anything over 98.6°F in CFIDS/FMS patients), occult infections (for example, Chlamydia and mycoplasma incognitus) are being found. Empiric therapy with doxycycline 100 mg bid for six months to two years (while on nystatin) can be very helpful. Recent research is showing that HHV-6, CMV, and EBV are also commonly active in CFIDS/FMS. Natural therapies with olive leaf 500-2000 mg 3-4 x day may be helpful as is immune stimulation with Thymic Protein A (Pro Boost). The latter is a wonderful product and is my favorite way to stimulate thymic immune function. In my experience, it knocks out most acute infections within 24 hours!

     Treating sleep, hormonal and nutritional deficiencies also will usually allow the person's immune system to heal so they can eliminate most infections without antibiotics.

Nutritional Deficiencies
    CFS and FMS patients are usually nutritionally deficient. This occurs because of (1) malabsorption from bowel infections, (2) increased needs because of the illness, and (3) inadequate diet. Although space does not allow a detailed discussion of all the nutritional deficiencies here, the B-vitamins (including B12), magnesium, iron, sulfur, amino acids, coenzyme Q10, malic acid, and aspartates, and other minerals are especially critical.²⁵ These nutrients (and others) are also critical for many other processes. Although blood testing is not reliable or necessary for most nutrients (proper supplementation will cover most of these), checking for iron and vitamin B12 deficiencies are very important.

     I would treat CFIDS/FMS patients with:

1.  Daily Energy Enfusion Powder (1 scoop /day in water) and one tablet of the accompanying B-complex (both made by Enzymatic Therapies. Because of my frustration with the incredible number of tablets a day these patients needed to take for proper nutritional support, I developed these products so that 1 scoop and 1 tablet a day replaces ~25 tablets while supplying solid nutritional support (for most people-not just those who are ill!).

2.  If the iron percent saturation is under 22% or the ferritin is under 40 mg/ml (check both!), give iron. Food decreases absorption by over 60%. Iron should not be taken within six hours of thyroid (and possibly other hormones), as it blocks thyroid absorption. This is not in the powder as you only want to give iron if it is low.

3.  If B12 is under 540 pg/ml, I recommend B12 injections, 3,000 micrograms IM three times a week times for twelve weeks, then as needed (prn). Recent reports on CFIDS are showing absent or near-absent CSF B12 levels with low normal serum B12 levels (Regland, B).²⁶ Metabolic evidence of B12 deficiency is seen even at levels of 540 pg/ml or more.²⁷ Severe neuropsychiatric changes are seen from B12 deficiency even at levels of 300 pg/ml (a level over 209 is technically normal).²⁸ As an editorial in The New England Journal of Medicine notes, the old-time doctors may have been right about giving B12 shots.²⁹ Compounding pharmacies can make B12 at 3,000 mcg/cc concentrations. I use hydroxycobalmin. The powder has a very high amount of B12 (500 mcg).

4.  Coenzyme Q10, 200 mg a day is often helpful during the first 3-6 months of treatment. Take with oil to improve absorption.

5.  Essential fatty acids ~ 5000 mg /day can be helpful if the patient has dry eyes, mouth and/or skin. I would use fish or flaxseed oil (or 3-4 servings of tuna or salmon a week) with some added borage or primrose oil.

6.  K-Mg aspartate. This is very helpful in fatigue states.³⁰ The dose is 500 milligrams, 2 bid for three months (then stop). Most brands may not work as they are not chemically fully reacted (Hicks, 1964).³¹ General Nutrition Centers' house brand appears to be an effective product.

7.  The patient should avoid sugar, caffeine, and excess alcohol (warn him or her that there may be a seven to ten-day withdrawal period when coming off the sugar and caffeine).

Resources
     For the last 27 years (since I developed CFS/FMS in 1975), my team and I have had a straightforward goal – making effective treatment available for everyone with these syndromes. To do this we developed effective treatment (based on the work of scores of giants in the field of Holistic Medicine) and did the solid studies needed to both demonstrate the treatment's effectiveness, while also protecting the practitioners using it. These patients are very complex (a new patient visit in my office takes ~ 4 hours – mostly for the counseling and teaching). I recognize that most practitioners cannot spend this much time. Because of this we developed a sophisticated computer program on our Web site (www.endfatigue.com) that the patient can use in their home. It will elicit a detailed history and analyze it, along with the patient's labs (and can even give the patient a lab requisition) to create a thorough medical record. It will also then analyze the data to determine which of over 100 diagnoses are contributing to their CFS or FMS, make detailed treatment recommendations (with both prescription and non-prescription options) and give detailed information sheets (basically a book written for that patient's case). This will free up hours of time so you can listen to and be present with the patient – instead of wasting your time doing what a computer can do!

     Because of the cost of developing (~$500,000 in time and programming costs) and maintaining the program (>$3000/mo) we do charge a modest $160 for a patient to do the program. Practitioners can get the codes wholesale @$95 and Medicaid patients can get a code for free.

     To assist patients in finding practitioners, the Web site also has a referral list that any practitioner can add their name to (at no charge) if they use a significant part of our protocol (simply click on "physicians" and enter your info). We will be beginning 2-day workshops for both prescribing and non-prescribing practitioners on November 2-3, 2002. Those who take the training will be highlighted on the referral list. E-mail Amy@endfatigue.com for more information.

     The Web site has the full text of both studies and many other free resources.

     My nutritional and sleep formulas by Enzymatic Therapies will be a dramatic benefit for most of your patients who need nutritional or sleep support. We will likely develop a line of products to help your patients. As my entire royalty goes to charity, this money can then be used for other wonderful causes!

Final Thoughts
     Many illnesses are associated with various psychological profiles. For example, a "helpless/hopeless” attitude is associated with cervical cancer and hostility with ASCVD. In CFIDS/FMS, a common profile is a "mega-type-A” overachiever who, because of childhood low self esteem, overachieves to get approval. They tend to be perfectionists and have difficulties protecting their boundaries – that is, they say yes to requests when they feel like saying no. Instead of responding to their body's signal of fatigue by resting, they redouble their efforts. Taking time to rest, and getting and staying out of abusive work environments (even after they feel better on treatment!) is critical. As they start to feel better, they need to be instructed to take it slow, and not to go back to the level of over-functioning that made them sick in the first place. They especially need to be instructed not to make up for lost time.

     In treating over 2,000 CFIDS/FMS patients, a treatment protocol has now evolved that offers effective therapy for the >6 million Americans unnecessarily crippled with CFS/FMS. Our initial pilot study and our follow-up randomized trial show that over 85% of patients improved with treatment (Teitelbaum, Bird, 1995 and 2001) (see www.endfatigue.com).³² These very ill patients require time and compassion – as well as an organized treatment approach.

     References available on request or in the Appendix A section of my book From Fatigued to Fantastic!

Correspondence:

Jacob Teitelbaum, MD
Diplomate American Board of Internal Medicine
466 Forelands Road
Annapolis, Maryland 21401 USA
410-573-5389
Fax 410-266-6104