2-Minute Consultation: Fatigue as a Side Effect

Pharmacy Times
Volume 0

Clinicians should recognize the signs and symptoms of fatigue and the role of medications in triggering it.

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.


Fatigue Signs and Symptoms





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 experience16,17

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.


Medications that Can Cause Fatigue

Agent or Class

Fatigue Potential

Suggested Mechanisms Behind Fatigue

ACE inhibitors







Very high

Antineoplastic agents

Very high

Cancer itself has been associated with profound fatigue



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



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





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



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



May alter diurnal rhythm and cause sleep disturbances

Disease-modifying drugs


Immune system dysregulation may increase cytokine levels and lead to fatigue

Dopaminergic agents

Very high






Very high



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



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

Immune system?modulating agents

Very high





Opioid analgesics




Skeletal muscle relaxant


ACE = angiotensin-converting enzyme.


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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.
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  • 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.
  • Avlund K, Rantanen T, Schroll M. Tiredness and subsequent disability in older adults: The role of walking limitations. J Gerontol A Biol Sci Med Sci. 2006;61(11):1201-1205.
  • Yennurajalingam S, Bruera E. Palliative management of fatigue at the close of life: "It feels like my body is just worn out". JAMA. 2007;297(3):295-304.
  • Trendall J. Assessing fatigue in patients with COPD. Prof Nurse. 2001(7);16:1217-1220.
  • Johnson JE, Nail LM, Lauver D, King KB, Keys H. Reducing the negative impact of radiation therapy on functional status. Cancer. 1988;61(16):46-51.
  • Burish TG, Snyder SL, Jenkins RA. Preparing patients for cancer chemotherapy: effect of coping preparation and relaxation interventions. J Consult Clin Psychol. 1991;59(4):518-525.
  • Minton O, Stone P, Richardson A, Sharpe M, Hotopf M. Drug therapy for the management of cancer related fatigue. Cochrane Database Syst Rev. 2008;(1):CD006704.
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