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Evidence-based Pharmacy Practice (EBPP):
Fatigue
Ilse Truter
PharmITCom® Consulting
This article will provide a general overview of fatigue and then focus on Chronic Fatigue Syndrome
(CFS), a disorder that is characterised by debilitating fatigue with several associated physical, constitutional and neuropsychological complaints.
Introduction
The modern lifestyle with its demands “to achieve” places an
enormous physical and emotional burden on many individuals. Relaxation and exercise are often neglected. Many people
are not able to maintain the pace, and it is not surprising that
symptoms such as fatigue develop. Fatigue can, however,
also be a symptom of other conditions such as depression,
insomnia or premenstrual syndrome. Sometimes fatigue is a
symptom of an underlying organic disease, for example, anaemia, infection, malignancy, sub-clinical vitamin and/or mineral
deficiency, hypotension or hypoglycaemia.1 Medicines can also
lead to fatigue, such as recent anaesthesia, oral contraceptives
and anxiolytics such as benzodiazepines.1
Fatigue is common and a symptom of many different conditions. It is said that one in 400 sustained episodes of fatigue
generate a consultation with a general practitioner.2 Two percent of these consultations result in a referral to a specialist.2
Almost any disease process can cause tiredness and fatigue,
whether physical or psychological. Physical causes account
for approximately 9% of cases, with 75% having symptoms
of emotional distress.2 The challenge is to know what exactly
causes the fatigue and whether it is serious enough to seek
professional help.
Definition of fatigue
(less than one month), prolonged fatigue (more than one
month) and chronic fatigue (more than six months).4
It is important to differentiate fatigue from other medical concepts with which the symptoms are often confused. Fatigue
is different from drowsiness. Drowsiness is feeling the need
to sleep, while fatigue is a lack of energy or motivation. The
desire to sleep may, however, accompany fatigue. Listlessness
is also different from fatigue. Listlessness indicates a state of
fatigue or exhaustion where the patient loses interest in his or
her surroundings. Asthenia is the lack of strength or the feeling
of inability to carry out daily tasks.4 It is more intense towards
the end of the day and usually improves after a period of sleep.
Weakness is the reduction or loss of muscular strength, and is
a key symptom in muscular diseases.4
General terms that are often used by lay persons to describe
fatigue are weakness, sluggishness, dullness, apathy, loss of
concentration, sleepiness, lack of motivation, irritability and “not
feeling like doing anything”.1
Fatigue is generally described and measured as a multidimensional phenomenon and it has a multifactorial aetiology. Cognitive, motivational and physical fatigue are strongly interrelated.
Fatigue is furthermore a nonspecific symptom.5 The prevalence
of fatigue is estimated to range from 5% to 10%.5
Fatigue is defined as mental or physical tiredness, following
prolonged or intense activity.3 It is a desire to rest that reflects
exhaustion. Fatigue is the inability of an organism, an organ or
a tissue to give a normal response to a stimulus until a certain
recovery period has lapsed.3 Incorrect or inadequate food
intake or disease may predispose a person to fatigue.3 Fatigue,
therefore, is a condition characterised by a lessened capacity
for work and reduced efficiency of accomplishment, usually accompanied by a feeling of weariness. Fatigue can be acute and
develop suddenly or it can be chronic and persist.
Fatigue often remains the only (symptom) diagnosis in an
episode of care. Serious functional impairment, psychological symptoms and disturbed sleep often accompany fatigue.
Knowledge about the course of fatigue and related symptoms
in a heterogeneous population is scarce, because most longitudinal studies on fatigued populations have been performed
in selected groups, such as patients with CFS, post-viral
fatigue or cancer.5
Generally, a distinction between the different types of fatigue
is made based on the time to evolution, namely recent fatigue
There are many possible physical and psychological causes of
fatigue. Examples are2,6:
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Aetiology of fatigue
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Aetiology of fatigue
••
••
••
••
••
An allergy that leads to hay fever or asthma.
Anaemia, including iron deficiency anaemia.
Depression or grief.
Persistent pain.
Sleep disorders such as ongoing insomnia, sleep apnoea
or narcolepsy.
•• Under- or overactive thyroid gland.
•• Use of alcohol or drugs such as cocaine or narcotics, especially with regular use.
Fatigue can also accompany the following diseases6:
•• Addison’s disease.
•• Anorexia or other eating disorders.
•• Arthritis, including juvenile rheumatoid arthritis.
•• Autoimmune diseases such as systemic lupus erythematosus.
•• Cancer.
•• Congestive heart failure.
•• Diabetes mellitus.
•• Fibromyalgia.
•• Infection, especially an infection that takes a long time
to recover from or to treat such as bacterial endocarditis,
parasitic infections, tuberculosis and mononucleosis.
•• Irritable Bowel Syndrome (IBS).
•• Renal disease.
•• Liver disease.
•• Malnutrition.
Certain medicines may also cause drowsiness or fatigue,
including antihistamines, antihypertensives, various central
Stress
Overwork
Sleep difficulties
Depression and anxiety
Chronic fatigue
syndrome
Fibromyalgia
Medical
illnesses
Nutritional
factors
Medications
Inactivity and
overweight
Alcohol
(Source: http://www.health.harvard.edu/healthbeat/Hb_images/causes-of-fatigue.jpg)
nervous system medicines, steroids and diuretics. Table I
gives a comprehensive list of possible causes of fatigue, and
Table II provides a summary of medicine classes that may
lead to fatigue.
Diagnosis of fatigue
Symptoms of fatigue typically include:
•• Weakness, lack of energy, tiredness and exhaustion.
•• Passing out or feeling as if you are going to pass out.
•• Palpitations.
•• Dizziness.
•• Vertigo.
•• Shortness of breath.
Patients with fatigue have as their typical complaint that they
Table I: Conditions or diseases causing fatigue7
Cause
Specific examples
Sleep disturbances
Not enough sleep, too much sleep, sleep apnoea, shift work (changing shifts or night shifts), alcohol
Heart disease
Congestive heart failure, cardiomyopathy
Lung disease
Asthma, emphysema or chronic obstructive pulmonary disease (COPD), pneumonia
Nutritional disorders
Malnutrition (kwashiorkor, protein deficiency or marasmus, total calorie deficiency), obesity, vitamin deficiency
(thiamine, vitamin B12, vitamin B6, folate, vitamin C)
Electrolyte disturbances
Low potassium, low magnesium, low or high calcium, low sodium
Endocrine disorders
Hypo- or hyperglycaemia, hypo- or hyperthyroidism, low cortisol (Addison’s disease), high cortisol (Cushing’s
syndrome)
Gastrointestinal disorders
Gastro-oesophageal reflux disease, peptic ulcer disease
Neurological disorders
Multiple sclerosis, stroke, Lou Gehrig disease
Infectious causes
Any chronic disease, HIV/AIDS, tuberculosis, hepatitis, mononucleosis, chronic fatigue syndrome, urinary tract
infections
Connective tissue disorders
Osteo- and rheumatoid arthritis, systemic lupus erythematosus, fibromyalgia, acromegaly
General disorders
Cancer, anaemia
Gynaecologic conditions
Pregnancy, menopause
Exercise disturbances
Lack of exercise, too much exercise, excessive workload
Psychological
Depression, anxiety, grief, stress
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Table II: Medicines that may cause fatigue7
Medicine class
Rationale and specific examples
Antihypertensives
The ultimate decrease in blood pressure also means a decrease in the amount of work the heart is doing,
which can lead to a feeling of fatigue. Some of the medicines also act on the central nervous system.
Examples: beta-blockers, calcium channel blockers, diuretics and ACE inhibitors
Cardiac medicine
Fatigue can be related to the effect of the medication on the heart or to the effects on other areas of the body.
Examples: Digoxin, amiodarone, procainamide
Central nervous system
medicines
Medicines for depression and anxiety work by increasing the neurotransmitters in the brain that have a calming
effect on the body, thus stimulating fatigue.
Examples: Antidepressants, antipsychotics and anxiolytics
Narcotics
Many analgesics are opiate derived. Drowsiness can be caused by opiates (codeine, hydrocodone, oxycodone
and propoxyphene).
Muscle relaxants
They work by decreasing the contraction of muscles. This relaxation can lead to total body relaxation, which
may cause the person to feel fatigued.
Example: Orphenadrine
feel “run down” and need something to give them energy.
Thorough history-taking is necessary to exclude obvious
causes such as death of a loved one or a family crisis. The
pharmacist should also enquire about associated symptoms
and factors if an organic cause is suspected, such as1:
•• Diet, for example a vitamin or mineral deficiency, anaemia
or low blood sugar.
•• Fever and/or pain due to, for example, a malignancy or an
infection.
•• Chronic conditions, such as diabetes mellitus, hypo- or
hyperthyroidism, or asthma.
•• Conditions such as sleep apnoea or a female who is perimenopausal.
•• Light headedness if the patient stands up suddenly, which
may be due to hypotension.
Tests that may be performed include:
•• Urinalysis to test for protein, blood and glucose.
•• Full blood count to check for anaemia, diabetes and possible infection. In children especially, serum ferritin should
be checked.
•• Thyroid, kidney and liver function tests.
Counselling approach to follow
Since fatigue is extremely common, most patients will first selfmedicate with vitamin and/or mineral supplements, tonics or
stimulants. Any patient requesting advice on fatigue should be
thoroughly questioned by the pharmacist since it is most likely
that the fatigue has either not responded to over-the-counter
(OTC) medication or the symptoms are troublesome enough
for the patient to seek advice.
A thorough medical and drug history should be taken to enable
the pharmacist to rule out serious pathology. A number of specific questions should be asked of the patient (see Table III).
The pharmacist should also enquire about the person’s social
history (for example, working conditions, and family life and circumstances) since factors such as stress, tension and anxiety
can play a significant role in fatigue. It is often useful to ask the
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patient what he or she thinks is wrong, because that may give
an idea of the patient’s emotional state.
Usually a physical examination will be performed and further
tests may be conducted depending on the outcome of the
history taking and physical examination. It is important to
reassure the patient if there is no obvious underlying pathology. The patient should also be counselled that there is a
relationship between psychological and emotional factors and
fatigue, and by being aware of this, can help the patient to
deal with the symptoms.
When to refer
The following patients need urgent referral1,2:
•• A patient with depression, for example a patient with suicidal tendencies.
•• If the condition does not improve after two weeks of treatment.
•• If an organic cause is suspected.
•• Significant weight loss.
•• Localising or focal neurological signs.
•• Any unexplained sudden symptoms, such as syncope,
chest pain, shortness of breath, bleeding, severe pain or
headache, irregular or fast heartbeat, or if other people and/
or pets in the same household have the same unexplained
symptoms (possible carbon monoxide poisoning).
Children presenting with sustained fatigue of any duration with no
obvious cause should always be referred for paediatric review.2
Treatment
Non-pharmacological treatment
Non-pharmacological measures include:
•• Get adequate, regular and consistent amounts of sleep at night.
•• Eat a healthy, well-balanced diet and drink enough water
throughout the day.
•• Exercise regularly.
•• Learn ways to relax, such as yoga or meditation.
•• Maintain a reasonable work and personal schedule.
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Table III: Specific questions to ask the patient with fatigue6,7
Aspect
Specific questions to ask
Onset
•
•
How long have you had the fatigue? Did it develop recently or a while ago?
Have you experienced fatigue in the past?
Quality
•
•
•
•
•
Does the level of fatigue remain constant throughout the day?
Does it get worse as the day progresses, or are you fatigued at the start of the day?
Is there a pattern to your fatigue? Time of day or year?
Does your fatigue occur at regular cycles?
What usually helps to relieve the fatigue?
Medication
•
Do you take any prescription or over-the-counter medicines? If yes, what are you taking?
Emotional state
•
•
•
•
Are you feeling unhappiness or disappointment in your life?
Has anyone close to you recently passed away?
Do you feel depressed, anxious or stressed?
Are you bored?
Sleep pattern
•
•
•
•
How much do you sleep?
What hours do you sleep?
Do you awake rested or fatigued?
How many times do you wake during a typical night? Are you able to fall back asleep? Are you snoring?
Exercise
•
Do you get regular exercise?
Stress
•
Have you had any new stressors in your life, for example moving home, work problems or travelling (jet
lag)?
Were there any recent changes in your relationship, job, school or living arrangements?
•
Diet
•
•
•
•
•
Associated symptoms
•
•
Do you eat a balanced diet?
Do you take in adequate fluid? Do you regularly consume alcohol? How often do you drink coffee or beverages containing caffeine?
Are you currently on a diet?
Have you had any recent change in appetite (more or less)?
Have you experienced a weight change (increase or decrease)?
Do you experience any fever, pain, nausea, vomiting, diarrhoea, blood in urine or stool, shortness of
breath, chest pain, constipation, muscle cramps or aches, easy bruising, cough, changes in thirst or urination, inability to sleep lying flat, inability to walk up more than one flight of stairs, menstrual irregularities,
swollen legs or any lumps?
Do you have any symptoms possibly indicative of poisoning?
•• Change stressful circumstances if possible.
•• Avoid alcohol, nicotine, excessive consumption of energy
drinks and drug use.
•• Antibiotics to control infections.
•• Vitamins and/or minerals for marginal vitamin/mineral
deficiencies
The most common cause of persistent fatigue is stress and
the emotional response to it. People who feel fatigued most
of the time do not necessarily have more stress in their lives,
but they may be more sensitive to its effects or may not be
able to handle stress well. Stress-induced emotions consume
huge amounts of energy. Relaxation therapy in combination
with cognitive behavioural therapy (CBT) may therefore be
beneficial. Relaxation therapies may include a wide variety of
therapies, for example, meditation, yoga, self-hypnosis, tai chi,
progressive muscle relaxation, aromatherapy and massage.
Preparations which can be used to relieve fatigue mainly contain
a central nervous system stimulant such as caffeine, together
with various vitamins and minerals, or plant extracts1, such as
ginseng. There are a wide variety of these products available
on the South African market. Stimulants (including caffeine) are,
however, not effective for the long-term treatment of fatigue.
Pharmacological treatment
If there is an underlying disorder causing the fatigue, such as
chronic pain or depression, that should be treated first. Many
causes of fatigue can be treated with medication, for example:
•• Iron supplements for anaemia.
•• Medicine or devices to help with sleep apnoea.
•• Medicine to control blood glucose or thyroid function.
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Chronic fatigue syndrome
Chronic fatigue syndrome (CFS) is defined as longstanding,
severe, disabling fatigue without demonstrable muscle weakness.8 Underlying disorders that could explain the fatigue are
absent. Depression, anxiety, and other psychological diagnoses are typically absent. The intense fatigue of unknown
cause limits the patient’s functional capacity, producing various
degrees of disability. Treatment is rest and psychological support, often including medicines to alleviate symptoms.
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The definition of CFS has several variants and the diverse
names for the syndrome over the years, reflect the many
and controversial hypotheses about its aetiology.9 CFS
was previously known as Myalgic Encephalomyelitis (ME)
which means “inflammation of the brain and spinal cord with
muscle pain”. ME is used in the ICD-10 classification system
of the World Health Organization as a subheading under
Brain Disorders – Post-viral fatigue syndrome. CFS and ME
are commonly used as synonyms. Further names that have
been used to refer to CFS are, for example, allergic encephalomyelitis, immune dysfunction syndrome, neuroendocrine
immune dysfunction syndrome, post viral syndrome, Iceland
disease, neurasthenia, Royal Free disease4 and “yuppie
flu”. Prevalence is therefore difficult to estimate accurately,
but it is said to vary from 7 to 38 in 100 000 people.8 Other
sources estimate the prevalence at 0.2% to 2.6%.2 CFS occurs more in females, and patients are generally between 25
and 45 years of age.8,9
Aetiology
The aetiology of CFS is controversial, and the precise cause
remains unknown. CFS seems to be distinct from typical
depression, anxiety or other psychological disorders. Several
hypotheses have been postulated, namely4,8:
Infectious theory
A chronic viral infection has been proposed as a cause because
many patients relate the onset of CFS to an event similar to
influenza or mononucleosis. Epstein-Barr virus (EBV) has also
been proposed as a cause, but immunologic markers of exposure do not appear to be sensitive or specific.8 Approximately
10% of patients are diagnosed with CFS after EBV.9 Other possible but unproven viral causes include enteroviruses, human
herpesvirus 6, and human T-cell lymphotropic virus.8
Immunological theory
Allergic reactions have also been proposed (about 65% of
patients report previous allergies, and the rate of cutaneous reactivity to inhalants or food is 25% to 50% higher in this group
than in the general population).8 Immunisation has also been
mentioned as a possible cause.2
Various immunologic abnormalities have been reported in
patients with CFS. They include low levels of immunoglobulin
G (IgG), decreased lymphocytic proliferation, low interferon-g
levels in response to mitogens, and poor cytotoxicity of natural
killer cells.8 Some patients have abnormal IgG, with circulating
autoantibodies and immune complexes. Many other immunologic abnormalities have been studied, but none provides
adequate sensitivity and specificity for defining the syndrome.8
There is, therefore, no scientific evidence to attribute the cause
of CFS to a primary disorder of the immune system.
Neuroendocrinological and other theories
Other proposed mechanisms include neuroendocrine abnormalities, abnormal levels of neurotransmitters, inadequate
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cerebral circulation and elevated levels of angiotensin converting enzyme (ACE).8 Data indicate that relatives of patients
with CFS have an increased risk of developing the syndrome,
suggesting a familial or genetic component.8
Symptoms, signs, diagnosis and prognosis
The onset of CFS is usually abrupt, and many patients report
an initial viral-like illness with swollen lymph nodes, extreme fatigue, fever and upper respiratory symptoms. The main symptom is fatigue (usually for six months or more) that interferes
with daily activities (see Table IV for the diagnostic criteria).
Because the cause is unknown, diagnosis is by clinical criteria.
Further evaluation aims to exclude treatable disorders. There
is no laboratory test that can diagnose the condition or measure its severity. A reasonable assessment includes a full blood
count and measurement of electrolytes, erythrocyte sedimentation rate (ESR) and thyroid-stimulating hormone. In some
cases, chest X-ray and tests for antinuclear antibody, rheumatoid factor, hepatitis, and HIV could be added.8 Viral antibody
and other expensive tests are usually unlikely to shed light on
the diagnosis or cause. Obvious depression or severe anxiety
excludes the diagnosis of CFS.
There is an average time of five years from the beginning of
the symptoms to the diagnosis of the syndrome, with reported
total recovery rates of between zero and 37%, and improvement between 6 and 63%.4 Younger patients and patients
without concomitant psychiatric diseases are thought to show
the best prognosis, although other studies have shown that the
rates for both groups are similar.4 It is estimated that 55% of
adults will still have symptoms after six months, with the risk
increasing three times if there is an existing history of anxiety
or depression.2 Generally the prognosis is better for children.2
Treatment
Many symptoms of CFS respond to treatment. Even modest
improvements in symptoms can make an important difference to
the patient’s degree of self-sufficiency. Nonsteroidal anti-inflammatory drugs alleviate headache, diffuse pain and feverishness.
Allergic rhinitis and sinusitis are common, and antihistamines
Chronic
fatigue syndrome
Depression
Loss of motivation
Loss of appetite
Fibromyalgia
Myalgia/arthralgia
Tender points
Unrefreshing sleep
headaches
Prolonged
fatigue states
Fatigue
Pain
Poor concentration
Irritable mood
Anxiety
Panic attacks
Avoidant behaviour
Irritable
bowel syndrome
Diarrhoea/constipation
Abdominal pain
Bloating
(Source: http://www.eheintl.com/newsltrs/images/chronic_fatigue_syndrome.gif)
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Table IV: Diagnostic criteria for chronic fatigue syndrome8
Unexplained, persistent, or relapsing chronic fatigue that is:
•
new or has a definite onset
•
not due to ongoing exertion
•
not substantially alleviated by rest, and
•
substantially reduces occupational, educational, social or personal activities
At least four of the following for 6 months
or longer (must not predate the fatigue):
Impaired short-term memory (self-reported) severe enough to substantially reduce occupational,
educational, social or personal activities
Sore throat
Low-grade fever
Tender, enlarged, painful cervical or axillary lymph nodes
Muscle pain
Abdominal pain
Multijoint pain without joint swelling or tenderness (arthralgia)
Headaches that are new in type, pattern or severity
Unrefreshing sleep
Postexertional malaise lasting more than 24 hours
Cognitive difficulties (especially with concentrating and sleeping)
and/or decongestants may be helpful. Non-sedating antidepressants are commonly prescribed, although their value is undetermined. Although they improve mood and disordered sleep, they
may also attenuate the fatigue. Antiviral treatments with acyclovir and amantadine do not appear to be effective.8 Studies of
immunologic treatments, including high-dose immune globulins,
dialysable white blood count extract, amphigen, interferons, isoprinosine and corticosteroids have been inconclusive and mostly
disappointing.8 Dietary supplements and high-dose vitamins are
commonly used, but their usefulness has not been substantiated. Psychological intervention and/or physical rehabilitation
programmes may help some patients. Persistent or prolonged
rest should be firmly discouraged because it can worsen deconditioning and promote progressive frailty, and also negatively
impact on the patient’s self-image.
Conclusion
Fatigue can become a vicious cycle. If a person feels fatigued,
he or she may avoid most forms of physical activity, start
worrying about the fatigue and start taking various forms of
stimulants. This in turn may cause the person to become physically unfit, stressed about not getting better and dependant on
some or other type of “upper” to let him or her feel better. It is
difficult to break this cycle once established. There is no single
treatment for fatigue. It is imperative that the underlying cause
be determined. A thorough history-taking by the pharmacist is
therefore important to determine possible causes and also to
exclude serious underlying pathology.
There are numerous strategies to help a person regain the
physical and mental energy needed to enjoy life to its fullest.r
References
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4. Fernández AA, Martín AP, Martínez MI, Bustillo MA, Hernández FJB, Labrado J de la C, Peňas RD, Rivas EG, Delgado CP, Redondo JR & Giménez
JRR. 2009. Chronic Fatigue Syndrome: Aetiology, diagnosis and treatment.
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Family Medicine, 6 (6): 519-527.
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Although fatigue may be an inescapable part of life for most
people, there is no need “to take it lying down”. The body is
geared towards generating energy as well as expending it.
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