2-Minute Consultation: Fatigue as a Side Effect

Author: Jeannette Y. Wick, RPh, MBA, FASCP

---

Ms. Wick is a senior clinical research pharmacist at the National Cancer Institute, National Institutes of Health, Bethesda, Maryland. The views expressed are those of the author and not those of any government agency

---

Americans have a propensity to wear themselves out with their never-ending activity, multitasking, and ignoring their hardwired need for rest. The exhaustion continuum begins with simply being tired, progresses through periods that might be described as weary or worn out; can include indifference or apathy; and ends at overwhelming fatigue.¹ Like pain, fatigue is an objective and subjective state. When physical overexertion is the cause, fatigue is the extreme and expected end point. This type of fatigue occurs in otherwise mentally and physically healthy people when they eat poorly, exercise too much, and/or skimp on rest.²

Pathologic fatigue is decreased capacity for physical or mental work disproportionate to changes in activity or stimuli and unresolved by bed rest. If it occurs daily or almost daily for 2 weeks, fatigue becomes a serious problem.^1,3,4 Fatigue is normally distributed in the population; so for each individual who reports fatigue, another fortunate individual reports boundless energy.^5-7 Fatigue—an absence of energy—can make patients feel physically weak, mentally dull, or both (Table). Any effort exhausts fatigued patients quickly, and fatigue has physical, mental, and emotional components.

Acute (lasting <6 months) or chronic (lasting >6 months)4 fatigue troubles patients and confounds and frustrates physicians with its vague presentation. 10-12 Fatigue is the precipitating complaint for more visits to primary care physicians than colds, rashes, headache, or chest pain. Chronic fatigue can be disabling.

Numerous underlying conditions, especially cancer or HIV infection and their treatments, have been associated with fatigue. Also among the most common causes 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 to disease: overexertion, isolation, medication side effects, and paradoxically, boredom.¹³

How Common Is Fatigue?

Measuring fatigue's prevalence is a significant challenge due to its mercurial definitions. Determining how many people experience fatigue—and when it becomes abnormal—is an imprecise science. Simple validated tools are rare and cannot be used in all populations.³ Most come from clinical trials and can be difficult or time-consuming to use.¹ Thus, an exact prevalence is unknown.

To assess fatigue, clinicians often ask these questions and prompt patients to provide additional information:

• Are you experiencing fatigue?
• On a scale of 1 to 10, where 1 is no fatigue and 10 is fatigue so severe you cannot function, what is your average fatigue level in the last 2 weeks?
• How does fatigue interfere with your ability to function?¹

As they listen, clinicians should try to identify temporal patterns of onset, course, and duration; exacerbating and relieving factors; and specific distress associated with the fatigue. Sometimes asking patients, "Do you have any ideas about what caused this?" cuts to the chase. A fourth question, "Do bed rest or vacations alleviate the fatigue?" is helpful. Conducting a medication review is often illuminating.^14,15

Medications and Fatigue

Numerous medications are associated with fatigue. Sometimes, as with hydrochlorothiazide combination 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 problems that may cause or contribute to the fatigue, some clinicians will wait for a change in the patient's condition. This approach tends to distance and disappoint patients, however.⁴ A more aggressive approach combines available interventions. Clinicians must start with a careful discussion about what to expect, including:

• Reconciling patients' hopes with reasonable expectations¹⁴
• Advising patients that fatigue can be managed, but treatment or cure is unlikely¹⁴
• Reducing patients' anxiety and stress by describing what they can honestly expect, drawing from clinical evidence and experience^16,17

When a medication or a combination of medications is the cause and they cannot be eliminated, clinicians should consider:

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

Clinicians' Role

For all causes of fatigue, the health care team should promote active management strategies, like improved diet, more exercise, and better control of patients' underlying disease states. Increased aerobic activity, beginning with light exercise of short duration and increasing as tolerated, is essential unless it is clearly contraindicated.⁸ Patients with fatigue also need adequate sleep and good nutrition.⁶ Passive management strategies (sleeping through the fatigue period, limiting activities, or pushing through with activities despite fatigue) do not lead to improvement.

At the very least, clinicians should try to help patients identify the time of day when energy peaks and have them plan around that time and pace themselves; many elderly people learn to do this intuitively.^4,6 Getting adequate sleep is essential, and napping can be very helpful. Some patients benefit from reviewing their normal activities and identifying ways to conserve energy.

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

Pharmacists should be aware that patients may look to complementary or alternative medicines, especially coenzyme Q, cordyceps mushrooms, dehydroepiandrosterone, dong quai, evening primrose oil, ginseng, maitake, rhodiola, and vitamin B₁₂. Pharmacists should stress to patients that many of these are eliminated via the liver, and large doses may harm the liver. They also may interact with prescription drugs, and their use for fatigue is rarely supported by studies.⁹ Patients should ask their prescribers or pharmacists before taking 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

1. Ahlberg K, Ekman T, Gaston-Johansson F, Mock V. Assessment and management of cancer-related fatigue in adults. Lancet. 2003;362(9384):640-650.
2. Katerndahl DA. Differentiation of physical and psychological fatigue. Fam Pract Res J. 1993;13(1):81-91.
3. 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.
4. Ruffin MT 4th, Cohen M. Evaluation and management of fatigue. Am Fam Physician. 1994;50(3):625-634.
5. 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.
6. Liao S, Ferrell BA. Fatigue in an older population. J Am Geriatr Soc. 2000;48(4):426-430.
7. Chen MK. The epidemiology of self-perceived fatigue among adults. Prev Med. 1986;15(1):74-81.
8. Sharpe M, Wilks D. Fatigue. BMJ. 2002;325(7362):480-483.
9. Hepatitis C Support Project. A Guide to Understanding and Managing Fatigue.
10. 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.
11. Camarillo MA. The oncology patient's experience of fatigue. In: Whedon M. Quality of Life: A Nursing Challenge. Philadelphia, PA: Meniscus; 1991:39-44.
12. 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.
13. 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.
14. 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.
15. Trendall J. Assessing fatigue in patients with COPD. Prof Nurse. 2001(7);16:1217-1220.
16. 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.
17. 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.
18. 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.
19. Reineke-Bracke H, Radbruch L, Elsner F. Treatment of fatigue: modafinil, methylphenidate, and goals of care. J Palliat Med. 2006;9(5):1210-1214.
20. Lapierre Y, Hum S. Treating fatigue. Int MS J. 2007;14(2):64-71.