Pathophysiology and Diagnosis/Assessment: Overview
Chronic fatigue syndrome (CFS)and fibromyalgia (FMS) are two common names for an overlapping spectrum of disabling syndromes. Although we still have much to learn, effective treatment is now available for the large majority of these patients.1,2 Research suggests that mitochondrial and hypothalamic dysfunction are common denominators in these syndromes.3,4 Dysfunction of hormonal, sleep, and autonomic control (all centered in the hypothalamus) and energy production centers can explain the large number of symptoms and why most patients have a similar set of complaints.
To make it easier to explain to patients, we use the model of a circuit breaker in a house: If the energy demands on the body are more than it can meet, the body "blows a fuse." The ensuing fatigue forces the person to use less energy, protecting her from harm. On the other hand, although a circuit breaker may protect the circuitry in the home, it does little good if you do not know how to turn it back on or that it even exists.
This analogy actually reflects what occurs. Research in genetic mitochondrial diseases shows not simply myopathic changes, but also hypothalamic disruption. As the hypothalamus controls sleep, the hormonal and autonomic systems, and temperature regulation, it has higher energy needs for its size than other areas. In addition, inadequate energy stores in a muscle results in muscle shortening (think of writer's cramp) and pain which is further accentuated by the loss of deep sleep. Restoring adequate energy production through nutritional, hormonal, and sleep support and eliminating the stresses that overutilize energy (e.g., infections, situational stresses, etc.) restore function in the hypothalamic "circuit breaker" and also allow muscles to release, thus allowing pain to resolve. Our placebo controlled study showed that when this is done, 91% of patients improve, with an average 90% improvement in quality of life, and the majority of patients no longer qualified as having FMS by the end of three months (p < .0001 vs. placebo).2
CFS, fibromyalgia, and to some degree myofascial pain syndrome reflect an energy crisis in the body. It is similar to blowing a fuse in your home. There can be many causes, it protects the body from further harm, but it dramatically reduces function. Causes include infections, disrupted sleep, pregnancy, hormonal deficiencies, toxins, and other physical and/or situational stresses. The "blown fuse" is the hypothalamus – resulting in poor sleep and hormonal, autonomic, and temperature dysregulation.
A Simple Diagnostic Approach
If the patient has the paradox of severe fatigue combined with insomnia (if a person is exhausted, he should sleep all night), and these symptoms do not go away with vacation, she likely will have a CFS related process. If he also has widespread pain, fibromyalgia is probably present as well. Both respond well to proper treatment as discussed below.
An Integrated Therapeutic Approach
Two studies (including our RCT) showed an average 90% improvement rate when using the "SHINE" protocol for treating CFS and fibromyalgia. SHINE stands for Sleep, Hormonal support, Infections, Nutritional support, and Exercise as able. A free "Symptom Analysis" program at www.Vitality101.com can analyze your patients' symptoms (and, if available, the key labs) to determine the underlying causes of their CFS/FMS and will tailor a treatment protocol to their case – dramatically simplifying care.
Using the acronym SHINE will simplify treatment of these patients. Because of this, we will structure our treatment recommendations using this model. Let's begin with S for sleep.
A foundation of CFS/FMS is the sleep disorder. Many patients can only sleep solidly for three to five hours a night with multiple wakings. Even more problematic is the loss of deep stage 3 and 4 "restorative" sleep. Using natural therapies and/or medications that increase deep restorative sleep, so that the patient gets seven to nine hours of solid sleep without waking or hangover, is critical. Continue to adjust the treatments each night until the patient is sleeping eight hours a night without a hangover.
Most addictive sleep remedies actually decrease the time spent in deep sleep and can worsen fibromyalgia. Therefore, they are not recommended. There are over 20 natural and prescription sleep aids that can be tried safely and effectively in fibromyalgia and CFS. For a more detailed list, see my free "long form" treatment protocol (discussed under "Treatment Tools" at end of this article).
The natural sleep remedies that I recommend you begin with include the following:
If natural remedies are not adequate to result in at least 8 hours a night of sleep, consider adding low doses of the medications Zolpidem (Ambien) 5 to 10 mg; Neurontin 100 to 900 mg; Flexeril 5mg; and/or Trazodone (Desyrel) 25 to 50 mg.
1. Herbal: containing (per capsule) valerian (200 mg), passionflower (90 mg), L-theanine (50 mg), hops (30 mg), wild lettuce (18 mg), Jamaican dogwood (12 mg). These are all combined in an excellent product called the Revitalizing Sleep Formula by Integrative Therapeutics. Patients (and anyone with poor sleep) can take 1 to 4 caps at bedtime. I would note as an aside that, although I am very picky about what products I recommend, I have a policy of not taking money from any natural or pharmaceutical companies, and 100% of the royalties for my products also go to charity.
2. Melatonin: ½ mg–5 mg at bedtime (½ mg is usually optimal for sleep but higher doses may decrease nighttime acid reflux).
3. The smell of lavender helps sleep, 2 to 3 sprays on the pillow at bedtime
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 each medication's having its own independent half-life, CFS/FMS patients do better with combining low doses of several medications than with a high dose of one.
Although less common, other sleep disturbances must be considered. The first is sleep apnea. This should especially be suspected if the patient snores and is overweight and/or hypertensive. Some patients prefer to do their own inexpensive screening by videotaping themselves one night during sleep. This will also often detect restless leg syndrome (RLS), which is also fairly common in fibromyalgia.5 It is treated with supplemental magnesium, keeping ferritin levels over 60 (which is very important), and with Ambien and/or Neurontin.6
Evaluation and Treatment of Associated Hormonal Dysfunction
Hormonal dysfunctions are common in CFS/FMS. Sources of this dysfunction include hypothalamic/pituitary dysfunction and autoimmune processes such as Hashimoto's thyroiditis. When focusing on achieving hormonal balance, standard laboratory testing aimed at identifying a single hormone deficiency caused by gland failure is simply not reliable. Most blood tests use two standard deviations to define blood test norms. By definition, only the lowest or highest 2.5% of the population is in the abnormal (treatment) range. This does not work well if over 2.5 % of the population has a problem. For example, it is estimated that as many as 20% of women over 60 have positive anti-TPO antibodies and may be hypothyroid. Other tests use late signs of deficiency such as anemia for iron or B12 levels to define an abnormal lab value.
The goal in CFS/FMS management is to restore optimal function while keeping labs in the normal range for safety. One way to convey the difference between the "normal" range based on 2 standard deviations and the optimal range which the patient would maintain if he did not have CFS/FMS is as follows:
"Pretend your lab test uses 2 standard deviations to diagnose a 'shoe problem.' If you accidentally put on someone else's shoes and had on a size 12 when you wore a size 5, the normal range derived from the standard deviation would indicate that you had absolutely no problem. You would insist that the shoes did not fit although your shoe size would be in the normal range. Similarly, if you lost your shoes, the doctor would pick any shoes out of the 'normal range pile' and expect them to fit you."
Suboptimal thyroid function is very common and very important in CFS/FMS, and I recommend a trial of thyroid hormone in most cases (though there are exceptions, such as cases with a high or high normal T4, where they may have hyperthyroidism causing their illness). Many CFS/FMS patients also have difficulty in converting T4, which is fairly inactive, to T3, the active hormone. Additionally T3 receptor resistance may be present, requiring higher dosing of T3.7,8
Synthroid contains only inactive T4, while desiccated thyroid, or a compounded T4/T3 combination, have both inactive T4 and active T3. Many clinicians will give an empiric trial of desiccated thyroid, or T4 plus T3, ½ to 2 grains every morning, adjusted to the dose that feels best to the patient as long as the free T4 is not above the upper limit of normal.
Adjust the thyroid dose clinically using the dose that feels the best to the patient, as long as the free T4 test does not show hyperthyroidism. Do not use TSH or T3 levels to diagnose thyroid problems or monitor thyroid replacement.9 Because of the hypothalamic suppression, TSH may be low despite inadequate hormonal dosing. As T3 is largely produced and functions intracellularly, we do not have normal ranges for exogenously given T3. Therefore, I predominantly use clinical signs and symptoms to adjust therapy, while keeping free T4 levels in the normal range for safety.
The hypothalamic-pituitary-adrenal (HPA) axis does not function well in CFS/FMS.3,10 This, as well as adrenal exhaustion from chronic/severe stress, are two key causes of inadequate adrenal function. Because early researchers studying adrenal insufficiency and cortisol were not aware of what the physiologic doses were for cortisol, they treated with high doses and their patients developed severe complications. These side effects are not seen with adrenal glandular/herbal/nutritional support or with physiologic dosing of Cortef; that is, up to 20 mg a day.11 Twenty mg of hydrocortisone (Cortef) is approximately equivalent in potency to 4 to 5 mg of prednisone. Unfortunately, many hypoadrenal patients are only treated when they are ready to go into Addisonian crisis. Research and clinical experience show that this approach misses many hypoadrenal patients.
Symptoms of an underactive adrenal include weakness, hypotension, dizziness, sugar cravings with irritability when hungry, and recurrent infections – all of which are common in CFS/FMS. I recommend natural adrenal support for most patients with CFS/FMS – especially if they have any of the above symptoms. The needed natural therapies include:
•adrenal glandulars, which contain most of the "building blocks" needed for adrenal repair;
•licorice extract, which contains glycyrrhizin, a compound that raises adrenal hormone levels. Licorice also protects against stomach irritation, which can occur with Cortef and occasionally even with glandulars;
•pantothenic acid, vitamin C, vitamin B6, betaine, and tyrosine – these nutrients are critical for adrenal function and energy, and high doses are often needed
All of these are present in an excellent glandular/herbal for adrenal support called Adrenal Stress End (from Integrative Therapeutics), which is very safe and effective. I usually prescribe 1 to 2 capsules each morning (or 1–2 in the morning and 1 at noon), and they can be taken along with the Cortef. This helps both symptoms and with adrenal repair.
I would also consider a therapeutic trial of 5 to 15 mg Cortef in the morning, 2.5 to 10 mg at lunchtime, and 0 to 2.5 mg at 4 p.m. (maximum of 20 mg a day). Most patients find that 5 to 7.5 mg of Cortef each morning plus 2.5 to 5 mg at noon to be optimal (the equivalent of 1.5 to 3 mg prednisone daily). Alternatively, a sustained release compounded hydrocortisone can be used.
Research and clinical experience suggest that using Cortef at 20 mg a day or less in CFS and fibromyalgia patients is safe and often very helpful.12 An extensive review of the safety of using prednisone in doses of under 5 mg a day in rheumatoid arthritis patients long term also supports the safety of this approach.13
Most women need 5 to 10 mg a day and most men 25 to 50 mg a day. 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 women and 350 to 480 mcg/dl in men. Too high of a dose in women can cause elevated testosterone, resulting in acne, darkening of facial hair, and insulin resistance.
Low Estrogen and Testosterone
The use of bioidentical HRT has been discussed in many articles, and will not be discussed at length here. We are finding that low doses of Biest (0.1–0.5 mg a day) plus 30 mg of progesterone topically work well.
Testosterone deficiency is important in both men and women. It is important to check a free testosterone level rather than total testosterone, since free testosterone is a better measure of testosterone function. If the age-adjusted free testosterone is low or low-normal (lowest quartile), a trial of treatment is often very helpful. Among my CFS/FMS patients, 70% of men and many women have free testosterone levels in the lowest quartile, while their total testosterone levels are usually normal. A dose of 25 to 50 mg of bioidentical testosterone in men and 0.5 to 1 mg in women (topically) works well.
Immune Dysfunction and Infections
Immune dysfunction is an integral part of the CFS/FMS process. In fact CFIDS, the other name for CFS, stands for chronic fatigue and immune dysfunction syndrome. There are literally dozens of infections present in CFIDS/FMS, including viral, parasitic, candida, and antibiotic-sensitive infections. Most of these seem to resolve on their own as the immune system recovers with the SHINE protocol.
Some infections do require treatment. I treat all CFS patients for candida, and will treat all parasites (doing an O&P at Genova Labs). Dysbiosis may also need to be treated.
Chronic sinusitis responds poorly to antibiotics but responds well to antifungals. Conservative measures such as saline nasal rinsing and avoiding refined carbohydrates are more appropriate than chronic antibiotics. Chronic sinusitis is predominantly caused by a sensitivity reaction to yeast, with secondary bacterial infections due to swelling and obstruction. Most of our patients find that their chronic sinusitis goes away on the yeast protocol discussed below.
When initially treating the sinusitis and for acute flares, our patients find that a compounded nose spray containing a combination of Sporanox, xylitol, Bactroban, very low-dose bismuth, and cortisone can be very helpful. This is available from the ITC compounding pharmacy (888-349-5453; ask for the Sinusitis Spray – they can mail it to the patient after you call in the prescription). The dose is 1 to 2 sprays in each nostril twice a day for two to six weeks. Although the chronic sinusitis often resolves after six weeks of Diflucan and one bottle of the sinus spray, the patient can use the spray as needed if symptoms recur.
I treat all CFS/FMS patients for candida, and do not find additional candida testing to be necessary, reliable, or helpful.
Treatment for yeast in CFS/fibromyalgia patients consists of:
1. Acidophilus bacteria, 5 billion units per day. I recommend the Probiotic Pearls form (from Integrative therapeutics) 1 pearl a day for 5 months, as without the pearl coating, stomach acid kills over 99% of the probiotic bacteria. In addition, it is critical that patients avoid sugar, as yeast grow by fermenting sugar. My book Beat Sugar Addiction Now! can teach patients how to come off sugar more easily.
2. Anti-Yeast (a mix of natural antifungals by NutriElements) or another natural antifungal for five months.
3. After four weeks on the Anti-Yeast, add 200 mg of fluconazole (Diflucan) daily for six weeks, repeating the 200 milligrams per day for another six weeks if needed (or if symptoms of candida recur over time).
Because of the immune suppression, most of these patients need to be treated empirically for yeast/fungal/candida overgrowth. Nasal congestion/sinusitis and spastic colon are often caused by the candida and resolve with antifungal treatment.
Occasional patients will require an extended trial of antibiotics or antivirals. I base this on symptoms and clinical findings rather than lab testing, and I discuss these at length in my book and at www.EndFatigue.com.
CFS/FMS patients are often nutritionally deficient. Although blood testing is not reliable or necessary for most nutrients, I do recommend that you check B12, Fe, TIBC, and ferritin levels.
I begin patients with CFS/FMS on the following nutritional regimen:
1. A high potency multivitamin. A powdered vitamin is generally better tolerated, better absorbed, and less expensive. The one that I use in my practice for almost all of my patients is called the Energy Revitalization System by Integrative Therapeutics. A single good-tasting drink contains over 50 nutrients and replaces over 35 tablets of nutritional supplements each day. This should be taken long-term.
2. D-ribose (Corvalen- Douglas Labs) – as CFS/fibromyalgia represents an energy crisis, it is critical that the patients have what is needed for optimal mitochondrial function. Although most of these are present in the Energy Revitalization System vitamin powder discussed above, a potentially critical rate limiting nutrient in the production of energy is called ribose. The key energy molecules ATP, FADH, and NADH are made up predominantly of ribose plus B vitamins. Some of our patients improved markedly with improved energy and decreased pain when given one scoop (5 gm) of ribose three times a day for three weeks, followed by one scoop twice a day. Two studies with a total of 298 CFS/FMS patients done by 54 health practitioners showed an average ~60% increase in energy at 3 weeks.14,15 If ribose is going to help, improvement is usually seen within one month (one 280 gm container is a fair therapeutic trial). Ribose is a very powerful new addition to our therapeutic armamentarium for treating fatigue, pain, and cardiac dysfunction.>
D-ribose is natural, quite safe, tastes good (sweet like sugar but healthful – comes as a powder) and is very low in side effects. Rarely, it can cause a mild drop in blood sugar as it gets energy production moving. If patients feel overenergized/hyper when they take it, simply have them take it with a meal or lower the dose, and add adrenal support.
3. Iron: If the iron percent saturation is under 22% or the ferritin is under 60 mg/ml, supplement with iron. It should notbe taken within six hours of thyroid hormone, since iron blocks thyroid absorption. Continue treatment until the ferritin level is over 60.
4. If the B12 level is under 540 pg/ml, I recommend B12 injections, 3000 micrograms IM three times a week times for 15 weeks, then as needed. Studies on CFS show absent or near-absent CSF B12 levels despite normal serum B12 levels.16 Metabolic evidence of B12 deficiency is seen even at levels of 540 pg/ml or more.17 The Energy Revitalization System multivitamin also contains 500 micrograms of B12 daily for ongoing use.
5. Coenzyme Q10: 200 mg daily for 3 to 6 months
6. Acetyl-L-carnitine 1500 mg daily for ~ 4 months.
7. Diet: there is no one diet that is best for everyone. I recommend that patients eat those things that leave them feeling the best (which is not always the same as what they crave). Having said this, however, the majority of CFS patients find that they do best with a high-protein, low-carbohydrate diet. The patient should avoid sugar, as well as excessive caffeine (which is a loan shark for energy) and excess alcohol. If she has low blood pressure and/or orthostatic dizziness, increasing salt intake markedly should also be considered.
Exercise As Able
It is critical that patients prevent deconditioning. On the other hand, because of decreased energy production, too much exercise will result in "postexertional fatigue," often leaving the patient bedridden for a day or two after. Because of this, I recommend that patients see how far they can comfortably walk each day and initially walk that amount. After 2 to 3 months on the SHINE protocol, patients will find that they can usually begin conditioning, and increase the walk by a minute every 1 to 2 days, as able. Patients should only increase the exercise level as is comfortable to them.
General Pain Relief
Although pain will often resolve within three months of simply treating SHINE as discussed above, it is also critical to eliminate pain directly. Two excellent pain herbal mixes are the Pain Formula by Integrative Therapeutics (willow, boswellia, and cherry – excellent for arthritis and inflammatory pain) and Curamin (a mix of a special form of highly absorbed curcumin, Boswellia, DLPA, and nattokinase, which is remarkable for pain in general ) by EuroPharma. Have the patient begin with 2 tablets three times a day (of either or both together) for 6 weeks to see the optimal effect. Once pain is controlled, the dose can be lowered or it can simply be taken as needed.
The medications Neurontin, Ultram, Cymbalta, Lyrica, Savella, and Skelaxin are also far more effective for fibromyalgia pain than NSAIDs.
Many illnesses are associated with various psychological profiles. In CFS/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 bodies' signal of fatigue by resting, they redouble their efforts. Taking time to rest, and getting and staying out of abusive personal and work environments, are critical. As they start to feel better, they need to be instructed to take it slowly and not to go back to the toxic environment or level of overfunctioning that made them sick in the first place. A simplified approach is for patients to learn to say no to things that feel bad. In summary, follow your bliss!
Note: Preventing Practitioner Burnout
Although this article will give you an excellent start in treating fibromyalgia, CFS, and myofascial pain syndrome metabolically, the "treatment protocol" has over 250 useful natural and prescription therapies with resources and far more detailed instructions for use (organized by category). For example, there are dozens of sleep and pain therapies reviewed, and the information on each treatment is given in far more clinical detail.
These patients can be very complex and time-consuming, and cannot be properly cared for in the standard 5-minute doctor's visit.
To simplify patient care, I will be happy to e-mail you a free file, which includes long- and short-form patient questionnaires and treatment checklists that you can modify for use in your office, which can dramatically simplify the care of these patients. Simply e-mail me at Endfatigue@aol.com and ask for "Free Treatment Tools."
In addition, the free online "Symptom Analysis" program at www.EndFatigue.com can analyze your patients' symptoms and labs to determine the causes of their CFS/FMS, and tailor a treatment protocol to each individual patient. My books From Fatigued to Fantastic! and Pain Free 1-2-3 also contain more detailed information including over 500 references related to our treatment recommendations. I invite you to read my newest book, Real Cause, Real Cure (Rodale Press; 2011) which offers a "Natural Owner's Manual" for our bodies.
1.Teitelbaum J, Bird B. Effective Treatment of severe chronic fatigue: a report of a series of 64 patients. J Musculoskeletal Pain. 1995;3(4):91–110.
2.Teitelbaum JE, Bird B, Greenfield RM, et al. Effective treatment of CFS and FMS: a randomized, double-blind placebo controlled study. J Chronic Fatigue Syndr. 2001;8(2). The full text of the study can be found at www.Vitality101.com.
3.Demitrack MA, Dale K, Straus SE, et al. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clinical Endocrinol Metab. December 1991;73(6):1223–1234.
4.Teitelbaum J. Mitochondrial dysfunction [in CFS/FMS]. From Fatigued to Fantastic Newsletter. 1997;1(2). Contains numerous references on this topic.
5.Yunus MB, Aldag JC. Restless legs syndrome and leg cramps in fibromyalgia syndrome: a controlled study. Br Med J. 25 May 1996;312(7042):1339.
6.Wang J et al. Efficacy of oral iron in patients with RLS and a low normal ferritin; a randomized , double blind, placebo controlled study. Sleep Med. Epub 2009.
7.Lowe JC, Garrison RL, Reichman AJ, Yellin J, Thompson M, Kaufman D. Effectiveness and safety of T3 therapy for euthyroid fibromyalgia: a double-blind, placebo-controlled response driven crossover study. Clin Bull Myofascial Ther. 1997;2(2/3):31–58.
8.Lowe JC, Reichman AJ, Yellin J. The process of change during T3 treatment for euthyroid fibromyalgia: a double-blind, placebo-controlled, crossover study. Clin Bull Myofascial Ther. 1997;2(2/3):91–124.
9.Nordyke RA, Reppun TS, L.D. Madanay, et al. Alternative sequences of thyrotropin and free thyroxine assays for routine thyroid function testing. Quality and cost. Arch Int Med. 9 February 1998;158(3):266–272.
10.Griep EN, Boersma JN, de Kloet ER. Altered reactivity of the hypothalamic-pituitary axis in the primary fibromyalgia syndrome. J Rheumatol. March 1993;20(3): 469–474.
11.Jefferies WM. Safe Uses of Cortisol. 2nd ed. Springfield, IL: Charles C. Thomas; 1996.
12.Holtorf K. Diagnosis and treatment of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in patients with chronic fatigue syndrome (CFS) and fibromyalgia (FM). JCFS. 2008;14(3):1–14.
13.Da Silva JA, Jacobs JW, Kirwan JR, et al. Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data. Ann Rheum Dis. 2006 March;65(3): 285–293.
14.Teitelbaum JE, St.Cyr JA, Johnson C. The use of D-ribose in chronic fatigue syndrome and fibromyalgia: a pilot study. J Altern Complement Med. 2006;12(9):857–862.
15.Teitelbaum JE, Jandrain J, McGrew R. Effective treatment of chronic fatigue syndrome and fibromyalgia with D-ribose – a multicenter study. Scripps Conference 2010. San Diego, California (full study submitted for publication).
16.Regland B, Andersson M, Abrahamsson L, et al. Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome. Scand J Rheumatol. 1997;26(4):301–307.
17.Lindenbaum J, Rosenberg IH, Wilson PW, et al. Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr. July 1994;60(1): 2–11.