Fatigue: An Overview
Thomas C. RosenThal, mD; BaRBaRa a. majeRoni, mD; RiChaRD PReToRius, mD, mPh,
and KhaliD maliK, mD, mBa, Department of Family Medicine, University at Buffalo, Buffalo, New York
Fatigue, a common presenting symptom in primary care, negatively impacts work performance, family life, and social
relationships. The differential diagnosis of fatigue includes lifestyle issues, physical conditions, mental disorders, and
treatment side effects. Fatigue can be classified as secondary to other medical conditions, physiologic, or chronic. The
history and physical examination should focus on identifying common secondary causes (e.g., medications, anemia,
pregnancy) and life-threatening problems, such as cancer. Results of laboratory studies affect management in only
5 percent of patients, and if initial results are normal, repeat testing is generally not indicated. Treatment of all types of
fatigue should include a structured plan for regular physical activity that consists of stretching and aerobic exercise, such
as walking. Caffeine and modafinil may be useful for episodic situations requiring alertness. Short naps are proven per-
formance enhancers. Selective serotonin reuptake inhibitors, such as fluoxetine, paroxetine, or sertraline, may improve
energy in patients with depression. Patients with chronic fatigue may respond to cognitive behavior therapy. Scheduling
regular follow-up visits, rather than sporadic urgent appointments, is recommended for effective long-term manage-
ment. (Am Fam Physician.
2008;78(10):1173-1179. Copyright 2008 American Academy of Family Physicians.)
Patient information:
A handout on this topic is available at
one fifth of family medicine routines of exercise, sleep, diet, or other patients present with fatigue, activity that is not caused by an underlying and one third of adolescents medical condition and is relieved with rest. report having fatigue at least Chronic fatigue lasts longer than six months four days per week.1 men and women differ and is not relieved with rest.7 in the way they describe fatigue: men typi- cally say they feel tired, whereas women say Evaluation
they feel depressed or anxious.2,3 no etiol- Physicians should begin the evaluation of a ogy can be identified in one third of cases of patient presenting with fatigue by identifying evidence-based continu-ing medical education fatigue. overexertion, deconditioning, viral common causes. The doses and scheduling of illness, upper respiratory tract infection, prescribed and over-the-counter medications anemia, lung disease, medications, cancer, should be reviewed. medication classes that are and depression are common causes.
commonly associated with fatigue, although sleepiness is the impairment of the nor- sometimes only in the first week or two of use, mal arousal mechanism and is character- include sedative-hypnotics, antidepressants, ized by a tendency to fall asleep. Persons muscle relaxants, opioids, antihypertensives, who are sleepy are temporarily aroused by antihistamines, and many types of antibiotics. activity, whereas fatigue is intensified by even “nonsedating” antihistamines have an 8 activity, at least in the short-term.4 Patients to 15 percent sedation rate.8 six to 12 weeks with sleepiness feel better after a nap, but of fatigue is not unusual during recovery from patients with fatigue report a lack of energy, even minor surgery.9 The quality and quantity mental exhaustion, poor muscle endurance, of sleep in patients with fatigue should also be delayed recovery after physical exertion, evaluated (Table 1).
and nonrestorative sleep. Figure 1 provides a although it is possible for fatigue and questionnaire to help differentiate between depression to coexist, physicians should sleepiness and fatigue.5,6 attempt to distinguish between them in order Fatigue may be classified as secondary, to guide management. Patients with fatigue physiologic, or chronic. secondary fatigue report being unable to complete specific activ-is caused by an underlying medical con- ities because of a lack of energy or stamina, dition and may last one month or longer, whereas grief and depression are associated but it generally lasts less than six months. with a patient description that is more global, Physiologic fatigue is an imbalance in the such as being unable to do “anything.” Downloaded from the American Family Physician Web site at Copyright 2008 American Academy of Family Physicians. For the private, noncommercial use of one individual user of the Web site. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests.
Exercise therapy should be prescribed for patients There is no evidence that exercise therapy with fatigue, regardless of etiology.
Selective serotonin reuptake inhibitors, such as fluoxetine (Prozac), paroxetine (Paxil), or sertraline (Zoloft), may be helpful for patients with fatigue in whom depression is suspected.
Cognitive behavior therapy is an effective treatment for adult outpatients with chronic fatigue syndrome.
Stimulants seldom return patients to predisease Stimulants are associated with headaches, restlessness, insomnia, and dry mouth.
A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.
Patient Health Questionnaire: differentiating Between Sleepiness and Fatigue
How likely are you to doze off or fall asleep (as opposed to just
feeling tired) in the fol owing situations?Sitting and reading Inactively sitting in a public place (e.g., theater, meeting) As a passenger in a car for an hour, when circumstances permit Sitting quietly after lunch (without alcohol) Range 0 to 18: higher scores equate to greater sleepiness Fatigue
Exercise brings on my fatigue
I start things without difficulty but get weak as I go on Range 3 to 18: higher scores equate to greater fatigue noTE: Scores for each section are compared and balanced. They should be used to inform clinical judgment and are not absolute. Figure 1. Patient questionnaire for differentiating between sleepiness and fatigue.
Information from references 5 and 6.
Physical examination findings that sug- many physicians order a complete blood gest specific secondary causes of fatigue count, erythrocyte sedimentation rate, chem-include (indicating istry panel, thyroid-stimulating hormone tumor spread or recurrence), cardiac mur- measurement, and urinalysis. Women of murs (endocarditis), goiter (thyroid hor- childbearing age should receive a pregnancy mone imbalance), edema (heart failure, test. no other tests have been shown to be liver disease, or malnutrition), poor muscle useful unless the history or physical examina-tone (advancing neurologic condition), and tion suggests a specific medical condition.10-12 neurologic abnormalities (stroke or brain metastases).
Managing Secondary Fatigue
laboratory studies should be considered medications that may be causing fatigue (Table 210-12), although their results affect should be replaced or discontinued, if pos-management in only 5 percent of patients.12 sible, and physiologic parameters should be 1174  American Family Physician
Volume 78, Number 10November 15, 2008 Table 1. Questions to Evaluate the Quality and Quantity of Sleep in Patients Presenting with Fatigue
Regular bedtimes are associated with better sleep patterns.
Many patients read or watch television in bed before fal ing asleep.
After you lie down, how long does it take you This time is known as sleep latency; the duration reflects sleepiness or Do you leave the television or radio on as you are Television and radio programs are intended to be stimulating and keep After fal ing asleep, what time do you first wake up? Does the patient wake up due to pain or the urge to urinate? How often do you use the bathroom at night? Does the patient develop the urge to urinate within a few minutes of waking up, or does the urge awaken the patient? Does the patient have conditions, such as arthritis or muscle cramps, that How long does it take you to return to sleep after Do certain thoughts keep the patient from returning to sleep? Are they anxiety-provoking, worrisome, depressing? What time do you get out of bed in the morning? Is the patient trying to get too much sleep? Does the patient have a What time of day does the patient nap and for how long? Has the patient tried sleep aids? Is the patient taking a medication that Alcohol has a short half-life and, when used to assist sleep, often causes Evening exercise tends to be stimulating and may increase sleep latency.
corrected. With cancer, renal disease, or and the drugs are associated with headaches, other chronic diseases associated with ane- restlessness, insomnia, and dry mouth.21,22 if mia, patients are likely to be less fatigued if used, stimulants are best used as needed for their hemoglobin level is maintained at 10 episodic situations requiring alertness. g per dl (100 g per l), using erythropoietin agents if needed.13,14 nonanemic, menstruat- Physiologic Fatigue
ing women who have low normal ferritin lev- Physiologic fatigue is initiated by inadequate els report modest increased energy after four rest, physical effort, or mental strain unre-weeks of iron supplementation.15 lated to an underlying medical condition. Performing some form of daily exercise, Diminished motivation and boredom also sustaining interpersonal relationships, and play a role. Physiologic fatigue is most com-returning to work are consistently associated mon in adolescents and older persons. in the with improvement in fatigue of any etiol- united states, 24 percent of adults report ogy.16,17 Regular moderate aerobic activity having fatigue lasting two weeks or longer, (i.e., 30 minutes of walking or an equivalent and two thirds of these persons cannot iden-activity on most days of the week) reduces tify the cause of their fatigue.23 disease-related fatigue more effectively than During intense training, well-conditioned rest. Yoga, group therapy, and stress man- athletes occasionally misinterpret fatigue as agement diminish fatigue in patients with illness or depression.24 Conversely, fatigue cancer.18 Patients who have features sugges- and depression can emerge in a physically tive of depression may be offered a six-week fit athlete after as little as one week with trial of a selective serotonin reuptake inhibi- no exercise. submaximal exercise mitigates tor (ssRi).19 Psychostimulants (e.g., meth- these symptoms when training is limited ylphenidate [Ritalin], modafinil [Provigil]) because of injury.25improve fatigue in the short-term in patients with human immunodeficiency virus, mul- ManagEMEnT
tiple sclerosis, or cancer.20 stimulants seldom adequate sleep (i.e., generally seven to eight return patients to predisease performance, hours per night for adults) decreases tension November 15, 2008Volume 78, Number 10 American Family Physician  1175
Table 2. Laboratory Testing for Patients with Unexplained Fatigue
Liver disease, renal failure, protein malnutrition Chronic infection, if not previously tested Pregnancy, breathlessness due to progestins Chronic obstructive pulmonary disease, cancer Valvular heart disease, congestive heart failure Specialized blood testing (e.g., ferritin, iron, Iron deficiency, Addison disease, celiac vitamin B , and folate levels; iron-binding *—Arranged by the relative frequency that the tests produce results. Information from references 10 through 12. and improves mood.26 Patients should be conditions showed that participants had instructed to restructure their daily activi- fewer errors after consuming regular coffee ties to get the sleep they need, and to prac- (i.e., 200 mg of caffeine) or taking a 30-min- tice good sleep hygiene. Recommendations ute nap.30 modafinil, which is approved to for good sleep hygiene include the following: manage fatigue that is induced by shift work, maintaining a regular morning rising time; has the same effect on performance as 600 mg increasing activity level in the afternoon; of caffeine. modafinil and caffeine do not avoiding exercise in the evening or before have most of the adverse cardiovascular bedtime; increasing daytime exposure to effects and abuse potential that are associated bright light; taking a hot bath within the with amphetamines.30 although modafinil two hours before bedtime; avoiding caf- and caffeine temporarily improve perfor- feine, nicotine, alcohol, and excessive food mance, they are not a substitute for adequate or fluid intake in the evening; using the bed- rest, and long-term use of modafinil has been room only for sleep and sex; and practicing associated with depression.
a bedtime routine that includes minimizing Physical fitness also improves energy lev- light and noise exposure and turning off els. one study showed that truck drivers the television.27 naps may help, but should who engaged in 30-minute exercise sessions be limited to less than one hour in the early more than once a week had fewer traffic inci-afternoon. one study showed that when hos- dents.31 another study showed that 10 weeks pitals provided patient coverage for medical of supervised exercise increased energy lev-intern naps (averaging 40 minutes) during els among persons with fatigue, regardless of overnight shifts, the interns achieved morn- ing fatigue scores equivalent to those who
were not on call.28 Time off from work also chronic Fatigue
minimizes fatigue and decreases stress.29
Chronic fatigue is defined as fatigue that lasts longer than six months. medical condi- mance. a randomized, double-blind, cross- tions that may cause or contribute to chronic over study of persons driving in nighttime fatigue are listed in Table 3. The prevalence 1176  American Family Physician
Volume 78, Number 10November 15, 2008 Table 3. Selected differential diagnosis of chronic Fatigue
Cardiopulmonary: congestive heart failure, chronic obstructive pulmonary disease, peripheral vascular disease, atypical angina of idiopathic chronic fatigue ranges from five Disturbed sleep: sleep apnea, gastroesophageal reflux disease, al ergic or to 40 per 100,000, depending on the popula- Endocrine: diabetes mel itus, hypothyroidism, pituitary insufficiency, hypercalcemia, adrenal insufficiency, chronic kidney disease, hepatic EPidEMiOLOgy and naTURaL HiSTORy
Infectious: endocarditis, tuberculosis, mononucleosis, hepatitis, parasitic Chronic fatigue occurs in all age groups, disease, human immunodeficiency virus, cytomegalovirus including children. Women, minorities, and Inflammatory: rheumatoid arthritis, systemic lupus erythematosus persons with lower educational and occupa- Medication use (e.g., sedative-hypnotics, analgesics, antihypertensives, tional statuses have a higher prevalence of antidepressants, muscle relaxants, opioids, antibiotics) or substance abuse Psychological: depression, anxiety, somatization disorder, dysthymic on average, a typical family physician has in his or her practice two patients with fatigue of longer than six months for which no explanation can be determined.33 The diagnostic criteria for chronic fatigue syn- Table 4. diagnostic criteria for chronic Fatigue Syndrome
drome (Table 434) are useful for defining disability or for research purposes, but may Major criteria:
not be clinically helpful in all circumstances. At least six months’ duration; does not resolve with bed rest; reduces daily Two thirds of patients with chronic fatigue do activity to less than 50 percent; other conditions have been excluded not meet these criteria, but they share many Physical criteria:
similarities to those with the syndrome and Low-grade fever; nonexudative pharyngitis; lymphadenopathy Minor criteria:
only 2 percent of patients who are chroni- Sore throat; mild fever or chil s; lymph node pain; generalized muscle cally fatigued report complete long-term weakness; myalgia; prolonged fatigue after exercise; new-onset resolution of symptoms, but 64 percent have headaches; migratory noninflammatory arthralgia; sleep disturbance; neuropsychological symptoms (e.g., photophobia, scotomata, limited improvement. Patients whose symp- forgetfulness, irritability, confusion, inability to concentrate, depression, toms worsen for longer than 24 hours after difficulty thinking); description of initial onset as acute or subacute physical exertion have a poor prognosis.36,37 noTE: A diagnosis of chronic fatigue syndrome includes all major criteria plus: eight EvaLUaTiOn
minor criteria, or six minor criteria and two physical criteria. Detailed psychiatric and sleep histories may help determine possible psychosocial con-tributors to fatigue. a focused examination that communicates the physician’s interest in, in a British study, 90 percent of patients who and engagement with, the patient’s problem saw generalists for chronic fatigue received should be performed at every visit.38 labo- medication, diagnostic testing, or refer- ratory tests for chronic fatigue demonstrate ral.38 The patients, however, were seeking to some abnormality in 12 percent of patients and engage the physician, convey their suffering, lead to alternate diagnoses in up to 8 percent and receive reassurance; the patients reported of patients.39 however, when initial test results greatest satisfaction with physician explana-are normal, referral to an occupational sub- tions linking physical and psychological fac- specialist, psychiatrist, or another physician is tors to psychosocial management.
more helpful than repeating the tests.40,41 meta-analyses confirm the effectiveness of regular structured exercise. Four weeks ManagEMEnT
of aerobic, strength, or flexibility train- Patients who believe that their symptoms are ing is associated with improved energy and related to modifiable factors (e.g., workload, decreased fatigue,43 and moderate aerobic stress, coping strategies, depression, overcom- exercise (e.g., a daily 30-minute walk) has a mitment) are much more likely to recover than more consistently positive impact on fatigue those who believe that their symptoms are due than any other intervention studied.44 With to external factors, such as a viral infection.42 the exception of patients with depression, November 15, 2008Volume 78, Number 10 American Family Physician  1177
pharmacologic therapy (including stimu- medicine residency at Case Western Reserve University in lants) only has a short-term impact.45,46 Cog- nitive behavior therapy is effective.22,47,48 KHALID MALIK, MD, MBA, is an assistant professor of clin- a six-week trial of an ssRi (e.g., fluox- ical family medicine at the University at Buffalo. Dr. Malik earned his MBBS from Nishtar Medical Col ege in Multan, etine [Prozac], paroxetine [Paxil], sertraline Pakistan, and completed a family medicine residency at [Zoloft]) may be considered in patients with the University at Buffalo. chronic fatigue if depression is possible.22 if Address correspondence to Thomas C. Rosenthal, MD, the patient has difficulty getting restful sleep, University at Buffalo, Dept. of Family Medicine, Building trazodone (Desyrel, brand no longer available CC, Room 150, 462 Grider St., Buffalo, NY 14215 (e-mail: in the united states), doxepin, or imipramine [email protected]). Reprints are not available from (Tofranil) may be effective.49 if pain is pres-
ent, the patient may respond to venlafaxine Author disclosure: Nothing to disclose.
(effexor), desipramine (norpramin), nor-
triptyline (Pamelor), duloxetine (Cymbalta), REFEREncES
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November 15, 2008Volume 78, Number 10 American Family Physician  1179


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