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A Randomized, Double-blind, Placebo-Controlled Trial of Psychostimulants for the Treatment of Fatigue in Ambulatory Patients With Human Immunodeficiency Virus Disease
William Breitbart, MD;
Barry Rosenfeld, PhD;
Monique Kaim, PhD;
Julie Funesti-Esch, RN
Arch Intern Med. 2001;161:411-420.
ABSTRACT
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Background Fatigue is a commonly encountered symptom of human immunodeficiency
virus (HIV) disease, associated with significant psychological and functional
morbidity and poor quality of life. Preliminary studies on the treatment of
fatigue from the cancer and multiple sclerosis literature suggest that psychostimulants
may be effective in reducing fatigue.
Objective To compare the efficacy of 2 psychostimulant medications, methylphenidate
hydrochloride (Ritalin) and pemoline (Cylert), with a placebo intervention
for the treatment of fatigue in patients with HIV disease.
Methods In this double-blind trial, 144 ambulatory patients with HIV disease
and persistent and severe fatigue were randomized to treatment with methylphenidate,
pemoline, or placebo. Medications were titrated up to a maximum dose of 60
mg of methlyphenidate hydrochloride, 150 mg of pemoline, or 8 capsules of
placebo daily. Fatigue was measured using 2 self-reported rating scales, the
Piper Fatigue Scale (PFS) and the Visual Analogue Scale for Fatigue (VAS-F).
We also used the timed isometric unilateral straight leg-raising task, a measure
of muscular endurance. Quality-of-life and psychological well-being measures
included the Beck Depression Inventory, the Brief Symptom Inventory, and the
36-Item Short-Form Medical Outcomes Study Health Status Survey. Side effects
were monitored using the Systematic Assessment for Treatment Emergent Events
and the Extra-pyramidal Symptom Rating Scale. All measures were rated weekly.
Results One hundred nine subjects completed the 6-week trial; 15 patients (41%)
receiving methylphenidate and 12 patients (36%) receiving pemoline demonstrated
clinically significant improvement compared with 6 patients (15%) receiving
placebo. Patients receiving methylphenidate or pemoline demonstrated significantly
more improvement in fatigue on several self-reported rating scales (PFS total
score, P= .04; affective subscale, P= .008; sensory
subscale, P= .04; and VAS-F energy subscale, P=
.02). Analysis of the regression slopes by means of hierarchical linear modeling
demonstrated a significantly greater rate of improvement in PFS total scores
among patients receiving psychostimulants compared with the placebo group
(P= .02). There were no significant differences in the efficacy
between methlyphenidate and pemoline on any outcome measure studied. Improvement
in fatigue was also significantly correlated with improvement in measures
of depression, psychological distress, and overall quality of life. Severe
side effects were relatively uncommon among this sample, and only hyperactivity
or jitteriness occurred significantly more often among subjects receiving
active medication.
Conclusions Many patients with HIV- and acquired immunodeficiency syndrome–unrelated
fatigue respond favorably to treatment with methylphenidate or pemoline. Both
psychostimulants appear to be equally effective and significantly superior
to placebo in decreasing fatigue severity with minimal side effects. Moreover,
improvement of fatigue was significantly associated with improved quality
of life and decreased levels of depression and psychological distress.
INTRODUCTION
FATIGUE IS a commonly encountered symptom of human immunodeficiency
virus (HIV) disease, associated with significant psychological and functional
morbidity and poor quality of life (QOL).1, 2, 3, 4, 5
Recent reports estimate that fatigue is a distressing symptom in as many as
40% to 50% of patients with acquired immunodeficiency syndrome (AIDS) and
is even common among individuals with early asymptomatic HIV infection.2, 3, 4, 5 For example,
Longo and colleagues,4 using a semistructured
interview to elicit the physical and psychological concerns of men with AIDS,
noted that 41% of their sample described fatigue as a major physical concern.
In a more comprehensive study of fatigue, Darko and colleagues2
found that more than 50% of their sample of patients with AIDS had significant
levels of fatigue compared with only 10% of HIV-seronegative control subjects.
In their study, patients with AIDS reported significantly greater fatigue-related
interference with work, self-care, and social and daily activities and spent
a greater number of hours sleeping than controls.
Breitbart and colleagues1 also reported
a high prevalence of fatigue among their sample of 427 ambulatory patients
with AIDS. They classified 53% of their sample as having fatigue, and observed
significant associations between fatigue and anemia, pain, total number of
AIDS-related physical symptoms, and whether patients were currently receiving
treatment for AIDS-related medical disorders. In addition, demographic variables
such as sex and HIV transmission risk factor were significantly associated
with fatigue in their sample (women and injection drug users were more likely
to report fatigue). Patients with fatigue also reported significantly more
depressive symptoms and psychological distress and significantly poorer QOL.
Fatigue in HIV disease, as in cancer and other medical conditions, is
a complex multidimensional experience with diverse causes and correlates.
Fatigue in patients with HIV disease has been associated with anemia,1, 6 malnutrition and wasting,7
AIDS dementia and the consequences of central nervous system HIV infection,8 hypogonadism,9 HIV
myopathy,10 elevated cytokine levels and sleep
disturbance,2 depression,1
and pain.1, 11 In addition, fatigue
has been attributed to a variety of medications, chemotherapies, immunotherapies,
radiation therapy, opportunistic infections, and cancers.1, 2, 11, 12, 13
Fatigue management strategies are typically divided into those aimed
at treating the underlying cause of fatigue and those aimed at treating fatigue
directly.14 For example, Rabkin and colleagues9 observed improved fatigue after treatment of hypogonadism
in their sample of HIV-infected men. Revicki et al6
demonstrated improved QOL (including improved physical performance) after
treatment of anemia in patients with HIV and AIDS. Despite the prevalence
and clinical significance of fatigue in patients with HIV disease, there are
no published reports of controlled trials for the direct treatment of fatigue
in this population.
Interventions for fatigue related to cancer and multiple sclerosis that
have emerged in the clinical literature include nonpharmacological (eg, exercise
and energy conservation) and pharmacological therapies (eg, corticosteroids
and psychostimulants).12, 13, 14, 15, 16, 17, 18, 19
Of the latter, the pharmacological interventions that have shown the most
promise in treating fatigue in patients with cancer or multiple sclerosis
are psychostimulants; however, there have been few controlled studies of these
medications.15, 19 Two controlled
trials of psychostimulants have included fatigue as one of several outcome
variables studied.16, 19 Bruera
and colleagues16 demonstrated the utility of
psychostimulants for treatment of fatigue in a controlled trial of methylphenidate
hydrochloride (Ritalin) as an adjuvant analgesic for the treatment of cancer
pain; however, these authors assessed fatigue only as an ancillary outcome
variable. Weinshenker et al19 reported positive
results from a controlled trial of pemoline (Cylert) for fatigue in patients
with multiple sclerosis. In a double-blind, randomized crossover study, pemoline
was found to provide excellent or good relief of fatigue in 46% of patients
(N = 46), compared with 20% using placebo. Only 7% discontinued pemoline therapy
because of side effects, most commonly anorexia, irritability, and insomnia.
Moreover, 7 of the 46 patients continued to use pemoline after the trial,
finding it effectively relieved fatigue without intolerable side effects.
Given the potential utility of psychostimulants for the treatment of
fatigue, we sought to investigate the efficacy and safety of these medications
in patients with HIV and AIDS. This study used a randomized, double-blind,
placebo-controlled method to compare 2 psychostimulants (methylphenidate and
pemoline) for the treatment of fatigue. These medications were chosen because
of the preliminary research suggesting their possible efficacy in improving
symptoms of fatigue in patients with chronic illnesses. Although most research
has focused on drugs such as methylphenidate or dextroamphetamine sulfate
as the prototypical psychostimulants, we sought to compare a traditional psychostimulant
(methylphenidate) with an alternative psychostimulant (pemoline) with fewer
sympathomimetic effects and a side effect profile that may be better tolerated
by medically ill patients. We also improved on previous methods by measuring
fatigue with several multidimensional self-reported scales of fatigue, as
well as physiological measurements, to assess the impact of these treatments
on specific aspects of fatigue. Side effects were monitored by means of a
comprehensive side effects rating scale to assess the safety and tolerability
of these psychostimulants in this population. Finally, measures of psychological
distress and QOL were included to assess the impact of effective treatment
for fatigue. We hypothesized that both psychostimulants would be superior
to placebo in reducing fatigue, and that reductions in fatigue would correspond
to improved psychological well-being and QOL.
PATIENTS AND METHODS
PATIENTS
Ambulatory patients with HIV infection or AIDS were recruited from hospitals,
outpatient clinics, and agencies serving HIV-infected individuals throughout
the metropolitan New York City area. Advertisements were posted in these facilities
offering $25 in exchange for participation in a study of QOL and physical
symptoms (the nature of the study was not disclosed in these advertisements
to minimize the possibility that patients would exaggerate their fatigue to
participate). Patients who met inclusion and exclusion criteria were offered
$25 for each follow-up visit to compensate for their time and travel expenses,
and to maximize compliance with the study procedures.
Patients were eligible for study participation if they were seropositive
for HIV, received ambulatory care at the time of study entry, were older than
18 years, spoke English fluently (because most instruments were only validated
in English), and were able to swallow oral medications. In addition, all participants
were required to have had persistent fatigue (for at least 2 weeks or more)
that was rated 5 or greater on a numerical rating scale of 0 to 10. Patients
were excluded if they reported active substance abuse or had urine toxicologic
screening results that were positive for nonprescription controlled substances.
Patients were also excluded if they had a diagnosis of a major depressive
episode or cognitive impairment sufficient to preclude informed consent or
data collection (ie, evidence of HIV-associated dementia complex of moderate
or severe level of impairment), or if they reported insufficient fatigue.
In addition, patients were excluded if they had medical contraindications,
such as evidence of severe renal or hepatic disease (ie, creatinine levels
or results of liver function tests exceeding twice normal limits) or a history
of cardiac disease (ie, cardiac arrhythmia), seizure disorder, or psychosis,
or if they were prescribed medications that were contraindicated (monoamine
oxidase inhibitors, bupropion hydrochloride, guanethidine monosulfate, or
other sympathomimetic agents). This research study was approved by the Memorial
Sloan-Kettering Hospital Institutional Review Board, New York, NY. All participants
provided written informed consent after a discussion of the risks and benefits
of study participation.
PROCEDURE
After providing informed consent, all potential subjects underwent screening
for inclusion and exclusion criteria using the Mini-Mental State Examination20; the Structured Clinical Interview for Diagnosis
(SCID), Non-Patient, HIV Version21; and a battery
of neuropsychological tests sensitive to detecting cognitive impairments caused
by HIV-associated dementia. These measures included the digit symbol subtest
from the Wechsler Adult Intelligence Scale–Revised,22
the Trail-Making Test,23 the Grooved Pegboard
Test,24 and the Finger Tapping Test.25 Evidence of cognitive impairment on the Mini-Mental
State Examination (scores <22) or on the battery of neuropsychological
tests (ie, performance >1 SD below published norms on 3 of 4 tests) resulted
in exclusion from the study. In addition, all participants were required to
provide a urine sample for toxicologic screening (to rule out active substance
abuse) and clinical laboratory testing (eg, complete blood cell count, chemistry
screening panel including liver function tests) to screen and monitor for
safe completion of the study.
All subjects who met inclusion and exclusion criteria were administered
a battery of self-reported and observer-rated measures. These included 2 self-reported
measures of fatigue, the Piper Fatigue Scale (PFS)26
and the Visual Analog Scale for Fatigue Severity (VAS-F),27
as well as a measure of muscular endurance, the timed isometric unilateral
straight leg-raising task.28 Because validation
data for the PFS is considerably stronger than for other measures of fatigue,
we considered this measure our primary dependent variable. Patients were also
rated on the Karnofsky Performance Status scale29, 30
to assess their overall functioning abilities. Measures of psychological well-being
and QOL included the Beck Depression Inventory (BDI),31
the Brief Symptom Inventory,32 and the 36-Item
Short-Form Medical Outcome Study Health Status Survey.33
After baseline data collection, subjects were randomized (using block
randomization to ensure comparable numbers of HIV-infected patients with and
without an AIDS diagnosis) to one of the 3 study arms and prescribed methylphenidate
hydrochloride, 7.5 mg (1 capsule) twice daily; pemoline, 18.75 mg (1 capsule)
twice daily; or placebo, 1 capsule twice daily, as their initial starting
dose. Study participants and research staff were unaware of which medication
subjects were prescribed (all medications were prepared in identical capsules,
and randomization was completed by pharmacy personnel based on a random number
table). Study patients were then seen weekly for 6 weeks, and were contacted
by the research nurse (J.F.-E.) several times per week between weekly visits
to monitor medication and side effects and to titrate medications as rapidly
as possible to the maximum tolerated dose (or the maximum dose allowed by
the study protocol, ie, 60 mg/d for methylphenidate hydrochloride, 150 mg/d
for pemoline, and 8 capsules per day for placebo). At each weekly in-person
visit, patients were asked to complete the entire battery of assessment measures
(measures of fatigue and psychological well-being), with the exception of
SCID interviews and the Mini-Mental State Examination, which were conducted
only at baseline to assess exclusion criteria, and the neuropsychological
test battery, which was conducted at baseline and at study completion. Side
effects and adverse events were also rated during each weekly appointment,
using the Systematic Assessment for Treatment Emergent Events (SAFTEE),34 a multifaceted measure assessing 26 adverse effects
commonly observed in pharmacological interventions, the Extrapyramidal Side
Effects Rating Scale,35 designed to identify
the presence of tics or involuntary movements that may accompany psychostimulant
medications (not assessed by the SAFTEE), and weekly ratings of weight to
assess the impact of any appetite suppression that might result from psychostimulant
therapy. Pill counts were also obtained weekly to ensure medication compliance.
Patients were discontinued from study participation if they complained of
intolerable side effects of study medications or required hospitalization
for HIV-related medical problems (whether or not they were related to study
medications).
STATISTICAL ANALYSIS
Fatigue data were analyzed in the following 2 different ways: first
using change scores calculated from fatigue data obtained at baseline and
at the completion of the 6-week trial, and second using hierarchical linear
modeling to compare regression slopes of fatigue improvement. In the first
set of analyses, all fatigue-related outcome measures (including total scores
and subscale scores) were analyzed using a multivariate analysis of variance
(MANOVA), considering improvement in measures of fatigue as the dependent
variables and treatment arm as the primary independent variables. Subsequent
analysis of covariance (ANCOVA) models were used to allow for the influence
of additional covariates such as medication dosage and HIV/AIDS status. The
second level of analysis, which included all subjects who completed at least
3 follow-up assessments, compared the regression slopes derived for individual
subjects over time, with each slope reflecting the pattern of improvement
due to treatment (hierarchical linear modeling). Because improvement in fatigue
over time is not necessarily linear, regression models were fit to the overall
slope of the improvement curves by transforming the time intervals to reflect
the slope of improvement (this transformation resulted in essentially linear
improvement curves; the data are nevertheless presented without this transformation
to facilitate interpretation). These regression weights were then analyzed
using an analysis of variance (ANOVA) model to assess whether differences
existed across treatment arms with regard to the rate of improvement in fatigue
observed across each group. Planned contrasts were conducted to compare patients
prescribed active treatment with those taking a placebo, and then to compare
the methylphenidate and pemoline groups. Finally, Pearson product-moment correlations
between improvement in fatigue (change scores) and improvement in measures
of psychological distress and QOL were also used to assess the impact of treatment
on psychosocial functioning (statistical tests for these correlation coefficients
were calculated using a Bonferroni correction). Power analyses were conducted
before study initiation and indicated an optimal sample size of 40 subjects
per group to yield a power of 0.84, assuming a moderate effect size of 0.37.
Because no data were available for patients who refused to participate in
the study (after randomization), an intent-to-treat analysis was not feasible.
Instead, by using hierarchical linear modeling, we were able to include all
subjects who completed at least 3 of the 7 assessment periods (baseline and
2 follow-up visits), thus allowing for the inclusion of subjects who withdrew
from the study prematurely.
RESULTS
SAMPLE CHARACTERISTICS
Two hundred thirteen individuals underwent screening for possible study
inclusion. Of these prospective subjects, 34 were excluded because of active
substance abuse based on self-report or results of urine toxicologic screening
(this number would likely have been considerably higher had subjects not been
informed of the urine toxicologic screening at the time interviews were scheduled).
An additional 6 subjects were excluded because of medical contraindications;
23, a diagnosis of a major depressive episode (based on SCID interviews);
and 6, the presence of other psychiatric conditions (eg, dementia and history
of mania or schizophrenia). The remaining 144 subjects were randomized to
one of the 3 study arms. Of these 144 subjects, 109 completed the 6-week study
(Figure 1). Six subjects were randomized
but never began taking a study medication (ie, never arrived for the appointment
at which medications were dispensed). Seven subjects were discontinued from
the study because of medical complications that arose; 7, because of poor
compliance with study procedures (eg, excessive missed doses or failure to
attend follow-up appointments); 5, because of intolerable side effects; and
10, because of unknown reasons (ie, stopped participating in the study without
informing study personnel as to the basis for this decision). Table 1 presents the demographic characteristics of subjects who
underwent evaluation for possible participation (subjects who underwent screening),
those who met inclusion and exclusion criteria (subjects randomized), and
the subset of participants who completed the 6-week study (study completers).
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Table 1. Demographic Characteristics of Study Participants*
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There were no significant differences (ie, P<.05)
across the 3 study arms on any demographic or baseline clinical and medical
variables (eg, sex, race, transmission risk factor, baseline fatigue score,
hemoglobin level, Karnofsky Performance Status scale score, or BDI score),
indicating that the randomization procedure successfully generated equivalent
groups. Because there were no group differences, medical data are described
for the entire sample rather than for each study arm. Most subjects (77/109
[70.6%]) met criteria for a diagnosis of AIDS based on 1993 criteria of the
Centers for Disease Control and Prevention,36
although only 47 of these 77 subjects had a history of an AIDS-defining infection
(category C disease, Table 1).
The average Karnofsky Performance Status scale score for the sample was 75.5
(SD = 9.3), with 80 (73.4%) of 109 subjects obtaining scores of 70 or better.
The mean hemoglobin level for study participants was 134 g/L (SD = 18), and
only 9 (8.3%) of 109 subjects who completed the study had entry hemoglobin
levels below 110 g/L. Most subjects (86/109 [78.9%]) were receiving an antiretroviral
medication; 64 (58.7%) were receiving combination therapies, including protease
inhibitors. There were no significant group differences with regard to antiretroviral
or protease inhibitor therapies. The average BDI score was 14.2 (SD = 7.2),
indicating relatively mild level of depressive symptoms (particularly because
several BDI items assess somatic symptoms that may correspond to symptoms
of HIV disease rather than depression), and 21 of 109 subjects were prescribed
concomitant antidepressant medications (primarily selective serotonin reuptake
inhibitors). In addition, 6 patients (2 per study arm) were prescribed androgen
replacement therapies. Medication compliance was also comparable across groups,
with an overall total of 91% of the weekly pill counts revealing accurate
medication dosing.
Analysis of the effectiveness of the blind was assessed by asking subjects,
at the end of the 6-week trial, to guess whether they were receiving active
drug or placebo. This analysis demonstrated that although patients prescribed
a psychostimulant were in fact significantly more likely (P<.05) to guess that they were prescribed an active medication,
most patients receiving a placebo also guessed (incorrectly) that they were
prescribed a psychostimulant. Although relatively few patients receiving active
drug believed they were taking a placebo (6/58 [10.3%]), most patients receiving
placebo also held this belief (22/35 [62.9%]).
IMPROVEMENT IN FATIGUE ACROSS TREATMENT GROUPS
Univariate ANOVAs showed that the 3 treatment arms differed significantly
in terms of improvement on the PFS total score (F = 3.59 [P = .04]; effect size, 0.25; 95% confidence interval [CI], 0.06-0.44),
the affective subscale of the PFS (F = 5.06 [P =
.008]; effect size, 0.28; 95% CI, 0.09-0.47), and the sensory subscale of
the PFS (F = 3.39 [P = .04]; effect size, 0.24; 95%
CI, 0.05-0.43). However, there were no significant group differences on the
cognitive (F = 1.70 [P = .19]; effect size, 0.17;
95% CI, -0.02 to 0.36) or severity (F = 1.82 [P
= .17]; effect size, 0.18; 95% CI, -0.01 to 0.37) subscales of the PFS.
Improvement scores on the VAS-F also yielded no significant group differences
on the total score (F = 1.61 [P = .21]; effect size,
0.17; 95% CI, -0.02 to 0.36) or the fatigue subscale (F = 0.77 [P = .47]; effect size, 0.12; 95% CI, -0.07 to 0.31).
However, changes in the energy subscale of the VAS-F differed significantly
across the 3 groups (F = 4.28 [P = .02]; effect size,
0.23; 95% CI, 0.04-0.42). A MANOVA assessing the impact of treatment on improvement
in these measures of fatigue (using change scores as described above) demonstrated
an overall significant effect for the set of fatigue measures and subscales
(F = 1.79 [P = .04]).
Contrast analyses were used, first to compare the combined group subjects
assigned to 1 of the 2 treatment arms (methylphenidate or pemoline) with those
assigned to the placebo condition, and second to compare subjects prescribed
methylphenidate with those prescribed pemoline. These analyses demonstrated
a significant difference in improvement on the PFS total score and affective
and sensory subscales, as well as the energy subscale of the VAS-F. The VAS-F
total score also approached significance in this analysis (P = .06). There were no significant differences in improvement on any
of these measures, however, between subjects prescribed methylphenidate vs
those prescribed pemoline. The mean improvement scores across the 3 treatment
groups are listed in Table 2.
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Table 2. Improvement in Fatigue From Baseline to Week 6*
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We classified subjects as having demonstrated clinically significant
improvement of fatigue if their PFS total score decreased by 5 points or more
(the maximum possible improvement on this scale was 10 points) or their VAS-F
total score decreased by 50 mm or more (the maximum possible improvement on
this scale was 100 mm). Using this criterion, we observed a significant difference
across study arms in the proportion of patients who showed clinically significant
improvement ( 2 = 6.52 [P = .04]).
Of 37 patients taking methylphenidate, 15 (41%) demonstrated clinically significant
improvement, compared with 12 (36%) of 33 patients taking pemoline and only
6 (15%) of 39 patients taking placebo.
A second phase of analysis, using hierarchical linear modeling, incorporated
data from all 7 time points. Individual regression slopes were calculated
separately for each subject in which total scores from the PFS and VAS-F were
entered as dependent variables, and study week was entered as an independent
variable. These regression slopes, which reflect the rate of improvement for
each individual subject over time, were then compared across the treatment
arm using an ANOVA model similar to that used to analyze the change in scores
from baseline to the end of the study. Because of the nonlinear slope of these
data, the time variable was transformed using an inverse function before calculating
regression slopes (this transformation diminishes the slope of improvement
in early weeks while increasing the slope during later weeks, thus effectively
straightening an otherwise curvilinear improvement slope). This analysis,
depicted in Figure 2, demonstrated
a significantly more rapid decrease in PFS total scores for patients receiving
methylphenidate or pemoline compared with subjects receiving placebo (F2,116 = 4.63 [P = .02]). Contrast analyses
revealed that patients receiving methylphenidate or pemoline improved significantly
faster and more steadily than patients receiving placebo (F1,116
= 7.62 [P = .007]), whereas no differences existed
between active treatment groups (F1,116 = 0.46 [P = .51]). Although a similar pattern of results emerged for VAS-F
total scores (Figure 3), this difference
was not statistically significant (F2,116 = 1.75 [P = .20]). Contrast analyses comparing both stimulant groups with the
placebo group, however, approached significance (F1,116 = 3.46
[P = .07]), whereas no differences existed between
active treatment groups (F1,116 = 0.09 [P
= .78]).
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Figure 2. Improvement in fatigue over time,
measured by means of the Piper Fatigue Scale.
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Figure 3. Improvement in fatigue over time,
measured by means of the Visual Analog Scale for Fatigue (VAS-F).
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A post hoc ANCOVA was used to assess whether improvement patterns differed
depending on disease severity (ie, seropositive for HIV vs diagnosis of AIDS),
extent of depressive symptoms at baseline (the sample was divided betweenthose
with BDI scores  15 and >15), the presence of concomitant antidepressant
medications, or demographic variables such as sex, race, or risk transmission
factor. These analyses demonstrated no significant interaction effects (P<.05), indicating that the superiority of pharmacological
interventions over placebo was unrelated to disease severity, extent of depressive
symptoms, concomitant antidepressant medications, sex, race, or risk transmission
factor.
Given that the goal of dosage titration was to determine the optimal
dose at which fatigue improved without causing excessive side effects, we
used end-of-study medication dosages as the best indicator of optimal dosing.
The average dosage for patients receiving methylphenidate hydrochloride was
51.0 mg/d (SD = 12.6), with dosages ranging from 15 to 60 mg/d. Of the 37
subjects receiving methylphenidate hydrochloride who completed the study,
22 (59.5%) were taking this maximum dose (which was the maximum allowed in
our study protocol) and only 4 were receiving 30 mg/d or less. Thus, it is
unclear how many of these 22 subjects would have responded even more completely
with higher doses of methylphenidate. The average dosage for patients receiving
pemoline was 96.0 mg/d (SD = 47.5), with dosages ranging from 37.5 to 150
mg/d. Of the 33 subjects in the pemoline group, only 11 subjects were receiving
the maximum dose allowed by study protocol, whereas 9 of the 33 subjects were
receiving the minimum dose (37.5 mg/d).
SIDE EFFECTS AND TOXICITY
The presence of side effects caused by study medication was assessed
using the SAFTEE and Extrapyramidal Side Effects Rating Scale during each
weekly assessment. Only 5 subjects withdrew from study participation because
of side effects. Two subjects were receiving methylphenidate; 2 subjects,
pemoline; and 1 subject, placebo. One of the 2 patients prescribed methylphenidate
cited excessive jitteriness as the primary reason for study withdrawal after
4 weeks. The second patient, who withdrew during the final week of study participation,
cited a combination of symptoms including dry mouth, rapid heartbeat, difficulty
sleeping, and hyperactivity. One of the 2 patients receiving pemoline, who
withdrew after 2 weeks of study participation, complained of neuropathic pain
that he attributed to the study medication. One patient prescribed placebo,
who withdrew because of intolerable side effects after 5 weeks of study participation,
complained of constipation and hyperactivity.
With regard to the overall rate of side effects experienced by subjects
in the 3 treatment arms, the most commonly reported side effects were those
related to hyperactivity and jitteriness (Table 3). In fact, the only side effect that differed (in prevalence)
significantly across the 3 treatment arms was a summary variable consisting
of both symptoms. Nearly half of the subjects receiving methylphenidate and
pemoline reported experiencing one or both of these symptoms, whereas only
one quarter of the subjects receiving placebo reported such symptoms (22 = 6.96; n = 131 [P = .04]). There
were no other significant differences (P<.05)
across the 3 treatment arms in the rates of any side effects or symptoms (including
other summary variables corresponding to sleep and gastrointestinal tract
disturbances). Moreover, despite concerns that the psychostimulant medications
might cause extrapyramidal side effects (eg, tics, involuntary movements),
there was no difference in ratings made using the Extrapyramidal Side Effects
Rating Scale across the 3 treatment arms (24 =
5.07; n = 106 [P = .23]). There were no significant
differences in weight change across the 3 treatment arms (F2,99
= 0.37 [P = .69]). During the 6-week trial, patients
receiving methylphenidate gained, on average, 0.07 kg, whereas patients receiving
pemoline and placebo lost an average of 0.7 and 0.4 kg, respectively.
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Table 3. Prevalence of Side Effects Among Treatment Groups
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Given the frequency with which patients complained of feeling jittery
or hyperactive, we examined the dosages at which these symptoms occurred and
whether they responded to decreases in dosage or went away without any dosage
change. Of those subjects reporting jitteriness as an side effect of medication,
the average dosage at which subjects experienced this symptom was 35.36 mg/d
(range, 15-60 mg/d) of methylphenidate. Eight of the 14 subjects in the methylphenidate
arm who reported jitteriness experienced symptom relief, despite increasing
their methylphenidate dosage, whereas an additional 2 subjects experienced
relief at the same dosage at which the symptom started. Only 1 subject experienced
symptom relief when the dosage was decreased, and an additional 3 subjects
reported continued jitteriness despite medication changes. The average dosage
at which hyperactivity was experienced was 35.00 mg/d (range, 15-60 mg/d),
with 5 of these 11 subjects reporting symptom relief despite dosage increases.
An additional 3 subjects reported symptom relief at the same dosage at which
the symptom started, whereas 3 subjects required dosage decreases to alleviate
their hyperactivity, and 1 subject did not experience any relief from this
symptom.
Among subjects in the pemoline group, the average dosage at which jitteriness
was experienced was 69.89 mg/d (range, 37.5-150 mg/d). Of the 11 subjects
reporting this side effect, 10 experienced symptom relief despite equal or
increased dosages of this medication, whereas one subject did not experience
any symptom relief despite a reduction in dosage. The average dosage at which
subjects in the pemoline group reported hyperactivity was 45.54 mg/d (range,
37.5-56.25 mg/d). Of the 7 subjects reporting this side effect, 6 experienced
symptom relief despite equal or higher dosages of pemoline, whereas 1 subject
required a decrease in dosage (from 56.25 mg/d to 37.5 mg/d) to alleviate
hyperactivity. Data regarding the dosage of placebo at which side effects
occurred were not analyzed.
IMPACT OF TREATMENT ON PSYCHOLOGICAL DISTRESS AND QOL
There were significant correlations between the change scores derived
from baseline and end-of-study fatigue ratings (eg, degree of improvement
in fatigue) and improvement in most measures of psychological functioning
and QOL. As displayed in Table 4, changes in BDI scores were significantly correlated with improvement on the
PFS (r = 0.41 [P<.001])
and VAS-F (r = 0.34 [P<.001])
total scores, indicating that as overall ratings of fatigue severity decreased,
levels of depressive symptoms also decreased. The fatigue subscales most highly
correlated with improvement in depressive symptoms were the severity and cognitive
subscales of the PFS (r = 0.45 and r = 0.38, respectively) and the energy subscale of the VAS-F (r = 0.42). The PFS affective and sensory subscales were
less highly correlated with improvement on the BDI (r
= 0.29 and r = 0.30, respectively) as was the VAS-F
energy subscale (r = 0.09).
|
|
|
|
Table 4. Correlations Between Fatigue Improvement and Changes in Quality-of-Life
Variables*
|
|
|
Similarly, change scores derived from BSI Global Distress Index were
significantly correlated with improvement on the PFS and VAS-F total scores
(r = 0.37 [P<.001] and r = 0.27 [P<.001], respectively).
The strongest correlations between fatigue improvement and reduced psychological
distress were observed for the severity and cognitive subscales of the PFS
(r = 0.34 and r = 0.45,
respectively), whereas the PFS sensory and affective subscales and the VAS-F
fatigue and energy subscales were less highly correlated (r = 0.30, r = 0.22, r
= 0.28, and r = 0.18, respectively). Finally, improved
overall QOL, as measured by many of the Medical Outcomes Study Health Status
Survey subscales, were significantly correlated with changes in both the PFS
and VAS-F total scores (Table 4).
The strongest correlations between improved fatigue and changes in QOL were
observed in the role functioning subscale (r, 0.32-0.48
for 7 of 8 fatigue self-reported measures), indicating that improved fatigue
had the strongest effect on physical activity.
COMMENT
This study, which to our knowledge represents the first double-blind
placebo-controlled trial of psychostimulants for the treatment of fatigue
in patients with HIV, demonstrates that many patients with HIV- and AIDS-related
fatigue respond favorably to treatment with methylphenidate or pemoline. Both
psychostimulants appear to be equally effective and significantly superior
to placebo in decreasing fatigue severity with minimal side effects. Moreover,
improved fatigue was significantly associated with improved QOL and decreased
levels of depression and psychological distress. Thus, effective treatment
for fatigue in patients with HIV disease is available and may offer substantial
benefits for overall QOL in many patients. The use of psychostimulants in
the clinical management of fatigue in patients with HIV disease is most appropriate
as part of a comprehensive approach. This approach would include the identification
and treatment of AIDS-related conditions that can cause fatigue, such as anemia,
as well as the judicious use of combination antiretroviral therapies to reduce
viral load and restore immune function.14
The degree of improvement due to psychostimulants, however, was not
uniform across all measures of fatigue. The strongest, most consistent, and
most statistically significant group differences were evident on our primary
dependent variable, the PFS, a multidimensional self-reported scale that had
the most extensive validation data of any fatigue measurement tool available.
Somewhat more modest results were obtained using the VAS-F, a brief self-reported
rating scale with somewhat less extensive validation data relative to the
PFS. We found no evidence of a treatment effect on the physiological measurement
used, the timed isometric unilateral straight leg-raising task. Despite these
seemingly mixed results, we believe that these data nevertheless demonstrate
a clinically and statistically significant treatment effect for psychostimulants
compared with placebo, because significant results were obtained with the
most reliable measures of fatigue used. Significant results were obtained
for the total PFS score and 2 of the 4 PFS subscales (affective and sensory),
as well as 1 of the 2 VAS-F subscales (energy). The remaining self-reported
scales all followed a similar pattern, some of which approached statistical
significance, supporting the conclusion that psychostimulants were effective
in reducing fatigue. The only exception to this pattern emerged with our measure
of muscular endurance, the timed isometric unilateral straight leg-raising
task. Because this task simply measures the length of time patients can suspend
their leg in the air, it is likely influenced by many factors other than fatigue
(eg, degree of effort, motivation, physical discomfort, and strength). Although
physiological measurements to assess fatigue are clearly desirable in fatigue
intervention research, this task may be an inadequate and unreliable method
for assessing fatigue.
The other factor that likely influenced the extent of significant findings
observed was the sizable placebo effect evident in our data. Despite taking
an inactive substance, this group demonstrated a rapid and consistent reduction
in fatigue symptoms that, although somewhat less than that of subjects taking
active medication, was nevertheless substantial. In fact, examination of the
longitudinal data (Figure 1 and Figure 2) reveals a substantial (and comparable)
decrease in fatigue during the first week of study participation. During subsequent
weeks, however, patients receiving active medication appear to have continued
improvement, whereas no such pattern was evident for the placebo group (this
pattern is most clearly evident in the PFS data displayed in Figure 1). Support for this apparent placebo effect is also demonstrated
by the finding that most patients taking placebo believed that they were taking
1 of the 2 active medications and reported side effects (from placebo) that
were roughly comparable to those reported by patients receiving active medication.
Given the pattern of improvement described above, it may be that a longer
study period is necessary to assess whether placebo-induced benefits can be
maintained.
The nature and frequency of side effects among patients receiving placebo
was not substantially (or significantly) different from those reported by
patients receiving active medication. This finding, as well as the relatively
mild nature of side effects reported, is particularly noteworthy given the
extent of medical illness present in our study population. Of more than 135
patients treated in this study, only 5 withdrew because of intolerable side
effects, and 1 of these 5 patients had received an inactive placebo. Of those
side effects reported, the most common (and only side effects that were significantly
more prevalent among patients receiving active medication) were jitteriness
and hyperactivity, both of which are common side effects of psychostimulants.
Although several other side effects occurred slightly more often among patients
prescribed methylphenidate or pemoline, these differential prevalence rates
were small and not statistically significant. There have been no reports in
the literature to date of any adverse effects of psychostimulants such as
methylphenidate on immune function or disease progression in patients with
HIV disease.1, 4 Moreover, although
recent concerns have been raised regarding the risk for acute liver failure
in patients treated with pemoline, we observed no such reactions in our sample.
Nevertheless, given the possibility of such adverse effects, clinicians should
be aware of the Food and Drug Administration recommendations for informed
consent when prescribing pemoline.37
One obvious confounding factor in this study concerns the possibility
that the improvement in fatigue attributed to psychostimulant medications
was in fact due to an antidepressant effect. Methylphenidate and pemoline
have been noted to alleviate depressive symptoms in patients with medical
illness,38, 39, 40
and fatigue is, of course, a common symptom of depression. Thus, the apparent
benefits attributed to psychostimulants might reflect a more indirect influence
of these medications on the patient's depressive symptoms rather than a direct
effect on fatigue. Of course, patients with a major depressive disorder were
excluded from study participation specifically to minimize the possibility
of such a confound; however, many study participants had some degree of depressive
symptoms. The confound of antidepressant and antifatigue effects is further
clouded by our observation that the strongest impact of medications was on
the affective subscale of the PFS, presumably reflecting the fatigue items
with the highest correspondence to mood. Given the multidimensional nature
of fatigue, it is perhaps not surprising that psychostimulants would have
the strongest effect on the affective dimension of fatigue. On the other hand,
improvement in depressive symptoms (and other QOL measures) was less highly
correlated with the affective subscale of the PFS, and much more highly correlated
with overall fatigue improvement (total scores on the PFS and VAS-F) and fatigue
severity (ie, the severity subscale of the PFS). Thus, it appears likely that
the antidepressant effects observed were more likely to reflect the positive
impact of decreased fatigue severity rather than a more direct antidepressant
effect of these medications.
Despite the encouraging results described herein, a number of limitations
must be acknowledged in this study. First, the time frame used to study treatment
effects (6 weeks) limits any assessment of whether continued treatment with
psychostimulants would result in a further decline in fatigue symptoms or
even a maintenance of those gains achieved. Although we might speculate that
continued treatment would result in sustained or even additional improvement
in fatigue for patients actually taking medications, but that these gains
might gradually erode in patients taking a placebo, such speculation is untested.
However, to our knowledge, this 6-week study represents the longest trial
of psychostimulants published to date in the literature. It is also possible
that patients with HIV or AIDS might develop a tolerance for psychostimulant
medications and therefore would need higher dosages to achieve the same level
of symptom relief, or even show a resurgence of fatigue despite continued
treatment. Alternatively, the possibility of long-term adverse effects from
these medications could not be assessed in this study, given the 6-week treatment
period. Systematic long-term studies of these medications are necessary to
evaluate the long-term effects of these medications.
A second limitation of this study concerns the ambulatory status of
study participants. Since all subjects were living independently at the time
of participation, we had limited ability to monitor subject compliance with
the treatment regimen. Although our weekly pill counts demonstrated a high
degree of adherence to the protocol, it is nevertheless possible that unacknowledged
missed doses or refusal to titrate the medications despite recommendations
from study personnel might have resulted in somewhat more modest benefits
from treatment than would be observed in a more structured setting (eg, an
inpatient unit or long-term care facility). Of course, although imperfect
as a method of determining treatment efficacy, our study method accurately
mimics the real-world conditions for most potential treatment subjects. Patients
living at home or outside of institutions are likely to be faced with daily
dilemmas regarding whether they wish to take an additional medication to combat
yet another symptom of the illness. Although not analyzed systematically,
a number of subjects expressed reluctance to continue taking study medications
once the trial had ended, despite reporting substantial improvement. These
impediments to adequate symptom control are often neglected, yet may exert
considerable influence on which symptoms are addressed and which are not.
Further research into patient attitudes toward fatigue and the barriers to
adequate treatment may help elucidate these issues.
A final limitation in this study concerns the sample size and rate of
dropout. Our modest sample size (n = 109) may have failed to detect meaningful
differences between the 2 active treatments. Although some differences in
treatment response were evident (Table 2) and may have been statistically significant with a larger sample,
the magnitude of these group differences was quite modest (ie, a small-effect
size). In addition, because a substantial number of patients terminated the
study prematurely (Figure 1), it
is unknown whether these patients biased the outcome in any meaningful way.
Despite the limitations described above, this study reflects the first
empirical demonstration of the effectiveness of psychostimulants for the treatment
of HIV-related fatigue. This common and distressing symptom responded quickly
and substantially for most subjects, with relatively few troublesome side
effects. Thus, it appears that fatigue cannot only be treated safely and effectively
in patients with HIV, but that adequate treatment has a dramatic impact on
QOL and psychological well-being. Given the overwhelming number of stressors
faced by patients with HIV and AIDS, the ability to adequately resolve even
one common and distressing symptom appears worthwhile and necessary.
AUTHOR INFORMATION
Accepted for publication September 25, 2000.
This research was supported by grant MH54970 from the National Institute
of Mental Health, Rockville, Md (Dr Breitbart, principal investigator) and
the Faculty Scholars Program, Open Society Institute, Project on Death in
America (Dr Breitbart).
From the Department of Psychiatry and Behavioral Sciences, Memorial
Sloan-Kettering Cancer Center, New York, NY (Drs Breitbart and Kaim and Ms
Funesti-Esch); and the Department of Psychology, Fordham University, Bronx,
NY (Dr Rosenfeld).
Corresponding author and reprints: William Breitbart, MD, Psychiatry
Service and Pain and Palliative Care Service, Memorial Sloan-Kettering Cancer
Center, 1275 York Ave, Box 421, New York, NY 10021 (e-mail: breitbaw{at}mskcc.org).
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