Journal of Pain and Symptom Management
Volume 38, Issue 4 , Pages 587-596, October 2009

Cancer-Related Fatigue: Central or Peripheral?

  • Tugba Yavuzsen, MD

      Affiliations

    • The Harry R. Horvitz Center for Palliative Medicine, Taussig Cancer Institute, The Cleveland Clinic, Cleveland, Ohio, USA
    • ,
  • Mellar P. Davis, MD, FCCP

      Affiliations

    • The Harry R. Horvitz Center for Palliative Medicine, Taussig Cancer Institute, The Cleveland Clinic, Cleveland, Ohio, USA
    • Section of Palliative Medicine and Supportive Oncology, Department of Solid Tumor Oncology, The Cleveland Clinic, Cleveland, Ohio, USA
    • ,
  • Vinoth K. Ranganathan, MSE, MBA

      Affiliations

    • Neural Control Laboratory, Department of Biomedical Engineering, The Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio, USA
    • Department of Physical Medicine and Rehabilitation, Rehabilitation Institute, The Cleveland Clinic, Cleveland, Ohio, USA
    • ,
  • Declan Walsh, MSc, FACP, FRCP

      Affiliations

    • The Harry R. Horvitz Center for Palliative Medicine, Taussig Cancer Institute, The Cleveland Clinic, Cleveland, Ohio, USA
    • Section of Palliative Medicine and Supportive Oncology, Department of Solid Tumor Oncology, The Cleveland Clinic, Cleveland, Ohio, USA
    • Corresponding Author InformationAddress correspondence to: Declan Walsh, MSc, FACP, FRCP, The Harry R. Horvitz Center for Palliative Medicine, The Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Avenue, M76, Cleveland, OH 44195, USA.
    • ,
  • Vlodek Siemionow, PhD

      Affiliations

    • Neural Control Laboratory, Department of Biomedical Engineering, The Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio, USA
    • Department of Physical Medicine and Rehabilitation, Rehabilitation Institute, The Cleveland Clinic, Cleveland, Ohio, USA
    • ,
  • Jordanka Kirkova, MD

      Affiliations

    • The Harry R. Horvitz Center for Palliative Medicine, Taussig Cancer Institute, The Cleveland Clinic, Cleveland, Ohio, USA
    • ,
  • Dilara Khoshknabi, MD

      Affiliations

    • The Harry R. Horvitz Center for Palliative Medicine, Taussig Cancer Institute, The Cleveland Clinic, Cleveland, Ohio, USA
    • ,
  • Ruth Lagman, MD, MPH

      Affiliations

    • The Harry R. Horvitz Center for Palliative Medicine, Taussig Cancer Institute, The Cleveland Clinic, Cleveland, Ohio, USA
    • Section of Palliative Medicine and Supportive Oncology, Department of Solid Tumor Oncology, The Cleveland Clinic, Cleveland, Ohio, USA
    • ,
  • Susan LeGrand, MD, FACP

      Affiliations

    • The Harry R. Horvitz Center for Palliative Medicine, Taussig Cancer Institute, The Cleveland Clinic, Cleveland, Ohio, USA
    • Section of Palliative Medicine and Supportive Oncology, Department of Solid Tumor Oncology, The Cleveland Clinic, Cleveland, Ohio, USA
    • ,
  • Guang H. Yue, PhD

      Affiliations

    • Neural Control Laboratory, Department of Biomedical Engineering, The Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio, USA
    • Department of Physical Medicine and Rehabilitation, Rehabilitation Institute, The Cleveland Clinic, Cleveland, Ohio, USA

Accepted 2 January 2009. published online 10 June 2009.

Article Outline

Abstract 

To evaluate cancer-related fatigue (CRF) by objective measurements to determine if CRF is a more centrally or peripherally mediated disorder, cancer patients and matched noncancer controls completed a Brief Fatigue Inventory (BFI) and underwent neuromuscular testing. Cancer patients had fatigue measured by the BFI, were off chemotherapy and radiation (for more than four weeks), had a hemoglobin level higher than 10g/dL, and were neither receiving antidepressants nor were depressed on a screening question. The controls were screened for depression and matched by age, gender, and body mass index. Neuromuscular testing involved a sustained submaximal elbow flexion contraction (SC) at 30% maximal level (30% maximum elbow flexion force). Endurance time (ET) was measured from the beginning of the SC to the time when participants could not maintain the SC. Evoked twitch force (TF), a measure of muscle fatigue, and compound action potential (M-wave), an assessment of neuromuscular-junction transmission were performed during the SC. Compared with controls, the CRF group had a higher BFI score (P<0.001), a shorter ET (P<0.001), and a greater TF with the SC (CRF>controls, P<0.05). This indicated less muscle fatigue. There was a greater TF (P<0.05) at the end of the SC, indicating greater central fatigue, in the CRF group, which failed to recruit muscle (to continue the SC), as well as the controls. M-Wave amplitude was lower in the CRF group than in the controls (P<0.01), indicating impaired neuromuscular junction conduction with CRF unrelated to central fatigue (M-wave amplitude did not change with SC). These data demonstrate that CRF patients exhibited greater central fatigue, indicated by shorter ET and less voluntary muscle recruitment during an SC relative to controls.

Key Words: Cancer, sustained elbow flexion, muscle fatigue, neuromuscular function, voluntary recruitment

 

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Introduction 

Fatigue is common in cancer.1, 2, 3, 4 Reported prevalence of cancer-related fatigue (CRF) ranges from 25% to 99%.5 CRF is defined as a persistent subjective sense of tiredness related to cancer and/or its treatment that interferes with daily activities and worsens quality of life of the patients.6 CRF differs from normal fatigue as it is unrelieved by rest and not primarily caused by physical activities.7 Although CRF is a highly prevalent condition among cancer patients, mechanisms that contribute to it are very poorly understood.8 Without a good understanding of the underlying mechanisms, it would be difficult to accurately diagnose and develop targeted therapies for CRF.

Current literature provides little information about pathophysiological mechanisms behind CRF. In fact, many factors can contribute to muscle fatigue9 and the lack of an objective definition of CRF further hampers evidence-based research. Muscle fatigue can be measured as the failure to maintain force during a sustained isometric contraction. Muscle fatigue will be peripheral if the main cause is the failure of the muscle excitation/contraction mechanism or metabolic changes within the muscle. Fatigue may also be central, with loss of voluntarily activated muscle because of mechanisms proximal to the neuromuscular junction (NMJ).

This study focused on the question of whether CRF is of more central or peripheral origin by engaging cancer patients with CRF in a sustained motor activity that led to task failure as a result of fatigue. The advantage of this approach is that CRF can be investigated in the context of a reproducible standard motor activity-induced fatigue using a submaximal motor-effort task widely adopted in neuromuscular physiological research.10, 11, 12, 13, 14 Standard parameters are well established to assess central fatigue (the ability to maintain adequate cortical or descending command to drive performing muscle15, 16) and peripheral fatigue (the ability of the muscle to generate force).10, 11, 17 Contributions of the central and peripheral systems to fatigue can be objectively evaluated in CRF. Comparisons with healthy controls would determine whether the task-induced fatigue in cancer is mediated by the central or the peripheral systems.

Based on the observation that CRF is associated with greater subjective fatigue (measured by a variety of self-report inventories, such as the Brief Fatigue Inventory [BFI]), we hypothesized that the fatigue during a prolonged motor task in cancer would have greater central fatigue compared with healthy controls. The purpose of the study was to test this hypothesis.

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Methods 

Subjects 

The Institutional Review Board at The Cleveland Clinic approved the study. Twenty-nine advanced cancer patients referred to palliative medicine and 16 healthy controls were screened. Ten cancer patients refused consent, and three were ineligible. Sixteen patients with solid tumors (CRF) and 16 age-, gender-, and body mass index (BMI)-matched controls were enrolled (Table 1). The median age of the CRF patients was 62.5 years (range: 48–82 years) and that of the controls was 55 years (range: 36–75 years). Nine of 16 (56%) in each group were females. There was no statistical difference between groups for age (P=0.10) or BMI (P=0.15) by t-test. All neuromuscular tests were done at the Neural Control Laboratory in the Lerner Research Institute. Written informed consent was obtained from all subjects before participation.

Table 1. Demographics of the Control Group
Patient NumberAge (Years)GenderBMI (kg/m2)
157F24.8
259F33.5
370F25.1
442F26.0
572M47.9
656F28.3
758F26.0
849F22.2
954F23.4
1048F22.3
1136M35.3
1246M28.7
1374F30.1
1461M24.4
1558F32.6
1644M30.0

The recruited patients had not received chemotherapy or radiation therapy for four weeks before the study and had to be at least four weeks postoperative. We did not obtain previous treatment history as this was a pilot study. Patients were screened by the BFI,18 a nine-item self-assessment questionnaire, for the presence of fatigue. Patients were also screened by a single question, “Are you depressed?”, and were excluded if depression was present. Eligible patients had a hemoglobin concentration of more than 10g/dL, and no evidence of polyneuropathy, amyotrophy, or a myasthenic syndrome by history or physical examination. Patients with more than 10% of pre-illness body weight loss or with significant pulmonary compromise defined by oxygen dependence were excluded. Health controls were recruited through local advertisement. Free parking and a nominal stipend ($30) were provided for their participation. A single screening question, “Are you depressed?”, was also used to exclude depression in controls. Controls were not clinically depressed or currently on psychostimulants or antidepressants. Demographics of the controls and those with CRF are provided in Table 1, Table 2.

Table 2. Demographics of the Cancer-Related Fatigue Group
Patient NumberAge (Years)GenderBMICancer StageECOG
165M26.6Angiosarcoma-43
261M24.4Kidney-41
381M23.2Lung-42
448F19.8Thyroid-31
548F30.9Ovarian-42
671M22.5Colon-42
764F19.6Lung-31
875M22.1Colon-40
972F28.7Stomach-43
1048F37.2Cervical-42
1148M21.7Liver-40
1257F31.6Lymphoma-31
1363F21.4Peritoneum-41
1458F30.8Lung-31
1560F31.0Chondrosarcoma-41
1668M20.2Breast-43

ECOG=Eastern Cooperative Oncology Group Performance Score.

Experimental Protocol 

The protocol was as follows: (1) Participants completed the BFI. (2) Maximum elbow flexion force (MEF) was measured. Before the measurement of MEF, participants performed two trials of submaximal elbow contraction (∼30% perceived maximal effort) as warm-up activities and as familiarization to correctly do the elbow flexion. (3) Maximum electric stimulation-evoked compound muscle action potential (M-wave) and twitch force at rest (TFrest) were recorded. (4) Participants performed a sustained elbow flexion contraction (SC) at 30% MEF until subjective exhaustion. The time from the end of the MEF to the beginning of the SC was five minutes. During the SC, electrical stimulation-evoked TF (TFsc) was measured at 30-second intervals to monitor participants' ability to voluntarily recruit the biceps brachii (BB) muscle. (5) After the SC, evoked M-wave, TF (TFfatigue), and MEF force were repeated without rest to capture the effects of muscle fatigue on these measures.

Maximum Elbow Flexion Force Measurement 

The dominant arm MEF was measured by a force transducer (JR3 Universal Force-Moment Sensor System, Woodland, CA), with subjects seated, forearm in a neutral position, and an elbow joint angle of ∼100° (Fig. 1). Participants were encouraged to exert maximal strength. The MEF force was displayed on an oscilloscope and recorded onto a personal computer using a Spike2 data acquisition system (1401 Plus, Cambridge Electronic Design, Ltd., Cambridge, UK). Two MEF measurements were made before the SC and the highest value was used for analysis. If the percentage difference in force between the two measurements was more than 5%, a third measurement was performed to ensure that true maximum force was achieved. Only one MEF trial was performed immediately after the SC.

Sustained Contraction to Induce Fatigue 

An isometric elbow flexion SC of the dominant arm was performed at a target force of 30% MEF. The target force was displayed during the SC on an oscilloscope using a horizontal cursor. Participants matched the target force and maintained SC at 30% MEF until they felt exhausted and terminated the task. They were vigorously encouraged to continue the SC as long as possible. Endurance time (ET) was measured from the start of the SC to the time of SC termination, because of failure to maintain the target force for five seconds. Although ET was a measure of time during which the participants could hold the SC, the length of ET depended on when the SC was terminated. The timing of the termination depended on participants' subjective feeling of exhaustion and failure to maintain force.

Twitch Force at Rest 

Maximal TFrest was assessed before SC to measure muscle force generating capability (FGC). Stimulation electrodes were attached to the skin over the BB muscle, one of the major elbow flexors. Supramaximal-intensity single electrical pulses (one-millisecond duration) were applied through a digital stimulator (Grass S8800, Astro Med Inc., West Warwick, RI) to evoke TF. The TF was measured using the same force transducer for MEF. Immediately after SC, the TF was assessed again under fatigue condition (TFfatigue). It is well-known that FGC of a muscle declines if the muscle is fatigued.9 The TFrest and TFfatigue were normalized to the pre-SC MEF force. The ratio of normalized TFfatigue to normalized TFrest is a widely used objective assessment of muscle fatigue.9, 10, 11, 17

Twitch Force During Sustained Contraction 

TFsc was measured every 30 seconds during the SC by stimulating the BB muscle using the same method as TFrest. The TFsc reflects muscle reserve and inversely the ability to voluntarily recruit muscle during the voluntary contraction. At the beginning of SC, muscle reserve is high (indicated by the amplitude of TFsc), as only 30% of the muscle capacity (30% MEF target force) is used. As fatigue increases, more muscles are voluntarily recruited to sustain the target force and less stimulation-evoked force (TFsc) is elicited because of diminished muscle reserve. As severe fatigue occurs, ideally all available muscles would be voluntarily recruited to sustain the target force. TFsc should be minimal if no more muscle reserve is available to be recruited, and if TFsc is negligible, then fatigue is largely peripheral (i.e., muscle fatigue) as voluntary central drive recruits all muscle fibers. On the other hand, if TFsc is maintained near the time of exhaustion, then central fatigue is significant, because the central nervous system (CNS) has failed to voluntarily recruit all muscle fibers. Therefore, TF during a fatigue voluntary contraction is an objective measure of central fatigue.15, 16

M-Wave 

The M-wave was assessed before (M-waverest) and immediately after (M-wavefatigue) the SC. The M-wave was elicited by stimulating the radial nerve in the upper arm through a single supramaximal stimulus, and EMG response (M-wave) recorded from the brachioradialis (BR) muscle. Because the stimulation was proximal to the NMJ (upper arm radial nerve) and the M-wave recorded from the BR distal to the junction, M-wave is a measurement of NMJ-propagation function.9, 10, 11, 17 The M-wave amplitude was quantified from peak (negative) to peak (positive). M-wave in CRF could provide information regarding the mechanism causing lower SC-induced muscle fatigue in CRF patients.

Statistical Analysis 

Student's t-test and paired t-test were performed for between- and within-group comparisons. Between-group comparisons were made on the BFI scores, normalized TFs, M-wave amplitude, ET, and strength (MEF force). Within-group comparisons of dependent variables were made at different experiment time points; for example, TFrest vs. TFfatigue, TFsc comparisons among different time points during SC, or M-waverest vs. M-wavefatigue.

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Results 

Brief Fatigue Inventory 

BFI scores were higher (P<0.001) in the CRF group than those in the controls (Fig. 2). The mean (±standard deviation) BFI score of the nine questions was 5±0.18 for patients and 0.09±0.1 for controls. Question 3 of the BFI asks about the worst fatigue in the last 24 hours and correlates the best score with fatigue interference of daily activities.19 The mean score of the controls for Question 3 was 1.8 (numerical rating scale: 0=no fatigue, 10=severe fatigue), and for the CRF group, it was 6.6. Nine of 16 individuals with CRF scored 7 or higher on Question 3, indicating severe fatigue interference with daily activity, and only one individual scored Question 3 as a 7.

  • View full-size image.
  • Fig. 2 

    Mean intensity of the BFI score (0–10) for each question in CRF group and control group (P<0.001) (means±standard deviation). Question 1—please rate your fatigue (weariness, tiredness) by circling the one number that best describes your fatigue right now; Question 2—please rate your fatigue (weariness, tiredness) by circling the one number that best describes your usual level of fatigue during the past 24 hours; Question 3—please rate your fatigue (weariness, tiredness) by circling the one number that best describes your worst level of fatigue during the past 24 hours; Question 4—circle the one number that describes how, during the past 24 hours, fatigue has interfered with your: 4a—general activity, 4b—mood, 4c—walking ability, 4d—normal work (includes both work outside the home and daily chores), 4e—relations with other people, 4f—enjoyment of life.

Endurance Time 

ET was shorter (P<0.001) in the CRF group (335 seconds) than in the controls (543 seconds). This means that the CRF group developed exhaustion, which caused them to be unable to maintain force, leading to termination of the 30% MEF significantly sooner than controls during the SC.

Twitch Force at Rest 

Normalized TFrest was similar between the groups (Fig. 3). After the SC, normalized TFfatigue was greater in the CRF group (P<0.05). TF decreased (TFfatigue vs. TFrest) in both groups after SC, but the decrease was less in the CRF group (15%, P<0.01) than in the controls (37%, P<0.001), indicating that the CRF group experienced less muscle fatigue than controls.

Twitch Force During Sustained Contraction 

Amplitude of TFsc normalized to TFrest decreased similarly in both groups. However, the last TFSC amplitude before termination of SC was greater (P<0.05) in the CRF group (Fig. 4), indicating reduced ability to voluntarily recruit muscle to sustain the motor task and greater central fatigue.

Muscle Compound Action Potential 

M-Wave amplitude in the CRF group was only about half that of the controls, before and after SC (P<0.01). However, neither group had significantly diminished M-wave amplitude with fatigue (M-wavefatigue vs. M-waverest; P>0.1), suggesting that muscle fatigue had little effect on NMJ conduction.

Maximal Elbow Flexion Force 

The MEF force was lower (P<0.01) in the CRF group (186±69N) than in the controls (257±77N) before SC, suggesting that, in general, CRF patients are weaker in the tested joint. MEF force after SC was reduced in both groups (P<0.05), but this was much greater in the controls (66%) than in the CRF group (46%), which is additional evidence for less muscle fatigue in the CRF group.

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Discussion 

Measuring TF during a SC is a standard physiological method of assessing the degree of central fatigue.15, 16, 17, 20 TF elicited at rest by the same method has been widely used to examine muscle fatigue in human10, 11, 17 and animal19, 21, 22, 23 models. Our findings are novel in that we have demonstrated central mechanisms underlying CRF during motor performance using standard objective methods to assess central and peripheral (muscle) fatigue. This study found that CRF patients had greater perceived (subjective) fatigue (higher BFI score) and shorter ET, but lower muscle fatigue (greater relative TF) after a prolonged muscle contraction (SC) than healthy controls. TF near the termination of the SC (TFsc) was greater in the CRF group than in the controls, indicating that the patients were unable to continue the SC because their CNS was fatigued and unable to recruit muscle as well as controls, despite putting forth the best effort. Together, these results suggest that central fatigue plays a more prominent role in CRF than in normal individuals during a submaximal motor task that requires endurance. Submaximal contraction is a better reflection of day-to-day activity. This observation suggests that CRF is associated with a malfunction of the CNS related to cancer or its treatment. Greater central fatigue led to less significant muscle fatigue in CRF group. Differences in TFfatigue between the groups cannot be explained by a smaller muscle mass in patients, because TFrest values were similar. Furthermore, we normalized TFrest and TFfatigue to the maximal elbow flexion force, which should make baseline differences because of strength irrelevant.

The impaired NMJ function might partially explain differences in muscle fatigue between the groups, that is, central signals would be inefficiently transmitted across the NMJ so that the muscle would be incompletely recruited. NMJ transmission was generally reduced in CRF, and impairment could have shortened ET. Reduced NMJ function with reduced Type Ia (spindle) afferent input could increase central fatigue through motor cortex or propiospinal pathway by negative feedback. Reduced NMJ conduction has been reported in prostate cancer patients with fatigue during radiation therapy; this improved five to six weeks after radiation, with improved fatigue.24

M-Wave area and latency could not be reliably measured because of the muscle group used for SC (BB, brachialis, and brachioradialis). M-Wave can only be easily recorded from the BR.25The nerve (radial nerve) at which the stimulus was applied was close to the recording muscle (BR). Consequently, the stimulus artifact (SA) overlapped the M-wave. This meant that we could not separate the M-wave from the SA or vice versa, nor measure the correct area or latency data. Because the two peaks are easily identified (the SA and the M-wave), the M-wave amplitude could accurately be quantified.

Neuromuscular correlates of CRF vary with cancer stage, type of exercise, physiological tests, and muscles tested. Several CRF studies (including ours) involved healthy controls for comparison.24, 26, 27, 28, 29, 30, 31, 32, 33, 34 Correlations between CRF, physical inactivity, poor performance status, and altered neuromuscular function have been investigated.26, 27, 30 Handgrip dynamometers, chair-rise time,26, 27, 30 treadmill tests, maximum aerobic capacity (VO2 max),24, 30 physical performance tests,31 actometer, mental concentration test, reaction time task,33 aerobic exercise, and psychosocial assessments have been related to CRF.33 Performance status correlates with energy consumption for neurophysiological function but correlates poorly with CRF.34 Although physical function is poorer in CRF patients than in those with subjective fatigue and cancer without fatigue, correlation between muscle fatigue and maximal physical performance is also low.32, 34 A weak correlation is found between fatigue perception and handgrip strength.23 To our knowledge, no previous study has attempted to separate and define central/peripheral mechanisms in CRF.

Reduced central drive in healthy individuals normally contributes approximately 20% to fatigue, as measured by reductions in muscle maximum voluntary contraction force and TF.11 CRF resembles chronic fatigue syndrome (CFS), in which central drive is also reduced.35, 36, 37, 38 However, in CFS, muscle performance, voluntary activation, and twitch properties are normal.39 Those with early stage motor neuron disease have reduced ability to activate and recruit muscle.40, 41 Postoperative fatigue, poststroke fatigue, Parkinson's disease, multiple sclerosis, post-poliomyelitis syndrome, and hypothalamic and pituitary disorders are also associated with central fatigue.42 Additional clinical clues to central fatigue include autonomic nervous system dysfunction, abnormal sleep patterns, cognitive deficits, weight changes, anorexia, and endocrine abnormalities.42 In contrast, central fatigue is unimportant in heart failure.43

The diagnosis of CRF depends on symptoms attributable to fatigue, which exclude the contribution of depression and anxiety.42 These psychological symptoms influence either the prevalence or the severity of CRF.28, 29, 31, 33, 44, 45 It is difficult to distinguish CRF from depression using validated screening tools because of overlapping psychological symptoms. We assessed depression by a single question. This did not exclude mild depression but makes it unlikely that significant depression influenced our findings. Single questions as a screen for depression have a negative predictive value of 0.94. A single screening question will miss 5 out of 1000 individuals with clinically significant depression. Our interest in this study was not to make a diagnosis of depression but simply to rule out clinically important depression, which would have contributed to fatigue. Methylphenidate has been used to treat depression and fatigue in cancer.46, 47, 48 Besides altering cortical monoamines, methylphenidate improves neuromuscular transmission in a dose-dependent manner.49, 50, 51 Our findings give impetus to understanding the correlation of physiology with subjective responses to methylphenidate in the treatment of CRF, and perhaps, provide an objective methodology to study CRF interventions.

Study limitations included a small sample size, and an inability to control for medications (antibiotics, anticholinergics, corticosteroids, and opioids) that may influence neuromuscular conduction. We did not screen for acetylcholine receptor or voltage-gated calcium channel antibodies, which could impair NMJ conduction. None of our patients clinically had the Lambert-Eaton Syndrome; few had lung cancer. We did not evaluate lean body mass, albumin, or body composition or measure alterations in muscle afferent feedback, which could contribute to CRF.13 The median age between groups differed but the ranges overlapped. The small group size may account for this difference. It is unlikely that these age differences influenced our results. Older individuals do not differ in NMJ conduction or ET compared with younger individuals.52, 53, 54, 55 Weight loss may contribute to fatigue, but fatigue does not correlate with lean body mass.26 Muscle disuse atrophy does not increase fatigability. An inverse relationship exists between force and fatigability with deconditioning.53 By definition, CRF may be fatigue from treatment or active cancer. Neuromuscular correlates of cancer or its treatment will be examined in the future by including cancer controls. Finally, studying CRF by engaging patients to standard fatigue motor tasks has obvious advantages but it is also a weakness. The results inform us about central/peripheral mechanisms contributing to fatigue induced by exhaustive motor activities but they do not explain why CRF patients are fatigued while at rest.

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Conclusions 

CRF was associated with greater perceived fatigue, but less muscle fatigue during a motor-endurance task. CRF patients were unable to voluntarily recruit as much muscle as healthy controls to prolong motor performance. Central fatigue seems to play a major role in the loss of endurance in CRF.

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 The Harry R. Horvitz Center for Palliative Medicine is a World Health Organization Demonstration Project in Palliative Medicine.This study was supported in part by a Cleveland Clinic internal grant (RPC6700) and a Department of Defense grant (DAMD17-01-1-0665).A version of this article was presented at the Fourth Research Forum of the European Association for Palliative Care, Venice, Italy, May 25–27, 2006.

PII: S0885-3924(09)00450-3

doi:10.1016/j.jpainsymman.2008.12.003

Journal of Pain and Symptom Management
Volume 38, Issue 4 , Pages 587-596, October 2009

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