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More MS news articles for January 2003

MS-Related Fatigue Toward a Consensus for Pharmacologic Therapy

http://mscare.com/s0210/page_01.htm

International Journal of MS Care, October 2002 Supplement
Based on proceedings from the Annual Meeting of the Consortium of Multiple Sclerosis Centers - June 5, 2002 in Chicago

Contents
 
Introduction
Randall Schapiro, MD

The Pathophysiology of MS-Related Fatigue: What Is the Role of Wake Promotion?
Randall Schapiro, MD

Measuring MS-Related Fatigue
Lauren B. Krupp, MD

Clinical Trials on MS-Related Fatigue
Jay H. Rosenberg, MD
 
Pharmacologic Management of MS-Related Fatigue
Randall Schapiro, MD
 
Introduction

Randall Schapiro, MD
Director, Fairview Multiple Sclerosis Center
Minneapolis

By now, the often-quoted statistics on multiple sclerosis (MS)-related fatigue are familiar to the majority of clinicians who treat MS patients. According to some studies, MS-related fatigue affects more than 90% of those with MS, over half of whom have reported that it is the single most disabling symptom that they experience.

There remains much work to be done in understanding the pathophysiology of MS-related fatigue and how best to assess the patient’s level of fatigue, so that we can determine whether the therapies we prescribe are having an impact. Pharmacologic agents used for the treatment of MS-related fatigue act along a number of pathways, with stimulant medications causing global central nervous system activation. In contrast, the wake-promoting drug modafinil appears to have activity that closely resembles the body’s normal mechanisms of wakefulness. Therefore, it may offer efficacy without the adverse effects and risk for abuse that are often seen with stimulants.

In October 2001, the Working Group for Pharmacologic Therapy in MS-Related Fatigue met to review the evidence related to drug treatment for MS-related fatigue. This supplement to the International Journal of MS Care reviews the current trial information on MS-related fatigue since the MS Council for Clinical Practice Guidelines were published in 1998, and offers preliminary recommendations based on the findings of the Working Group. While it is our intention to further refine these recommendations prior to their ultimate publication, we believe that they reflect accurately the state of MS-related fatigue treatment, and the best approach both to fatigue assessment and to pharmacologic therapy. We hope that you find this program to be a valuable learning tool for your own practice.

The Pathophysiology of MS-Related Fatigue: What Is the Role of Wake Promotion?

Randall Schapiro, MD
Randall Schapiro is Director of the Fairview Multiple Sclerosis Center in Minneapolis.

While fatigue affects the majority of persons with multiple sclerosis (MS), its pathophysiology remains poorly understood. MS-related fatigue does not correlate with many disease characteristics, including clinical subtype, duration, and level of disability. Recent findings of reduced glucose utilization in the frontal lobe of the brain and an association with depression and cognitive dysfunction suggest that fatigue may act along common pathways with these signs and symptoms. This article reviews some of the evidence on the pathophysiology of MS-related fatigue, and the role that different pharmacologic agents can play in reducing fatigue symptoms.

Fatigue is the most common symptom encountered in multiple sclerosis (MS), and is associated with a high level of disability. It has been reported by more than 90% of those with MS, and has been described by over half as their most disabling symptom—more so than balance problems, bowel/bladder dysfunction, and weakness or paralysis.1,2

The diagnosis and management of fatigue in MS are complicated by a number of issues, including the many forms that the symptom can take. The MS Council for Clinical Practice Guidelines has defined MS-related fatigue as a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual or desired activities.3 Like any healthy person, an individual with MS can go through periods of normal fatigue. Persons with MS also experience what can be termed a “short-circuiting” fatigue, in which nerve conduction deficits prevent motor movement despite continued neuronal firing. Fatigue can be secondary to deconditioning in those who fail to get sufficient exercise,4 as well as be a symptom of depression.5 Furthermore, persons with MS may engage in a number of behaviors that precipitate fatigue, including poor sleeping and eating habits.

The vast majority of persons with MS experience what is generally referred to as primary MS-related fatigue, or “lassitude,” which is an overwhelming sense of tiredness that cannot be attributed to an identifiable cause. This type of fatigue severely limits energy and endurance,6 affects mood and the ability to cope with the disease,7 and decreases quality of life.5 Primary MS-related fatigue also decreases physical activity levels, which in turn, can increase fatigue in a vicious cycle.

Despite the prevalence of primary fatigue among persons with MS, little is known about its pathophysiology. The symptom is not characteristic of late or early MS, but rather presents across the board, at all stages of disease. It does not correlate well with other disease factors, including disability, gender, age, or clinical subtype, nor does it correlate with magnetic resonance imaging findings.8,9

However, two factors have been shown to correlate at least moderately with MS-related fatigue: depression1 and cognitive function.10 In a study by Bakshi and colleagues, a significant correlation was found between scores on the Beck Depression Inventory and scores on the Fatigue Severity Scale.1 In a study by Krupp and colleagues, MS patients were found to perform significantly worse on verbal learning tests after performing continuous cognitively effortful tasks of mathematical calculations.10 These factors may provide clues as to the pathophysiology of MS-related fatigue, as it may be that demyelination of nerves occurs along common pathways that affect fatigue, depression, and cognitive functioning.

Recent studies also have suggested that hypometabolism in certain brain regions may be implicated in primary MS-related fatigue. Positron emission tomography scans of MS patients have demonstrated a relationship between fatigue and hypometabolism in the frontal cortex and basal ganglia.11,12 This degree of hypometabolism is most likely related to some alteration in the cortex of MS patients due to a combination of demyelination, inflammation, and axonal injury.

Determinants of Wakefulness in the Brain

While the pathophysiology of MS-related fatigue remains poorly understood, it is clear that the condition does respond to the use of pharmacologic therapies. Agents that have been used to treat primary MS-related fatigue appear to act along different pathways in the brain. The first, termed the “normal” wakefulness pathway, is controlled by ascending projections from the tuberomammillary nucleus in the anterior hypothalamus (Figure 1).13,14 This type of wakefulness does not involve activity in motor/reward circuits. Modafinil increases activity of the frontal cortex along this pathway and is believed to mimic the body’s own pathways of wakefulness.

Figure 1. Central nervous system (CNS) stimulants activate the body’s mesocorticolimbic system, which governs the arousal, or “fight or flight” response. The result is global CNS activation, with an accompanying increase in peripheral autonomic effects and activation of the body’s “reward system,” increasing the potential for abuse. Modafinil is believed to act along pathways that promote normal wakefulness, involving ascending projections from the tuberomammillary nucleus to activate the cortex. The result is a “normal” wakefulness, with minimal excess motor activity and little or no activation of the brain’s reward system.
Source: Cephalon, Inc. Data on file13; Stahl SM. J Clin Psychiatry. 2002.14

The second type of pathway, termed “stimulated vigilance,” is controlled by the mesocorticolimbic system, which governs the body’s “fight or flight” response (Figure 1).13,14 Medications such as central nervous system (CNS) stimulants act along these pathways to produce global CNS activation, with increased catecholamine release, autonomic effects, and motor activity.13 The brain areas affected by CNS stimulants include the striatum, which governs motor activity, and the nucleus accumbens, which governs mechanisms of reward and abuse.

Figure 2. The activity of modafinil is limited primarily to the anterior hypothalamus, which is believed to regulate normal wakefulness.
Source: Lin JS, et al. Proc Natl Acad Sci USA. 1996.15

Preclinical Models Demonstrate CNS Selectivity of Modafinil

Preclinical studies comparing the wake-promoting agent modafinil with CNS stimulants reflect the differences in brain activity that result from activation of the two pathways. In an animal study by Lin and colleagues, amphetamine and methylphenidate were shown to produce widespread cortical activation. In contrast, the activity of modafinil was limited primarily to the anterior hypothalamus, believed to be the area implicated in normal wakefulness (Figure 2).15 In a study by Edgar and colleagues that compared modafinil with methamphetamine, the two agents produced equivalent degrees of wakefulness; however, methamphetamine was associated with increases in locomotor intensity (hyperactivity). In contrast, the increase in wakefulness observed with modafinil was not associated with increased locomotor activity (Figure 3).16

Figure 3. In preclinical animal studies, modafinil achieved wakefulness equivalent to methamphetamine with no accompanying increase in unwanted motor activity.
Source: Edgar DM, Seidel WF. J Pharmacol Exp Ther. 1997.16

Conclusions

While the pathophysiology of MS-related fatigue remains poorly understood, the research to date indicates that it is a centrally-mediated phenomenon related to nerve demyelination and inflammation, as well as axonal destruction. Research on pharmacologic treatment of MS-related fatigue demonstrates the exceedingly complex neurochemistry of the brain, and the ability of different agents to act along pathways that either provide global CNS activation or mimic the body’s own pathways of normal wakefulness.

References

1. Bakshi R, Shaikh ZA, Miletich RS, et al. Fatigue in multiple sclerosis and its relationship to depression and neurologic disability. Mult Scler. 2000;6:181-185.

2. Freal JE, Kraft GH, Coryell JK. Symptomatic fatigue in multiple sclerosis. Arch Phys Med Rehabil. 1984;65:135-138.

3. Multiple Sclerosis Council for Clinical Practice Guidelines. Fatigue and multiple sclerosis: evidence-based management strategies for fatigue in multiple sclerosis. Washington, DC: Paralyzed Veterans of America; 1998.

4. Petajan JH, Gappmaier E, White AT, et al. Impact of aerobic training on fitness and quality of life in multiple sclerosis. Ann Neurol. 1996;39:432-441.

5. Schwartz CE, Coulthard-Morris L, Zeng Q. Psychosocial correlates of fatigue in multiple sclerosis. Arch Phys Med Rehabil. 1996;77:165-170.

6. Ng AV, Kent-Braun JA. Quantitation of lower physical activity in persons with multiple sclerosis. Med Sci Sports Exerc. 1997;29:517-523.

7. Ritvo PG, Fisk JD, Archibald CJ, et al. Psychosocial and neurological predictors of mental health in multiple sclerosis patients. J Clin Epidemiol. 1996;49:467-472.

8. Fisk JD, Pontefract A, Ritvo PG, et al. The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci. 1994;21:9-14.

9. Mainero C, Faroni J, Gasperini C, et al. Fatigue and magnetic resonance imaging activity in multiple sclerosis. J Neurol. 1999;246:454-458.

10. Krupp LB, Elkins LE. Fatigue and declines in cognitive functioning in multiple sclerosis. Neurology. 2000;55:934-939.

11. Bakshi R, Miletich RS, Kinkel PR, et al. High-resolution fluorodeoxyglucose positron emission tomography shows both global and regional cerebral hypometabolism in multiple sclerosis. J Neuroimaging. 1998;8:228-234.

12. Roelcke U, Kappos L, Lechner-Scott J, et al. Reduced glucose metabolism in the frontal cortex and basal ganglia of multiple sclerosis patients with fatigue: a 18F-fluorodeoxyglucose positron emission tomography study. Neurology. 1997;48:1566-1571.

13. Cephalon, Inc. Data on file.

14. Stahl SM. Awakening to the psychopharmacology of sleep and arousal: novel neurotransmitters and wake-promoting drugs. J Clin Psychiatry. 2002;63:467-468.

15. Lin JS, Hou Y, Jouvet M. Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat. Proc Natl Acad Sci USA. 1996;93:14128-14133.

16. Edgar DM, Seidel WF. Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the rat. J Pharmacol Exp Ther. 1997;283:757-769.

Measuring MS-Related Fatigue

Lauren B. Krupp, MD
Lauren B. Krupp is Professor of Neurology at the State University of New York at Stony Brook.

There are a number of tools available to measure fatigue in the patient with multiple sclerosis (MS), including unidimensional assessments, such as the Fatigue Severity Scale (FSS), and multidimensional assessments that consider physical, cognitive, and psychosocial functioning. All are similar in that they attempt to convey the patient’s perceived level of fatigue. A number of researchers also have incorporated performance-based measures of physical and cognitive functioning into fatigue assessment, while innovative methods that attempt to capture the patient’s level of fatigue in his or her natural environment are currently being studied.

Measuring fatigue in the patient with multiple sclerosis (MS) is a challenging problem that is compounded by our fundamental lack of understanding of the precise nature of this symptom. Generally, when patients describe their fatigue (or when caregivers describe fatigue on behalf of the patient), they tend to describe it in terms of an overwhelming sense of tiredness or exhaustion. The symptom often is characterized in the same way that persons without MS describe having an influenza infection.

The fatigue experienced by patients with MS is present in all clinical disease subtypes and is exceedingly common.1 What is surprising, however, is the level of disability that fatigue produces in this population. While MS is a disease state that may lead to overwhelming symptoms such as blindness, loss of dexterity, and lack of bladder control, affected persons continue to report fatigue as being the primary factor that prevents them from working.

It is important to distinguish fatigue from affect or mood disorders such as depression. Notably, some persons with MS do experience mood changes, and depression has been shown to correlate with fatigue in patients with MS.2 Therefore, it is essential to assess the impact that depression may be having on fatigue, as it is very difficult to manage fatigue effectively in the presence of depression.

While it has not been demonstrated through any clinical studies per se, the fatigue experienced by the patient with MS may be tied to his or her declining ability to meet personal expectations. Often, people report that they have “no sense of control” or that they feel “out of control.” To facilitate our understanding of patients with MS, we should keep in mind that they are used to being able to go to work, do household chores, and engage in other activities of daily living, and that they can no longer perform these functions because they often are exhausted.

The most common approach to fatigue measurement is to assess the patient’s perceived level of fatigue. This can be done using the Fatigue Severity Scale (FSS, Table),3 the Fatigue Impact Scale4 and the Modified Fatigue Impact Scale (MFIS),5 the Fatigue Descriptive Scale,6 and the Visual Analog Scale for Fatigue.7 There also are fatigue subscales of larger inventories, such as the Medical Outcomes Study Short-Form 368 and the Profile of Mood States.9 There has been a marked increase in the number of scales used to assess fatigue in recent years, which may reflect the increased attention that clinicians are giving to patients who are struggling with this debilitating symptom.
 
Table
Fatigue Severity Scale
Statement
Score
1. My motivation is lower when I am fatigued.
2. Exercise brings on my fatigue.   
3. I am easily fatigued.   
4. Fatigue interferes with my physical functioning.   
5. Fatigue causes frequent problems for me.   
6. My fatigue prevents sustained physical functioning.  
7. Fatigue interferes with my carrying out certain duties and responsibilities.  
8. Fatigue is among my three most disabling symptoms.  
9. Fatigue interferes with my work, family, or social life.  

Patients are instructed to choose a number from 1 to 7 that indicates their degree of agreement with each statement, where 1 indicates strongly disagree and 7, strongly agree.
Source: Krupp LB. Arch Neurol. 1989.3

The fatigue scales are similar in that each attempts to capture the patient’s self report of fatigue. Some try to capture individual aspects of fatigue along various dimensions, such as physical or mental fatigue. Others, such as the FSS, are unidimensional, attempting to capture the patient’s perceived global fatigue severity. A number of these scales have been specifically studied in the treatment of fatigue, and have been shown to have positive effects. For example, exercise has been shown to be associated with the lowering of the tiredness subscale of one of the more global fatigue assessment measures,10 while pharmacologic therapy with modafinil has been shown to decrease fatigue on multiple scales, including the FSS and the MFIS.11

Performance-Based Measures of Fatigue

Fatigue also is measured in terms of decrements in performance, an approach that tends to be more appealing to researchers because it is objective and tangible. Performance-based measures have been applied in a number of different ways, and often consider physical factors such as the ability to generate sustained muscle contractions and decreased motor unit firing.12 Performance-based measures also have been examined in terms of cognitive fatigue, which may take a significant toll on the MS patient’s degree of functioning as he or she continues to perform tasks throughout the day. A 1995 study by Kujala and colleagues noted a decline in vigilance during the last few minutes of cognitive testing in subjects with MS.13 Our own research, which tested patients with MS before and after three hours of “continuously effortful” cognitive tasks, also showed a decline in cognitive performance. In comparison, healthy individuals showed an improvement in performance due to a “practice effect.”14

Innovative Approaches to Fatigue Measurement

There are some innovative methods of fatigue measurement that are currently being explored. Ecological momentary assessment attempts to measure the patient’s degree of fatigue in his or her natural environment. This concept involves following the individual throughout a 24-hour period and assessing fatigue using different methods. For example, one method uses a hand-held computer, which asks the patient at different points throughout the day to record his or her level of fatigue (Figure). This method attempts to capture environment-based changes in fatigue throughout the day as patients engage in their activities of daily living.


 

Figure. Ecological momentary assessment attempts to capture the patient’s perceived level of fatigue in his or her natural environment by asking the patient to respond to questions regarding fatigue at various points throughout the day. A hand-held computer can be used to record responses in the morning and at scheduled and random points in a 24-hour period.

Gaining an Overall Understanding of the Patient

There is no uniform approach to the use of fatigue scales in the patient with MS. Generally, it is based on clinician preference. Fatigue scales can be administered easily at the beginning of every patient visit. It is important to keep in mind, however, that a number of factors can contribute to or mimic fatigue in the patient with MS, including pain, mood disorders, and sleep disorders. Therefore, these factors also should be considered.

Finally, while any of the available fatigue scales can prove useful in assessing perceived fatigue severity, they are limited because all are subject to rater bias. In addition, while some of these scales contain cognitive and psychosocial dimensions, none of the available fatigue scales provides a truly reliable measure of cognitive or psychosocial functioning, which can only be gained by delving further into the patient’s activities, such as verifying employment attendance or conducting an extended interview with the caregiver.
 

Conclusions

The available fatigue scales are useful tools for assessing the presence and severity of this debilitating symptom. Performance-based measures, which are largely used for research purposes, also are available to assess physical and cognitive functioning. Some form of fatigue assessment should be built routinely into each patient-provider interaction. Above all, it is critically important never to ignore what patients tell us in the description of their fatigue and related symptoms such as sleepiness, pain, and mood disorders.

References

1. Bakshi R, Shaikh ZA, Miletich RS, et al. Fatigue in multiple sclerosis and its relationship to depression and neurologic disability. Mult Scler. 2000;6:181-185.

2. Schwartz CE, Coulthard-Morris L, Zeng Q. Psychosocial correlates of fatigue in multiple sclerosis. Arch Phys Med Rehabil. 1996;77:165-170.

3. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale: application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989;46:1121-1123.

4. Fisk JD, Ritvo PG, Ross L, et al. Measuring the impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis. 1994;18 (suppl 1):S79-S83.

5. Multiple Sclerosis Clinical Practice Guidelines. Fatigue and multiple sclerosis:
evidence-based management strategies for fatigue in multiple sclerosis. Washington, DC: Paralyzed Veterans of America; 1998.

6. Iriarte J, Katsamakis G, de Castro P. The Fatigue Descriptive Scale (FDS): a useful tool to evaluate fatigue in multiple sclerosis. Mult Scler. 1999;5:10-16.

7. Weinshenker BG, Penman M, Bass B, et al. A double-blind, randomized, crossover trial of pemoline in fatigue associated with multiple sclerosis. Neurology. 1992;42:1468-1471.

8. Ware JE, Kosinski M, Keller SD. SF-36 Physical and Mental Health Summary Scales: A User’s Manual. Boston, Mass: The Health Institute, New England Medical Center; 1994.

9. McNair DM, Lorr M, Droppleman LF. Profile of Mood States Manual. 2nd ed. San Diego, Calif: Educational and Industrial Testing Service; 1992.

10. Petajan JH, Gappmaier E, White AT, et al. Impact of aerobic training on fitness and quality of life in multiple sclerosis. Ann Neurol. 1996;39:432-441.

11. Rammohan KW, Rosenberg JH, Lynn DJ, et al. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry. 2002;72:179-183.

12. Schwid SR, Thornton CA, Pandya S, et al. Quantitative assessment of motor fatigue and strength in MS. Neurology. 1999;53:743-750.

13. Kujala P, Portin R, Revonsuo A, Ruutiainen J. Attention related performance in two cognitively different subgroups of patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 1995;59:77-82.

14. Krupp LB, Elkins LE. Fatigue and declines in cognitive functioning in multiple sclerosis. Neurology. 2000;55:934-939.

Clinical Trials on MS-Related Fatigue

Jay H. Rosenberg, MD
Jay H. Rosenberg is a neurologist at the Kaiser Permanente Medical Center in San Diego.

Over the past two decades, numerous trials have been conducted on agents in the treatment of multiple sclerosis (MS)-related fatigue. The wake-promoting agent modafinil is the only agent to show efficacy compared with placebo on the Fatigue Severity Scale (FSS), a measure that is highly resistant to “impulse answering” and is thus viewed as one of the most difficult scales on which to show benefit. Amantadine has been studied for the longest period, and has shown efficacy in about one third of patients with MS-related fatigue on several commonly used scales. Two randomized trials of the central nervous system stimulant pemoline have yielded unimpressive results; efficacy was seen at higher doses but was associated with an unacceptable risk of adverse effects.

The etiology of multiple sclerosis (MS)-related fatigue remains poorly understood. Clinical observations, such as the sensitivity of MS-related fatigue to heat, support the theory that the symptom is a centrally-mediated phenomenon that is related to nerve demyelination and axonal destruction. Functional imaging studies showing reduced glucose utilization in areas of the brains of patients with MS also lend credence to this notion.1,2 Fatigue is generally the initial complaint of these patients upon presentation, emerging before clinical motor signs and symptoms. Therefore, it is important that health care providers are cognizant of the fact that fatigue is a very real and distinct phenomenon in MS, and has a major impact on patient functioning and quality of life.

Before beginning any pharmacologic therapy specifically for MS-related fatigue, it is important to address other potential secondary causes of fatigue. These may include sleep disturbances, depression, effects of other medications, issues related to ambulation, effects of systemic disease, and issues related to respiratory conditioning. If fatigue persists despite adequate attention to these possible causes, a decision can be made on a course of medication to be used. While a variety of medications in different classes have been tried, studies in MS-related fatigue generally have focused on three agents: the antiviral agent amantadine, the central nervous system (CNS) stimulant pemoline, and the unique wake-promoting agent modafinil.

Interpreting the data on agents for MS-related fatigue is challenging because the trials tend to be inconsistent, employing different outcome measures, different study designs, and inadequate study populations that often involve several MS clinical subtypes. In evaluating the literature on MS-related fatigue, the MS Council for Clinical Practice Guidelines published a report in 1998 that considered amantadine to be the first-line agent and pemoline to be the second-line agent for treatment, with insufficient evidence to support the use of other medications such as aminopyridines and antidepressants.3 However, all of these recommendations were made before the introduction of the wake-promoting agent modafinil in 1999 and prior to the U.S. Food and Drug Administration’s warnings surrounding pemoline. This article reviews the evidence surrounding amantadine, pemoline, and modafinil for MS-related fatigue.

Amantadine

Amantadine is a dopaminergic agent that appears either to increase dopamine release or decrease its uptake. It also may act as a direct dopamine receptor agonist. At therapeutic doses, the agent inhibits N-methyl-D-aspartate (NMDA) receptor-mediated release of acetylcholine from the striatum. Although its adverse-effect profile is generally favorable, the agent may cause nausea, lightheadedness, and insomnia in some patients. Irritability and depression occur less frequently while psychosis, urinary retention, and corneal opacities occur very infrequently in elderly individuals. Overall, fewer than 10% of patients experience adverse effects on amantadine therapy.

Four clinical trials have evaluated the use of amantadine.4-7 Taken together, these trials showed that approximately 20% to 40% of MS patients with mild-to-moderate MS-related fatigue experienced significant short-term reductions in fatigue. However, all of the trials used different scales, including the Fatigue Severity Scale (FSS), the MS-Specific Fatigue Scale, the Visual Analog Scale for Fatigue (VAS-F), and various other measures that had patients self-rate their level of fatigue.

Overall, amantadine may be considered to have a moderate effect on MS-related fatigue. It was adopted as a first-line agent in the MS Council for Clinical Practice Guidelines report, published in 1998, because of its tolerability profile and a lack of additional options.3 In this author’s experience, when patients respond to amantadine, they tend to respond very well. Some people become refractory to this medication and may benefit from a drug holiday.

Pemoline

Pemoline is a CNS stimulant that is chemically unrelated to amphetamines or methylphenidate. Its pharmacologic activity is similar to other stimulants in that it works through the dopamine system. As with amantadine, patients who respond to pemoline tend to respond favorably. However, with the report of more than a dozen cases of liver failure, the adverse-effect profile of this drug was changed dramatically, leading to a “black box” warning that was included in the product labeling in 1999.8

The data on pemoline are mixed, with one study showing efficacy at a high dose of 75 mg/d9 and another showing lack of efficacy compared with placebo at a dose of 37.5 mg/d.7 Pemoline is associated with a number of adverse effects, including anorexia, irritability, and unwanted weight loss. While it may be useful in individual cases when patients do not respond to other agents, it should not be used as a first-line therapy.

Modafinil

Since the report of the MS Council for Clinical Practice Guidelines was published, the wake-promoting agent modafinil, approved in 1999, has come to represent a new choice in the treatment of MS-related fatigue. Modafinil is chemically and pharmacologically distinct from CNS stimulants, and is believed to work selectively in areas of the brain involved in the regulation of normal wakefulness.10,11 Modafinil increases cortical activity in the frontal lobe through activation of the excitatory pathways from the tuberomammillary nucleus,11 and has been shown to facilitate wakefulness in a number of clinical models including narcolepsy, obstructive sleep apnea, sleep deprivation, and hypersomnia.12-14The agent has been shown to improve vitality subscales (energy level and fatigue) on the Short-Form 36 Health Survey (SF-36)15 in narcolepsy patients, with no effect on the integrity of sleep or nighttime sleep architecture.

In designing a trial on modafinil, we chose a number of fatigue scales that are commonly used in clinical practice.16 The FSS was chosen for its simplicity and because it is generally acknowledged as a difficult scale to impact. We also chose the Modified Fatigue Impact Scale (MFIS), which is a more complicated scale with three domains (physical, psychosocial, and cognitive). The MFIS, which is the scale cited in the MS Council for Clinical Practice Guidelines,3 registers benefit more easily than does the FSS. We also chose the VAS-F, a scale that is highly susceptible to impulse answering but has been used in other studies on MS-related fatigue.9

Our modafinil study was a nine-week, forced-titration, single-blind trial that included four treatment phases: a two-week placebo run-in, followed by two weeks of modafinil, 200 mg/d, two weeks of modafinil, 400 mg/d, and a three-week washout period. The study included 72 men and women ages 18 to 65 years (mean age, 44 years) with a diagnosis of MS with mild-to-moderate disability (Expanded Disability Status Scale scores of £ 6) and FSS scores of greater than 4 (mean of 5.9 at baseline), indicating that the patients were severely fatigued. Excluded from the study were patients with any secondary causes of fatigue, patients with significantly elevated blood pressure, and those with potential confounding factors such as a history of abusing alcohol, narcotics, and other drugs. In addition to the three fatigue scales, participants were assessed with the Epworth Sleepiness Scale (ESS).

Modafinil at the 200-mg dose performed significantly better than placebo on all three of the scales used to measure fatigue, providing important evidence of correlation among the scales (Figures 1A-C).16 The 400-mg dose, however, did not significantly improve fatigue. Consistent with the studies of this agent in narcolepsy, the 400-mg dose was significantly effective in improving ESS scores. The difference in findings suggests that there may be a different pathophysiologic mechanism involved in sleepiness than that involved in fatigue. Alternatively, the 400-mg dose may have provided the patients with marked initial relief from fatigue and caused them to overextend their activities, ultimately leading to more fatigue.

Figure 1. Clinically significant reductions in MS-related fatigue with modafinil on the A) Fatigue Severity Scale (FSS); B) Modified Fatigue Impact Scale (MFIS); and C) Visual Analog Scale for Fatigue (VAS-F). Correlations were seen among all three scales, with the 200-mg dose significantly reducing fatigue on each of the scales.
Source: Rammohan KW et al. J Neurol Neurosurg Psychiatry. 2002.16
Modafinil was well tolerated in this patient group. The most frequent adverse effects with the 200-mg dose were transient headache (17%) and nausea (11%).16 A number of patients at the 400-mg dose also experienced asthenia (14%). Overall, however, only four patients discontinued modafinil, citing adverse effects that included headache, dry mouth, anxiety, nausea, and agitation.

Comparing these results with findings of other agents used in the treatment of MS-related fatigue, modafinil has been the only agent to significantly change scores on the FSS compared with placebo. The average FSS score reduction in this study was 0.8 (P < .001 compared with placebo),16 compared with an average reduction of 0.2 for amantadine in the 1995 study by Krupp and colleagues that compared amantadine with pemoline and placebo.7

Conclusions

The trials of agents used in the treatment of MS-related fatigue demonstrate that the symptom can be effectively managed through the use of pharmacologic therapy. Since publication of the MS Council for Clinical Practice Guidelines report in 1998, modafinil has demonstrated significant benefit on a number of commonly used scales in MS-related fatigue, and is the only agent to significantly improve FSS scores compared with placebo. The dose response for improving fatigue appears to be different than that for improving daytime sleepiness, which may signify a different pathophysiologic mechanism for fatigue than that for excessive daytime sleepiness.

References

1. Bakshi R, Miletich RS, Kinkel PR, et al. High-resolution fluorodeoxyglucose positron emission tomography shows both global and regional cerebral hypometabolism in multiple sclerosis. J Neuroimaging. 1998;8:228-234.

2. Roelcke U, Kappos L, Lechner-Scott J, et al. Reduced glucose metabolism in the frontal cortex and basal ganglia of multiple sclerosis patients with fatigue: a 18F-fluorodeoxyglucose positron emission tomography study. Neurology. 1997;48:1566-1571.

3. Multiple Sclerosis Council for Clinical Practice Guidelines. Fatigue and Multiple Sclerosis. Washington, DC: Paralyzed Veterans of America; 1998.

4. Murray TJ. Amantadine therapy for fatigue in multiple sclerosis. Can J Neurol Sci. 1985;12:251-254.

5. Cohen RA, Fisher M. Amantadine treatment of fatigue associated with multiple sclerosis. Arch Neurol. 1989;46:676-680.

6. The Canadian MS Research Group. A randomized controlled trial of amantadine in fatigue associated with multiple sclerosis. Can J Neurol Sci. 1987;14:273-278.

7. Krupp LB, Coyle PK, Doscher C, et al. Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology. 1995;45:1956-1961.

8. Cylert® (pemoline) package insert. Chicago, III: Abbott Laboratories; June 1999. 9. Weinshenker BG, Penman M, Bass B, et al. A double-blind, randomized, crossover trial of pemoline in fatigue associated with multiple sclerosis. Neurology. 1992;42:1468-1471.

10. Lin JS, Hou Y, Jouvet M. Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat. Proc Natl Acad Sci USA. 1996;93:14128-14133.

11. Scammell TE, Estabrooke IV, McCarthy MT, et al. Hypothalamic arousal regions are activated during modafinil-induced wakefulness. J Neurosci. 2000;20:8620-8628.

12. US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy. Neurology. 2000;54:1166-1175.

13. Pigeau R, Naitoh P, Buguet A, et al. Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperature. J Sleep Res. 1995;4:212-228.

14. Arnulf I, Homeyer P, Garma L, et al. Modafinil in obstructive sleep apnea-hypopnea syndrome: a pilot study in 6 patients. Respiration. 1997;64:159-161.

15. Beusterien KM, Rogers AE, Walsleben JA, et al. Health-related quality of life effects of modafinil for treatment of narcolepsy. Sleep. 1999;22:757-765.

16. Rammohan KW, Rosenberg JH, Lynn DJ, et al. Efficacy and safety of modafinil (Provigil®) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry. 2002;72:179-183.

Pharmacologic Management of MS-Related Fatigue

Randall Schapiro, MD
In October 2001, the Working Group for Pharmacologic Therapy in Multiple Sclerosis (MS)-Related Fatigue met to review the evidence for pharmacologic therapies and establish a consensus on drug management of MS-related fatigue. This article presents the initial recommendations of the Working Group, whose members include Randall Schapiro, MD (Chair), Jack Burks, MD, Lauren B. Krupp, MD, Kottil W. Rammohan, MD, Stanley van den Noort, MD, and Howard Zwibel, MD.

A number of agents have been utilized in the management of multiple sclerosis (MS)-related fatigue, including the wake-promoting agent modafinil, the antiviral agent amantadine, central nervous system (CNS) stimulants, antidepressants, and aminopyridines. The evidence for the efficacy of these agents has been based on different forms of data, ranging from randomized clinical trials to anecdotal reports. In 1998, the MS Council for Clinical Practice Guidelines published a report on fatigue management, which was sponsored by such organizations as the National MS Society, the Paralyzed Veterans of America, the Consortium of Multiple Sclerosis Centers, and the American Academy of Neurology.1 The goal behind the report was to produce a multidisciplinary, evidence-based, fatigue-management tool for neurologists, rehabilitation specialists, nurses, and psychologists.

The clinical practice guidelines remain an excellent tool for management of the patient with MS-related fatigue. However, since their publication, a number of changes have occurred in the area of pharmacologic management, including the introduction of the wake-promoting agent modafinil2 and the imposition of a “black box” warning by the U.S. Food and Drug Administration for the CNS stimulant pemoline.3

In light of these new developments, the Working Group for Pharmacologic Therapy in Multiple Sclerosis-Related Fatigue met in October of 2001 to evaluate the advances in pharmacologic therapies for MS-related fatigue and to develop a set of recommendations to guide the prescribing neurologist. The group produced the following preliminary guidelines:

1. Pharmacologic Therapy Is an Established and Effective Means of Reducing the Symptoms of MS-Related Fatigue.

There is a substantial body of evidence to show that pharmacologic therapy can have a positive impact on MS-related fatigue.4-10 However, it has been our experience that most clinicians still do not treat MS-related fatigue with pharmacologic therapy. Therefore, it is incumbent upon clinicians to correctly identify cases of MS-related fatigue and to implement pharmacologic therapy after addressing potential secondary causes of fatigue, such as deconditioning or depression.

2. Brief Scales That Measure the Patient’s Perceived Level of Fatigue Are the Most Efficient Means of Assessing Fatigue in the MS Population.

There are a number of scales that can be used to assess the patient’s perceived level of fatigue, including the Fatigue Severity Scale (FSS),11 the Modified Fatigue Impact Scale (MFIS),1 and the Visual Analog Scale for Fatigue (VAS-F).8 Self-assessment scales are practical, and can be easily administered prior to the clinician visit. However, these scales are subject to rater bias, and none provides a true assessment of social, cognitive, or physical functioning. Nevertheless, these self-report scales remain the most useful tools available for assessing MS-related fatigue.

3. Amantadine Is Recommended as a First-Line Choice for Mild MS-Related Fatigue.

The antiviral agent amantadine has a proven safety profile and is effective in about one third of patients with MS-related fatigue.4-6,10 It should be a first-line agent in mild MS-related fatigue as defined by an FSS score of less than 4, starting at a dose of 100 mg twice daily.

4. Pemoline Cannot Be Recommended as an Initial Choice for the Treatment of MS-Related Fatigue.

This recommendation arises from the limited efficacy of pemoline in MS-related fatigue,6,8 as well as the imposition of a “black box” warning in the product labeling based on a number of cases of liver failure that occurred when the agent was used at high doses.3 The clinical evidence of benefit for pemoline is not impressive, with studies showing that it tends to work only at high doses (eg, 75 mg/d) when it does work at all.6,8 While use of the agent should not be ruled out, it cannot be recommended as a first-line therapy.

5. Modafinil Is Recommended as the First-Line Therapy for Patients With Moderate-to-Severe Fatigue, and Should Be the Agent of Choice in Patients Who Do Not Respond to or Who Develop a Lack of Response to Amantadine.

The Working Group recommends modafinil as the first-line therapy for patients with moderate-to-severe fatigue, as indicated by FSS scores of greater than or equal to 4. Modafinil is the only agent to show a change compared with placebo on the FSS, a scale that is generally acknowledged as difficult to impact because it is resistant to “impulse answering.”11,12 The evidence has demonstrated benefit for this agent on a number of additional scales, including the MFIS and VAS-F.2,9 Dosing should begin at 100 mg daily, and can be increased to 200 mg/d in a single or divided dose (morning and early afternoon) if an effect is not seen at the lower dose. The evidence does not currently support dosing higher than 200 mg/d.2

6. Other Medications Used in the Treatment of MS-Related Fatigue Have Insufficient Evidence to Support Their Use or Have Unacceptable Adverse-Effect Profiles.

There are additional medications that have been used in the treatment of MS-related fatigue, but the evidence is generally insufficient to support their use. Aminopyridines are potassium channel blockers that have been researched thoroughly over the past 15 years.13,14 They enhance nerve conduction in demyelinated nerves, which results in gains in patient strength. However, studies on aminopyridines have failed to show that they improve fatigue. CNS stimulants, such as amphetamine and methylphenidate, have a number of adverse effects, including anxiety, nausea, and motor agitation. Due to their Schedule II labeling, they also require significant additional paperwork on the part of the prescriber. Although antidepressant medications, especially those considered to have activating properties, such as venlafaxine or bupropion, may be tried, there is little evidence to support their use in MS-related fatigue.15

Conclusions

Pharmacologic therapy is an effective means of reducing or eliminating fatigue in the MS patient. Clinicians must remain alert to the presence of MS-related fatigue and ensure that the condition is not undermanaged. While additional work on the pathophysiology of MS-related fatigue is needed, effective agents for MS-related fatigue exist and should be employed in any patient who does not respond to nonpharmacologic interventions.

References

1. Multiple Sclerosis Council for Clinical Practice Guidelines. Fatigue and Multiple Sclerosis. Washington, DC: Paralyzed Veterans of America; 1998.

2. Provigil® (modafinil) package insert. West Chester, Pa: Cephalon, Inc; January 1999.

3. Cylert® (pemoline) package insert. Chicago, III: Abbott Laboratories; June 1999.

4. The Canadian MS Research Group. A randomized controlled trial of amantadine in fatigue associated with multiple sclerosis. Can J Neurol Sci. 1987;14:273-278.

5. Cohen RA, Fisher M. Amantadine treatment of fatigue associated with multiple sclerosis. Arch Neurol. 1989;46:676-680.

6. Krupp LB, Coyle PK, Doscher C, et al. Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology. 1995;45:1956-1961.

7. Rammohan KW, Rosenberg JH, Lynn DJ, et al. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry. 2002;72:179-183.

8. Weinshenker BG, Penman M, Bass B, et al. A double-blind, randomized, crossover trial of pemoline in fatigue associated with multiple sclerosis. Neurology. 1992;42:1468-1471.

9. Zifko UA, Rupp M, Schwarz S, et al. Modafinil in treatment of fatigue in multiple sclerosis. Results of an open-label study. J Neurol. 2002;249:983-987.

10. Murray TJ. Amantadine therapy for fatigue in multiple sclerosis. Can J Neurol Sci. 1985;12:251-254.

11. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989;46:1121-1123.

12. Petajan JH, Gappmaier E, White AT, et al. Impact of aerobic training on fitness and quality of life in multiple sclerosis. Ann Neurol. 1996;39:432-441.

13. Bever CT Jr. The current status of studies of aminopyridines in patients with multiple sclerosis. Ann Neurol. 1994;36 (suppl):S118-S121.

14. Sheean GL, Murray NMF, Rothwell JC, et al. An open-labelled clinical and electrophysiological study of 3,4 diaminopyridine in the treatment of fatigue in multiple sclerosis. Brain. 1998;121:967-975.

15. Duffy JD, Campbell J. Bupropion for the treatment of fatigue associated with multiple sclerosis. Psychosomatics. 1994;35:170-171.
 

© 2000 International Journal of MS Care