CHRONIC FATIGUE AND FIBROMYALGIA
| CHRONIC FATIGUE SYNDROME —Rosemary A. Underhill, MB, BS, Consultant for New Jersey Chronic Fatigue Syndrome
(CFS) Association, Upper Saddle River, New Jersey
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| Occurrence: many patients with CFS have family members (both blood and nonblood relatives) with CFS; CFS in another
family member found in 10% and 17% of 2 groups of patients with sporadic CFS; CFS occasionally occurs in epidemics
or cluster outbreaks
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| Possible causes of familial CFS: include shared heredity, shared environment, both factors, or “just chance”;
comments—aim of speaker’s study to investigate genetic and environmental risk factors, by determining prevalence of
CFS and chronic fatigue in affected family members of CFS patients, and by comparing prevalence of CFS in family
members to published community prevalence
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| Other names for CFS: chronic fatigue immune dysfunction syndrome (CFIDS); myalgic encephalomyelitis (ME);
chronic Epstein-Barr virus syndrome; chronic mononucleosis
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| Speaker’s questionnaire: asked CFS patients 1) about presence of symptoms specified by Centers for Disease Control
and Prevention (CDC) in its revised case definition, 2) whether CFS had been diagnosed by physician, and 3) about presence
of physician-diagnosed CFS and undiagnosed chronic fatigue resembling CFS in relatives; remark—questionnaire
return rate slightly >50%
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| Study participants: 219 classified as having CFS; family members classified as having CFS if diagnosis made by physician;
other “fatigued” family members categorized as having “chronic fatigue” if CFS not diagnosed by physician; data
also collected from 34 unselected support group attendees; 20.5% of survey responders and 17.6% of unselected patients
reported having family members with CFS; of 20.5% of survey responders who had family member with CFS, 9% had
family member with CFS living with them, 18% had ≥1 blood relatives with CFS, and 6% had blood relatives with CFS
living with them; 3% had nonblood relative household member with CFS; 46% of patients with chronic fatigue had affected
blood relatives and 25% of these also had relatives with CFS
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| Demographics and findings: >90% of population studied white; CFS prevalence 3.2% in spouses, 5.1% in offspring,
2.1% in first-degree relatives, and 0.8% in second- and third-degree relatives; female blood relatives with CFS outnumbered
males 4:1; twice as many spouses and partners had chronic fatigue as had CFS (≈6 times as many first-degree relatives
had chronic fatigue as had CFS)
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| Parents with CFS: 114 studied; 11% had offspring with CFS, but none had >1 offspring with CFS; 3% had offspring
with chronic fatigue as well as offspring with CFS, while 15% had offspring with only chronic fatigue; comments—only
50% of affected offspring developed CFS as children (<18 yr of age); recovery rate slightly <50%
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| Environmental vs hereditary factors: in genetically unrelated spouses and partners, CFS prevalence 8 to 14 times
that found in community; prevalence of CFS among second- and third-degree relatives 2 to 3 times that found in community;
study concluded both heredity and environment risk factors for CFS in family members, and supports published evidence
that genetic factors may be involved in pathogenesis of CFS; results of twin studies—concordance rate for CFS-
like illness 55% in monozygotic twins and 19% in dizygotic twins; genetic immune-system markers—presence of
HLA-DQ3 and HLA-DQ1 found in CFIDS patients and may confer susceptibility of immune system to development of
CFS; secondary cases of CFS—occurred in 9% of households of patients, and in genetically unrelated household members,
risk of developing CFS 8 to 14 times higher than in community
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| Postulated etiologies for CFS: psychiatric disorder; toxigenic disorder; immune system (autoimmune) disorder; exposure
to infectious agent; theories need not be mutually exclusive
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| Psychiatric disorder theory: CFS often considered form of depressive illness because fatigue, cognitive, and sleep
problems common with both; however, most other CFS symptoms not usually associated with major depression; in 1
study, 17% of significant others of long-term CFS patients had diagnosis of major depression
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 | Comments: mood disorders common in population and often follow stress; ≈20% of people develop significant depressive
illness sometime during their lives; ≈30% of patients have major or minor depression 1 yr after myocardial infarction
(MI); physiologic studies have shown CFS and major depression very different illnesses and associated with
different levels of cortisol, 5-hydroxyindoleacetic acid, and prolactin response; immune system tests abnormal in CFS
patients, but normal in those with major depression
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| Mental stress: high in spouses caring for CFS patients; can precede onset of CFS, but in <1% of patients; findings of
study—influenza-like illness or gastrointestinal (GI) symptoms main onset factors in ≈80% of patients; concluded that
stress does not usually act alone in etiology of CFS
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| Conclusions: psychiatric model (ie, depressive illness) does not explain high rate of CFS in families, because physiologic
tests differ between 2 conditions; mental stress might trigger CFS in spouse of CFS patient, but cannot account for 70%
of nonresident relatives with CFS
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| Toxigenic theory: some people have attributed CFS to exposure to various toxins, including vaccines, organophosphate
pesticides, depleted uranium, wood preservatives, formaldehyde, ciguatera fish poisoning, allergens, and CO2 ; average
home full of toxic products; some people have severe reaction to toxic agents and allergens, some have multiple chemical
sensitivities (MCS); symptoms of MCS and CFS do overlap, but not same disease (although 37% of study patients
had both); sick building syndrome—caused by unknown toxin; may affect people in sealed air-conditioned buildings;
symptoms improve within 1 to 2 days of leaving building (does not happen in CFS patients); British study investigating
possible toxigenic etiology for CFS—results negative
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| Conclusions: household toxins cannot account for CFS in 70% of nonresident family members of patients with CFS;
toxic exposure damages body systems (including immune system), increasing vulnerability to infectious agent
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| Immune system theory: postulates CFS due to innate immune system dysfunction; supporting evidence includes altered
immune system patterns in CFS patients; autoantibodies may be present, but usually in fairly low levels
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| Remarks: autoimmune disease theory fits several findings seen in CFS patients and suggests possible genetic basis, but
cannot explain why CFS occurs in nongenetically related household members or in epidemics
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| Infectious agent theory: pathogen causes CFS, either by altering immune system (“hit and run” theory) or by persisting
in patient; if pathogen persists, can shed into environment, making CFS potentially contagious; data from epidemics
show that CFS probably airborne infection; 2 studies have concluded CFS primarily endemic infectious disorder,
responsible for sporadic outbreaks and epidemics; they suggest infectivity of sporadic cases relatively low and that epidemics
occur when virulence of infectious agent increased or population immunity reduced
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| Observations: febrile viral illness often precedes onset of CFS (80% of cases in 1 study); CFS also develops in patients receiving
blood transfusions (6.5% in that study); altered immune system findings seen in CFS typical for viral illness; persistence
of pathogen in CFS patients could cause persistence of immune system changes; no specific pathogen linked to
CFS; possibility exists that >1 pathogen can cause CFS
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| Infectious agents found in some CFS patients: Epstein-Barr virus; enterovirus; retroviruses; herpes viruses; mycoplasma;
comments—these pathogens also found in control populations; these agents may cause opportunistic or reactivation
infections in CFS patients; data suggest most genetically unrelated contacts of sporadic CFS patients resistant to developing
CFS; most contacts of CFS patients do not become infected, but some may develop subclinical disease or become
clinically ill and recover
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| Problems with infectious disease theory: only anecdotal reports of person-to-person CFS transmission; most people develop
CFS in complete isolation; data lacking on how infectious agent spreads; remark—various studies suggest immune
system changes similar to those of CFS can occur in contacts of people with CFS
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| Postulate: if immune system changes in CFS patients caused by pathogen, same immune changes in healthy contacts could
be caused by same pathogen; corollary—some apparently healthy people could be silent carriers of pathogen and may
have subclinical infection; subclinical infection creates reservoir of healthy carriers of infectious agent; patients with sporadic
CFS possibly contract disease from carrier
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| Thoughts: CFS possibly caused by body’s reaction to persisting pathogen in susceptible individual; this could account for
increased CFS prevalence in household members of people with CFS; people with genetic predisposition to disease
more likely to develop CFS
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| FIBROMYALGIA —Kenneth E. Sack, MD, Professor of Medicine and Director of Clinical Programs in Rheumatology,
University of California, San Francisco, School of Medicine
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| Evolution of fibromyalgia: Hugh Smythe first coined term “fibrositis”; Philip Hench later changed term to “fibromyalgia”
to refer to condition characterized by widespread pain around muscles and in fibrous tissue, but no evidence of inflammation
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| Prevalence: occurs in 1% to 2% of population; ≈15% of patients in any rheumatology practice meet criteria for fibromyalgia
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| Clinical criteria: widespread pain; ≥11 of 18 possible tender points where muscles insert; persistence of pain ≥3 mo;
others—fatigue; Raynaud’s phenomenon (debatable); complaints of swelling; remark—irritable bowel symptoms and
chronic musculoskeletal pain often go hand in hand
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| Fatigue: Moldofsky found that pain patients tended to have abnormal sleep (alpha intrusion into delta wave sleep); he
then studied healthy medical school students and found they tended to have more pain if deprived of delta wave (deep)
sleep, unless they were distance runners; Moldofsky theorized aerobic activity protective and helpful in treating chronic
musculo-skeletal pain; non-rapid eye movement (non-REM) deep delta sleep—can be disturbed by many factors, including
drugs, coffee, alcohol, depression, stress, trauma, and sleep apnea; not all patients with disrupted delta sleep have
chronic pain or chronic fatigue
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| Localized myofascial pain: concept developed by Janet Travell; characterized by localized “trigger” points; female-
male ratio close to 1 (fibromyalgia more common in women); widespread systemic complaints absent; responds to trigger
point injections or vapo-coolant spray (counterirritant); prognosis fairly good (prognosis for fibromyalgia “lousy”)
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| Psychogenic pain: described as “fibromyalgia times 10”; characterized by bizarre descriptions of pain; pain typically quite
vague; “touch me not” syndrome; patients never respond to therapy
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| Hypothesis for sleep difficulties: Bennett postulates they may be related to problems in endocrine system (hypothalamic
adrenal system in particular); he speculates that 1) certain people born with proneness to microtrauma, 2) these
people have sleep disturbances, and 3) since most growth hormone (GH) made during delta wave sleep, these people lack
enough GH to replenish their muscles and therefore become further deconditioned and have pain; speaker’s rejoinder—
GH made at other times if there is interference in delta wave sleep
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| Speculated etiologic theories for fibromyalgia: history of child abuse (difficult to prove); depression; immune
system disorder; endocrine/metabolic disease; neurotransmitter problems; viral infections (hepatitis C and Epstein-
Barr viruses extensively studied; no clearcut causative pathogen so far has emerged)
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| Depression: anyone who does not feel well looks depressed; less symptom-charged inventory needed for depression if one
wants to study depression in chronic pain patients; speaker prefers term chronic musculoskeletal pain syndrome to fibromyalgia
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| Goals of therapy: maintain patient’s function and ability to live relatively happy life (not freedom from pain); deal with
issue of secondary gain when present; acknowledge pain is real and that all pain processed through brain
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| Diagnostic work-up: includes history and physical examination; differential diagnosis includes Parkinson’s disease,
polymyalgia rheumatica, thyroiditis, neoplasia, vitamin D deficiency, and celiac disease; blood tests to perform include antitissue
transaminase, and 25-hydroxy vitamin D levels; remark—in history, ask about domestic violence or spousal abuse
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| Treatment: aerobic exercise—proven modality; ask patient to set aside 30 min 3 to 4 times weekly for aerobic activity;
start gradually; ultimate goal 20 to 30 min of aerobic exercise; 2 15-min sessions just as effective as 1 30-min session;
drugs—low dose (pain-modifying doses) of tricyclic antidepressants effective in some patients (all studies short-term);
job modification—sometimes helps; continuous positive airway pressure (CPAP)—may help some pain patients;
diet—stress cardioprotective low-saturated fat diet; pets—“prescribe a dog” to walk with patient daily
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| Questions and answers: narcotics—avoid narcotics initially; however, consider use if everything else fails; speaker
uses low-dose methadone (≤30 mg/day) in some patients; guaifenesin—low effectiveness for chronic pain;
corticosteroids—may make patients worse; HIV testing—not routinely warranted in fibromyalgia patients; however,
consider use if “sensors up” for possible HIV infection; injection of tender points with lidocaine every 6 wk—
evidence lacking for efficacy; notion that chronic pain is disease in itself—some evidence exists; cognitive behavioral
therapy—important element of management; safe and often quite helpful; efficacy of muscle relaxants—some
tranquilizers and tricyclics (cyclobenzaprine [Flexeril]) erroneously promoted as muscle relaxants; baclofen real muscle
relaxant, but used sparingly in fibromyalgia patients; long-term benefits of tranquilizers miniscule
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Educational Objectives
| The goal of this program is to educate the listener about chronic fatigue syndrome (CFS) and fibromyalgia. After hearing
and assimilating this program, the clinician will be better able to:
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| 1. Describe the way CFS tends to run in families.
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| 2. Evaluate the various etiologies (eg, psychogenic, toxicologic, immunologic, infectious) that have been theorized for
CFS.
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| 3. Review the clinical criteria for fibromyalgia.
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| 4. Consider the various proposed etiologies for fibromyalgia.
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| 5. Manage patients with fibromyalgia.
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Discussed on This Program
Baclofen [Lioresal, Lioresal Intrathecal]
Cyclobenzaprine HCl [Flexeril]
Guaifenesin (glyceryl guaiacolate) [several trade names]
Lidocaine HCl (several trade names)
Methadone HCl [Dolophine HCl, Methadone HCl Diskets, Methadone HCl Intensol, Methadose]
Suggested Reading
Bennett R: The rational management of fibromyalgia patients. Rheum Dis Clin North Am 28:181, 2002; Bohr TW: Fibromyalgia
syndrome and myofascial pain syndrome: do they exist? Neurol Clin 13:365, 1995; Bradley L et al: Central
nervous system mechanisms in fibromyalgia and other musculoskeletal disorders: behavioral and psychologic treatment approaches.
Curr Opin Rheum 14:45, 2005; Burckhardt CS: Multidisciplinary approaches for management of fibromyalgia.
Curr Pharm Des 12:59, 2006; Clayton AH, West SG: Combination therapy for fibromyalgia. Curr Pharm Des
12:11, 2006; Glozier N: Chronic fatigue syndrome: it’s tiring not knowing much – an in-depth review for occupational
health professionals. Occup Med (Lon) 55:10, 2005; Goldenberg D, Smith N: Fibromyalgia, rheumatologists, and the
medical literature: a shaky alliance. J Rheumatol 30:151, 2003; Goldenberg DL et al: Management of fibromyalgia syndrome.
JAMA 292:2388, 2004; Grans H et al: Gene expression profiling in the chronic fatigue syndrome. J Intern Med
258:388, 2005; Gur A: Physical therapy modalities in management of fibromyalgia. Curr Pharm Des 12:29, 2006; Jones
K et al: Individualizing the exercise prescription for persons with fibromyalgia. Rheum Dis Clin North Am 28:419, 2002;
Kaushik N et al: Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome. J
Clin Pathol 58:826, 2005; Krupp LB et al: An overview of chronic fatigue syndrome. J Clin Psychiatry 52:403, 1991;
Kurtais Y et al: Exercise and cognitive-behavioural treatment in fibromyalgia syndrome Curr Pharm Des 12:37, 2006;
Mannerkorpi K. Ekdahl C: Assessment of functional limitation and disability in patients with fibromyalgia. Scan J.
Rheumatol 26:4, 1997; Mannerkorpi K: Exercise in fibromyalgia. Curr Opin Rheumatol 17:190, 2005; Moldofsky
H: Management of sleep disorders in fibromyalgia. Rheum Dis Clin North Am 28:353, 2002; Ozgocmen S: New strategies
in evaluation of therapeutic efficacy in fibromyalgia syndrome. Curr Pharm Des 12:67, 2006; Prins JB et al: Chronic
fatigue syndrome. Lancet 367:346, 2006; Ranjith G: Epidemiology of chronic fatigue syndrome. Occup Med (Lon) 55:13,
2005; Reid S et al: Chronic fatigue syndrome. Clin Evid 12:1578, 2004; Rimes KA, Chalder T: Treatments for chronic fatigue
syndrome. Occup Med (Lon) 55:32, 2005; Sack K: Fibromyalgia. Johns Hopkins Adv Studies in Med 4:401, 2004;
Schneider MJ: Tender points/fibromyalgia vs trigger points/myofascial pain syndrome: a need to clarify terminology and
differential diagnosis. J Manipulative Physiol Ther 18:398, 1995; Shuttleworth A: Understanding chronic fatigue. Nurs
Times 102:20, 2006; Tofferi JK et al: Treatment of fibromyalgia with cyclobenzaprine: a metaanalysis. Arthritis Rheum
51:9, 2004; Vernon SD et al: Challenges for molecular profiling of chronic fatigue syndrome. Pharmacogenomics 7:211,
2006; Wallman KE et al: Exercise prescription for individuals with chronic fatigue syndrome. Med J Aust 183:142,
2005; White PD: What causes chronic fatigue syndrome? BMJ 329:928, 2004; Yoshiuchi K et al: Patients with chronic
fatigue syndrome have reduced absolute cortical flow. Clin Physiol Funct Imaging 26:83, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty
reported nothing to disclose.
Dr. Underhill was recorded April 30, 2005, at the annual Spring Chronic Fatigue Syndrome Conference, sponsored
by the Robert Wood Johnson Medical School of the University of Medicine and Dentistry of New Jersey, and the
New Jersey Chronic Fatigue Syndrome Association, and held in New Brunswick, New Jersey. Dr. Sack was recorded
June 9, 2005, in San Francisco at Pain Management and End-of-Life Care, sponsored by the University of California,
San Francisco, School of Medicine. The Audio-Digest Foundation thanks the speakers and the sponsors for making
this program possible.
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