2-Minute Consultation: Fatigue as a Side Effect

Ms. Wick is a senior clinical researchpharmacist at the National CancerInstitute, National Institutes of Health,Bethesda, Maryland. The views expressedare those of the author and not those ofany government agency

Americans have a propensity towear themselves out with theirnever-ending activity, multitasking,and ignoring their hardwired need forrest. The exhaustion continuum beginswith simply being tired, progressesthrough periods that might be describedas weary or worn out; can include indifferenceor apathy; and ends at overwhelmingfatigue.¹ Like pain, fatigue isan objective and subjective state. Whenphysical overexertion is the cause, fatigueis the extreme and expected end point.This type of fatigue occurs in otherwisementally and physically healthy peoplewhen they eat poorly, exercise too much,and/or skimp on rest.²

Pathologic fatigue is decreased capacityfor physical or mental work disproportionateto changes in activity orstimuli and unresolved by bed rest. Ifit occurs daily or almost daily for 2weeks, fatigue becomes a serious problem.^1,3,4Fatigue is normally distributedin the population; so for each individualwho reports fatigue, another fortunateindividual reports boundless energy.^5-7Fatigue—an absence of energy—canmake patients feel physically weak,mentally dull, or both (Table). Anyeffort exhausts fatigued patients quickly,and fatigue has physical, mental, andemotional components.

Acute (lasting <6 months) or chronic(lasting >6 months)4 fatigue troublespatients and confounds and frustratesphysicians with its vague presentation.10-12 Fatigue is the precipitating complaintfor more visits to primary carephysicians than colds, rashes, headache,or chest pain. Chronic fatigue can bedisabling.

Numerous underlying conditions,especiallycancer or HIV infection andtheir treatments, have been associatedwith fatigue. Also among the most commoncauses are bacterial and viral infections,arthritis, sleep disorders, anxiety,depression,chronic fatigue syndrome,fibromyalgia, cardiovascular disease,multiple sclerosis (MS), and lung disease.Patients also report causes unrelated todisease: overexertion, isolation, medicationside effects, and paradoxically,boredom.¹³

How Common Is Fatigue?

Measuring fatigue's prevalence is a significantchallenge due to its mercurialdefinitions. Determining how manypeople experience fatigue&#8212;and whenit becomes abnormal&#8212;is an imprecisescience. Simple validated tools are rareand cannot be used in all populations.³Most come from clinical trials and canbe difficult or time-consuming to use.¹Thus, an exact prevalence is unknown.

To assess fatigue, clinicians often askthese questions and prompt patients toprovide additional information:

• Are you experiencing fatigue?
• On a scale of 1 to 10, where 1 is nofatigue and 10 is fatigue so severeyou cannot function, what is youraverage fatigue level in the last 2weeks?
• How does fatigue interfere withyour ability to function?¹

As they listen, clinicians should tryto identify temporal patterns of onset,course, and duration; exacerbating andrelieving factors; and specific distressassociated with the fatigue. Sometimesasking patients, "Do you have any ideasabout what caused this?" cuts to thechase. A fourth question, "Do bed rest orvacations alleviate the fatigue?" is helpful.Conducting a medication review isoften illuminating.^14,15

Medications and Fatigue

Numerous medications are associatedwith fatigue. Sometimes, as with hydrochlorothiazidecombination products,an interaction magnifies the fatigue.

Table

Fatigue Signs and Symptoms

Apathy

Forgetfulness

Lethargy

Moodiness

Poor communication

Poor decision making

Reduced vigilance

Sleeping at inappropriate times

Slowed reaction time

Thought fixation

Source: references 8 and 9.

Treatment is, by necessity, empiric.After correcting any underlying problemsthat may cause or contribute tothe fatigue, some clinicians will waitfor a change in the patient's condition.This approach tends to distance anddisappoint patients, however.⁴ A moreaggressive approach combines availableinterventions. Clinicians must startwith a careful discussion about what toexpect, including:

• Reconciling patients' hopes withreasonable expectations¹⁴
• Advising patients that fatigue can be managed, but treatmentor cure is unlikely¹⁴
• Reducing patients' anxiety and stress by describing whatthey can honestly expect, drawing from clinical evidenceand experience^16,17

When a medication or a combination of medications isthe cause and they cannot be eliminated, clinicians shouldconsider:

• Tapering to the lowest effective dose is prudent.
• Dosing so that the most profound period of fatigue, ifit is predictable, occurs during the night, can minimizefatigue's impact.
• Using less sedating alternatives (eg, lamotrigine insteadof carbamazepine)may help.
• Adding new medications to the patient's regimen only ifthey are absolutely necessary.
• Determining if depression is a factor, and treating it withnonsedating agents may improve the fatigue.

Clinicians' Role

For all causes of fatigue, the health care team should promoteactive management strategies, like improved diet, more exercise,and better control of patients' underlying disease states.Increased aerobic activity, beginning with light exercise ofshort duration and increasing as tolerated, is essential unlessit is clearly contraindicated.⁸ Patients with fatigue also needadequate sleep and good nutrition.⁶ Passive managementstrategies (sleeping through the fatigue period, limiting activities,or pushing through with activities despite fatigue) do notlead to improvement.

At the very least, clinicians should try to help patients identifythe time of day when energy peaks and have them planaround that time and pace themselves; many elderly peoplelearn to do this intuitively.^4,6 Getting adequate sleep is essential,and napping can be very helpful. Some patients benefitfrom reviewing their normal activities and identifying waysto conserve energy.

If fatigue is profound and the agent causing it cannot bediscontinued, clinicians might consider prescribing methylphenidateor modafinil to increase alertness and energy.Amantadine also has been used to treat fatigue associatedwith MS, with mixed results.^18-20

Pharmacists should be aware that patients may look tocomplementary or alternative medicines, especially coenzymeQ, cordyceps mushrooms, dehydroepiandrosterone,dong quai, evening primrose oil, ginseng, maitake, rhodiola,and vitamin B₁₂. Pharmacists should stress to patients thatmany of these are eliminated via the liver, and large dosesmay harm the liver. They also may interact with prescriptiondrugs, and their use for fatigue is rarely supported by studies.⁹Patients should ask their prescribers or pharmacists beforetaking these agents.

Table

Medications that Can Cause Fatigue

Agent or Class

Fatigue Potential

Suggested Mechanisms Behind Fatigue

ACE inhibitors

Moderate

Alfuzosin

Moderate

Amlodipine

Moderate

Anticonvulsants

Very high

Antineoplastic agents

Very high

Cancer itself has been associated with profound fatigue

Antiretrovirals

Moderate

Fatigue among HIV-infected patients may be due to hepatic decline, coinfection, anemia, increased cytokine levels, adrenal insufficiency, depression, anxiety, and a host of other comorbid conditions

Beta-blockers

Moderate

Cardiac conditions have been associated with chronic low-level inflammation, which may exacerbate fatigue

Buspirone

Moderate

Carvedilol

Moderate

Cardiac conditions have been associated with chronic low-level inflammation, which may exacerbate fatigue

Clonidine

Moderate

Cardiac conditions have been associated with chronic low-level inflammation, which may exacerbate fatigue

Corticosteroids

Moderate

May alter diurnal rhythm and cause sleep disturbances

Disease-modifying drugs

High

Immune system dysregulation may increase cytokine levels and lead to fatigue

Dopaminergic agents

Very high

Duloxetine

High

Famciclovir

Moderate

Guanfacine

Very high

Hydrochlorothiazide/metoprolol

Moderate

Cardiac conditions have been associated with chronic low-level inflammation, which may exacerbate fatigue

Hydrochlorothiazide/irbesartan

High

Cardiac conditions have been associated with chronic low-level inflammation, which may exacerbate fatigue

Immune system?modulating agents

Very high

Irbesartan

Moderate

Metformin/rosiglitazone

High

Opioid analgesics

High

Pravastatin

Moderate

Skeletal muscle relaxant

Moderate

ACE = angiotensin-converting enzyme.

References

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• Katerndahl DA. Differentiation of physical and psychological fatigue. Fam Pract Res J. 1993;13(1):81-91.
• Lai JS, Cella D, Chang CH, Bode RK, Heinemann AW. Item banking to improve, shorten and computerize self-reported fatigue: an illustration of steps to create a core item bank from the FACIT-Fatigue Scale. Qual Life Res. 2003;12(5):485-501.
• Ruffin MT 4th, Cohen M. Evaluation and management of fatigue. Am Fam Physician. 1994;50(3):625-634.
• Fernandes R, Stone P, Andrews P, Morgan R, Sharma S. Comparison between fatigue, sleep disturbance, and circadian rhythm in cancer inpatients and healthy volunteers: evaluation of diagnostic criteria for cancer-related fatigue. J Pain Symptom Manage. 2006;32(5):245-254.
• Liao S, Ferrell BA. Fatigue in an older population. J Am Geriatr Soc. 2000;48(4):426-430.
• Chen MK. The epidemiology of self-perceived fatigue among adults. Prev Med. 1986;15(1):74-81.
• Sharpe M, Wilks D. Fatigue. BMJ. 2002;325(7362):480-483.
• Hepatitis C Support Project. A Guide to Understanding and Managing Fatigue.
• Vogelzang NJ, Breitbart W, Cella D, et al. Patient, caregiver, and oncologist perceptions of cancer-related fatigue: results of a tripart assessment survey. The Fatigue Coalition. Semin Hematol. 1997;34(3 Suppl 2):4-12.
• Camarillo MA. The oncology patient's experience of fatigue. In: Whedon M. Quality of Life: A Nursing Challenge. Philadelphia, PA: Meniscus; 1991:39-44.
• Lane TJ, Matthews DA, Manu P. The low yield of physical examinations and laboratory investigations of patients with chronic fatigue. Am J Med Sci. 1990;299(5):313-318.
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