A Randomized, Double-Blind, Placebo- Controlled Trial Assessing the Impact of Dexamphetamine on Fatigue in Patients with Advanced Cancer

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1 Vol. 37 No. 4 April 2009 Journal of Pain and Symptom Management 613 Original Article A Randomized, Double-Blind, Placebo- Controlled Trial Assessing the Impact of Dexamphetamine on Fatigue in Patients with Advanced Cancer Kirsten Anne Auret, FRACP, Stephan A. Schug, FFPMANZCA, Alexandra P. Bremner, PhD, and Max Bulsara, MSc Rural Clinical School of Western Australia (K.A.A.), University of Western Australia, Albany; School of Medicine and Pharmacology (S.A.S.), University of Western Australia, Perth; School of Population Health (A.P.B., M.B.), University of Western Australia, Crawley, Western Australia, Australia Abstract Fatigue is very common in patients with cancer. Current guidelines suggest that psychostimulants are reasonable to consider for severe fatigue. This randomized, doubleblind, placebo-controlled trial investigated the hypothesis that dexamphetamine in fatigued patients with advanced cancer would produce a clinically significant improvement with minimal side effects. Fifty patients with advanced cancer, who were receiving palliative care, were randomized to dexamphetamine 10 mg twice daily or placebo for eight days. Effectiveness was assessed using the Brief Fatigue Inventory and the McGill Quality-of-Life Questionnaire. The side effects were recorded. The results were analyzed on an intention-to-treat basis. The baseline demographics, fatigue levels, and quality-of-life scores were similar between the two arms. Patients were elderly, had impaired performance status (Eastern Cooperative Oncology Group score ¼ 3), and were taking a range of neurologically active medications. Thirty-nine patients completed the trial. There was a transient improvement in the fatigue levels on day 2, but no significant difference in fatigue (P ¼ 0.267) or quality of life (P ¼ 0.579) by the end of the study. Statistical modeling did not reveal any significant predictors of response to dexamphetamine. These results suggest that dexamphetamine 20 mg daily, although well tolerated, does not significantly improve fatigue or quality of life in patients with advanced cancer, as measured by the selected instruments. J Pain Symptom Manage 2009;37:613e621. Ó 2009 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Fatigue, cancer, palliative care, psychostimulant drugs, dexamphetamine This study was funded by grants from the University of Western Australia and the Hollywood Private Hospital Research Foundation. The funding sources played no role in the design, collection, or analysis of data, interpretation of results or in the decision to submit the results for publication. Ó 2009 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. Address correspondence to: Kirsten Anne Auret, FRACP, University of Western Australia, 48 Frederick Street, Albany, Western Australia 6330, Australia. Kirsten.Auret@uwa.edu.au Accepted for publication: April 3, /09/$esee front matter doi: /j.jpainsymman

2 614 Auret et al. Vol. 37 No. 4 April 2009 Introduction Cancer-related fatigue is defined as a persistent, subjective sense of tiredness related to cancer or cancer treatment that interferes with normal functioning and is not relieved by rest. It is the most common symptom reported by patients with cancer. 1 Cancer-related fatigue is thought to be a multifactorial condition attributed to cancer itself, side effects of therapy, diminished activity, poor nutrition, depression, and intercurrent illness. The prevalence varies between 60% and 96%, depending on the stage, tumor site, and treatments. The patients felt that it had a larger impact on their daily lives than pain, depression, or nausea. In contrast with the expectations of doctors, alleviation of fatigue, rather than pain, is the priority of many patients. The majority of patients, however, continue to believe that fatigue is a symptom to be endured, and only half will discuss it with their doctor. 2 Current therapy suggested for fatigue is based on education, exercise, correcting potential etiologies (e.g., erythropoietin for anemia, antidepressants, and adequate nutrition), and providing symptomatic pharmacological treatments. The latter group includes prescription of low-dose steroids, modafanil, and psychostimulants, such as dexamphetamine, methylphenidate, or pemoline. 1,3,4 The evidence for the effectiveness of psychostimulants in the setting of cancer-related fatigue is weak, mainly extrapolated from randomized studies in other diseases 5,6 or other symptoms, 7 or based on non-randomized trials. 8e13 There has been one randomized, placebo-controlled study recently reported that investigated the impact of patient-controlled use of methylphenidate for cancer fatigue over one week. Although fatigue levels in both arms improved during the trial period, there was no significant difference between them. 14 Three reviews have been published describing psychostimulant use for symptoms in patients with cancer. Rozans et al. in 2002 looked at 49 articles on methylphenidate for opioid-induced somnolence, depression, and cognitive function. They concluded that placebo-controlled trials were needed in palliative care. 15 Dalal and Melzack summarized six papers on morphineeamphetamine combinations, suggesting that the combination may potentiate analgesia, and eight papers on morphineemethylphenidate showed the potential to counteract sedation. They concluded that psychostimulants were well tolerated. 16 The third review reported on 15 papers that confirmed that psychostimulants are effective for depression in the medically unwell. 17 The United States National Cancer Institute (NCI) guidelines on cancer-related fatigue state that, although there are no published trials in the field, limited experience suggests that methylphenidate or dexamphetamine starting at a dose of 2.5e5 mg at 8 AM and at noon is reasonable to consider for severe fatigue. 4 Dexamphetamine (dextroamphetamine) was selected as the psychostimulant for this study. It is a noncatecholamine, sympathomimetic amine that causes pronounced stimulation of the cerebral cortex and respiratory and vasomotor centers, increasing motor activity, mental alertness, and euphoria. It has a rapid onset of action in less than 24 hours and an approximate plasma half-life of hours. The usual daily dose is 10e20 mg, with a maximum dose of 60e90 mg/day. 18 Based on the available evidence, the NCI currently recommends a dose of 5e30 mg/day for cancer-related fatigue. 4 This randomized, double-blind, placebocontrolled trial was designed to investigate the hypothesis that the use of dexamphetamine in fatigued patients with advanced cancer would produce a clinically significant improvement with minimal side effects. Methods Fifty patients were recruited through the Palliative Care Unit at Hollywood Private Hospital, Perth, Western Australia, from March 2003 to October 2004, and follow-up continued until January The study was approved by the hospital Research Ethics Committee, and all patients gave written informed consent. Cancer patients with a prognosis estimated at more than two months, who were under the care of a Palliative Care Service, were included in the study if they were not bedbound and rated their fatigue as at least 4 of 10 on a 0e10 numerical rating scale. Patients were excluded if they were currently having

3 Vol. 37 No. 4 April 2009 Dexamphetamine for Fatigue in Advanced Cancer 615 chemotherapy, suffering from anxiety requiring medication or had an untreated depression as assessed by the referring clinician, had recently taken monoamine oxidase (MAO) inhibitors, had an uncontrolled medical illness, or had a hemoglobin level of less than 100 g/l with a transfusion planned. Patients were randomized by the hospital pharmacy to either the dexamphetamine or placebo arm. The patients and research staff were blinded to which medication was prescribed. The active drug (5 mg dexamphetamine) and the lactose placebo were prepacked into generic capsules. Patients took two capsules twice daily at 8 AM and noon, i.e., patients in the dexamphetamine group received a daily dose of 20 mg. If a patient was unable to tolerate the prescribed dose, it was reduced to one capsule twice daily, and the patient continued on the trial. To assist with compliance and post-trial tablet count, the medications were pre-packed into bottles clearly marked with each day of the trial. All data were collected by the research assistant, beginning with baseline measurements. Each patient was contacted daily (by telephone if the patient was at home) to record acceptability and to improve compliance. Data collected at each measurement point included: 1. How tired patients felt using the Brief Fatigue Inventory (BFI). Patients rate their fatigue now, usually, and at its worst in the last 24 hours (0e10), and how fatigue interfered with general activity, mood, walking ability, normal work, relations with other people, and enjoyment of life (0e10). Patients are scored between 0 and 10 by adding their scores and dividing by How patients regarded their quality of life using the McGill Quality-of-Life Questionnaire (MQOL). Patients rate their answers by degree of severity (0e10). A total score out of 10 is calculated by adding their scores and dividing by Performance status using the Eastern Cooperative Oncology Group (ECOG) Scale Self-reported and clinician-suspected side effects by using a specifically designed questionnaire (documenting presence or absence of anxiety, dry mouth, gastrointestinal upset, insomnia, headache, tremor, anorexia, cardiac problems) and review of the clinical notes. 5. Pulse rate and blood pressure (measured by sphygmomanometer, with calculated mean arterial blood pressure [MABP ¼ (SBP þ 2 DBP)/3], where SBP is systolic blood pressure and DBP is diastolic blood pressure). Demographic data (age, sex, diagnosis, albumin and hemoglobin levels, O 2 saturation on room air) and the co-prescription of other medications (opioids, dexamethasone, antidepressants, sedatives, and antiepileptics) were collected at baseline only. Measurements were repeated every two days until completion of the study after eight days, and were taken in the afternoon. Measurements were continued, if possible, for patients who were unable to tolerate the medication/ placebo. Patients who died or withdrew from any follow-up were recorded. A previous work suggests that the minimally important clinical difference in fatigue levels on a 10-point scale is approximately 2 points. 22 Local consultation with clinicians suggested that they were unlikely to prescribe a new medication to their patients, who are often on multiple tablets already, with lesser degrees of effect. Therefore, looking for a difference of two or more, and allowing for a 20% dropout rate, power analysis indicated an optimal sample size of 25 per arm to yield a power of 90%, with a P-value of Results were analyzed on an intentionto-treat basis with repeated measures analysis of variance using generalized linear mixed modeling. T-tests were used to compare equality of continuous measures, subject to a normal distribution within each group. Wilcoxon tests, rather than T-tests, were used for the individual and average BFI scores, because responses were generally not normally distributed in each group. Fisher s exact test was used to test whether proportions were equal when expected frequencies were small. McNemar s test was used to determine whether the number of people in the treatment group who correctly guessed that they were on treatment was the same as the number of people in the placebo group who correctly guessed that they were taking a placebo. Statistical analysis was

4 616 Auret et al. Vol. 37 No. 4 April 2009 performed using S-PLUS Significance was set at P < 0.05 and two-sided P-values are reported. Results Fifty patients participated in the trial. The participant flow is documented in Fig. 1. Seven patients died in the dexamphetamine arm and eight in the placebo arm within six weeks of the beginning of trial. There were no significant differences in baseline demographics between the groups, except for pulse rates (P ¼ 0.050) and number of days spent in hospital (P ¼ ) (Table 1). Patients suffered from a wide range of cancers, with most malignancies affecting the genitourinary, digestive, and respiratory systems. There were no significant differences in the baseline BFI scores between the arms: the mean average fatigue score was 5.8 out of 10 (standard deviation [SD] 1.8) in the dexamphetamine arm and 5.9 (SD 2.0) in the placebo arm (P ¼ 0.756). These scores are defined as fatigue of moderate severity. 18 There was no significant difference in baseline MQOL scores also, with mean average scores of 6.9 (SD 1.7) and 6.7 (SD 1.7), respectively (P ¼ 0.691). Although there was an overall decrease of 1.08 in the mean BFI score (median 1.22) for the dexamphetamine group by the end of the trial, compared with a reduction in the placebo group of 0.98 (median 0.50), this was not a statistically significant improvement (P ¼ 0.414). Modeled over the eight days, the average decrease in BFI score for the dexamphetamine group was 0.57 compared with the placebo group, which was not statistically significant (P ¼ 0.267). Modeling, which included age, sex, day of treatment, ECOG, Total patients referred by clinicians for consideration n = 70 Patients excluded as not meeting criteria n = 20 Patients randomized n = 50 Dexamphetamine arm n = 25 Placebo arm n = 25 Non-completer n = 4 (2 dropped out, 2 died) Non-completers n = 7 (6 dropped out, 1 died) Completed 8-day trial n = 21 (18 on 2 bd, 3 on 1 bd) Completed 8-day trial n = 18 (17 on 2 bd, 1 on 1 bd) Fig. 1. Participant flow.

5 Vol. 37 No. 4 April 2009 Dexamphetamine for Fatigue in Advanced Cancer 617 Table 1 Demographic and Baseline Information Variable Dexamphetamine Arm Placebo Arm Test P value Number Age (years) Mean t-test SD Sex F9 F5 M 16 M 20 Fisher s exact test ECOG Median 3 3 Wilcoxon test SD Pulse n ¼ 24 Mean t-test SD MABP n ¼ 24 Mean t-test SD Serum albumin (g/l) n ¼ 23 n ¼ 22 Mean t-test SD Hemoglobin (g/l) n ¼ 24 n ¼ 22 Mean t-test SD O 2 saturation (%) Mean t-test SD On every opioid Fisher s exact test Mean opioid dose (as oral Wilcoxon test morphine every 24 hours, mg) On every steroid Fisher s exact test On every antidepressant 4 6 Fisher s exact test On every sedative Fisher s exact test On every antiepileptic 3 3 Fisher s exact test Days in hospital Mean Wilcoxon test SD and the variables that were different at baseline (pulse and days in hospital), showed no significant effect of dexamphetamine on fatigue (P ¼ 0.557), although it did demonstrate that age and sex were significant predictors of fatigue severity (youngerdworse fatigue, P ¼ 0.030; maledworse fatigue, P ¼ 0.047). In particular, the effect of days in hospital was not significant (P ¼ 0.344). Table 2 demonstrates that although all patients in the study did show some improvement in their BFI from baseline to day 8, these improvements were not significant in either arm. As Fig. 2 illustrates, there was a transient significant difference in fatigue in the dexamphetamine arm compared with placebo on day 2 of the study (P ¼ 0.039), which became nonsignificant for the later measurements. This brief improvement is not explained by changes in other variables or reflected in change in MQOL score or ECOG at any point. The fatigue interference items of the BFI were analyzed separately and were not significantly different between arms (Table 3). The MQOL scores are illustrated in Fig. 3. There was no significant difference in the average change in quality-of-life score when modeled from day 0 to day 8 between the two arms (P ¼ 0.579). There was an overall increase of 0.05 in the mean MQOL average score in the dexamphetamine arm, compared with 0.13 in the placebo arm (P ¼ 0.978). Generalized linear modeling for MQOL average scores showed that there was still no significant difference (P ¼ 0.927) when age, sex, day of treatment, ECOG, pulse, and days in hospital were included. The effects of age (youngerd worse, P ¼ 0.003), sex (maledworse, P ¼ 0.048), and ECOG at baseline (P ¼ 0.050) on assessment of quality of life were significant. The averages of the individual subscales of the MQOL questionnaire (physical symptoms,

6 618 Auret et al. Vol. 37 No. 4 April 2009 Table 2 Comparison of Day 0 and Day 8 Values in Each Arm of the Study Tool Group Day 0 Median Day 0 Range Day 8 Median Day 8 Range P-value a BFI Dexamphetamine e e Placebo e e MQOL Dexamphetamine e e Placebo e e a From Wilcoxon tests. existential well-being, psychological symptoms, and support) and the single item scores ( considering all parts of my lifedemotional, social, spiritual and financialdthe quality of my life has been: 0e10 ) were also separately analyzed with age and sex included in the models, and there were no significant effects of treatment in these domains. Responders (as defined by a drop in two or more points in the average BFI between day 0 and day 8; n ¼ 7) vs. nonresponders within the dexamphetamine arm were analyzed with respect to age, sex, ECOG, pulse, MABP, days in hospital, or time to death. None of these variables was demonstrated as a potential predictor of a patient response. There was a significant mean increase in pulse rate in the dexamphetamine arm (P ¼ 0.014), but MABP and ECOG did not significantly change from baseline in either arm BFI average score Group Placebo Treatment Day Fig. 2. Box plot of BFI average score over eight days of trial. Each box shows the spread of the middle 50% of scores, with the horizontal line in the box marking the median score and the vertical lines extending to the minimum and maximum scores. Differences between arms are not significant, apart from Day 2 (P ¼ 0.039). (P ¼ and 0.734, respectively). There were transient increases in dry mouth (P ¼ 0.011), insomnia (P ¼ 0.024), tremor (P ¼ 0.023), and anorexia (P ¼ 0.024) seen on days 6 and 8 in the dexamphetamine group. Four of 25 patients did not complete the study in the dexamphetamine group, whereas seven of 25 did not complete the study in the placebo group. These proportions are not significantly different (P ¼ 0.496). At the end of the trial, there was no significant difference in the ability of participants to guess which arm they were on (four guessed correctly in the dexamphetamine arm vs. 10 in the placebo arm; P ¼ 0.289), suggesting participants were well blinded. Discussion This randomized, double-blind, placebocontrolled study of the use of dexamphetamine targeted a typical palliative care service patient population: older, ECOG 3 (i.e., capable of only limited self-care, confined to bed or chair more than 50% of waking hours), with advanced cancer, taking a range of neurologically active medications, and facing death in the foreseeable future. The result that dexamphetamine 10 mg twice a day, although well tolerated, does not improve fatigue or quality of life in such patients, as measured by the selected instruments, differs from studies showing evidence of effect on fatigue in men with human immunodeficiency virus (HIV) 5,6 or weaker levels of evidence suggesting effect in hospice patients. 9,13 This study agrees with the null effect findings reported by Bruera et al. in their randomized controlled trial investigating the use of methylphenidate prescribed in an as required manner for cancer-related fatigue (average dose ¼ 11.5 mg/day). As with our study, both arms demonstrated an improvement

7 Vol. 37 No. 4 April 2009 Dexamphetamine for Fatigue in Advanced Cancer 619 Table 3 Absolute Differences in Mean BFI Scores Between the Dexamphetamine Group and the Placebo Group from Day 0 to Day 8 BFI Question Difference a Standard Error P- value b Difference a,c Standard Error c P-value b A B C D E F Average BFI¼ Brief Fatigue Inventory. a Mean reductions in BFI scores in the dexamphetamine group compared with the placebo group. A negative difference indicates an increase in the score. b From Wald tests in linear mixed models. c Adjusted for age, sex, pulse, and days in hospital. from baseline, suggesting some aspects of the research protocol to be therapeutic in their own right. The patients in Bruera et al. s study were of a younger group on average (55 vs. 73 years old for the treatment arms), and there is no information given as to how close to death these patients were. 14 The tools selected for this study are appropriate to make our results valid. The BFI was designed for cancer patients. It is internally reliable (Cronbach s coefficient a ¼ 0.96), and 98% of patients were able to be complete it. It has been tested against previously validated scales and is significantly correlated. 19 The MQOL average score Group Placebo Treatment Day Fig. 3. Box plot of average MQOL score over eight days of trial. Each box shows the spread of the middle 50% of scores, with the horizontal line in the box marking the median score and the vertical lines extending to the minimum and maximum scores. MQOL scale was developed for, and tested in, palliative care patients. It measures quality of life in four domains: physical and psychological symptoms, support and existential wellbeing. It has been demonstrated as internally consistent (a > 0.70) and acceptable to patients, including those two weeks close to death. 20 There are two other randomized controlled trials that may be extrapolated to the question of psychostimulants in cancer-related fatigue, and are, therefore, also relevant to this discussion. The first study was carried out by Breitbart et al., in which 144 ambulatory HIVpositive patients with fatigue were considered, and methylphenidate (mean of 51 mg/day) vs. 150 mg/day pemoline vs. placebo for six weeks were compared. As measured by the Piper Fatigue Scale, a positive response was observed in 41% (15 of 37) with methylphenidate; 36% (12 of 33) with pemoline; and 15% (six of 38) with placebo. There was also a better quality of life, and less depression and psychological distress in the psychostimulant arms. Response at one week was sustained for six weeks. 5 A second, smaller (n ¼ 23), two-week, double-blind, randomized, placebo-controlled study, also in HIV-positive men with depression and fatigue, by Wagner and Rabkin, demonstrated a significant improvement in mood, energy (using the Chalder Fatigue Scale) and quality of life with dexamphetamine therapy (eight of 11 vs. three of 12, P < 0.05). The mean dose of dexamphetamine was 22 mg/day. 6

8 620 Auret et al. Vol. 37 No. 4 April 2009 Both of these randomized controlled trials showed rapid response when psychostimulants were effective, demonstrating that our trial was not too short to provide a clinically useful answer. Our trial also was specifically designed to be short to minimize the effects of progressive illness and disease-related death during the study. Compared with this trial, Breitbart used a dose of methylphenidate that would be over double the equivalent dose of dexamphetamine, 5 but the Wagner study used a very similar dose. 6 Their results are in contrast with the lack of effect demonstrated by this study and Bruera et al. s 14 study, suggesting that the pathophysiology of fatigue in the advanced cancer setting may not be the same as that which occurs in HIV. There are also a number of open-label studies 8e11,13 and case series 12,23,24 of psychostimulants used for depression in hospice, hospitalized oncology or medically unwell patients that elucidate tolerability and dosing in cancer patients, and have led to suggestions that the medication may be useful for fatigue in these patient groups. Our study does not confirm these observations. It could be argued that the lack of effect seen in this study is because the dose of dexamphetamine was too low. However, it was sufficient to cause a physiological effect, with a demonstrated rise in pulse rate, and it follows the doses discussed in other reports. The specific exclusion of patients who were felt to have untreated depression by referring clinicians contrasts with the open-label trials 9e11,13 that discuss improvement of fatigue and may account for the contrasting lack of efficacy demonstrated in this trial in the hospice population. Doses used in these studies were similar to those in our study. Macleod et al. 8 reported the use of methylphenidate (mean dose, 17.7 mg/day) in 26 hospice inpatients with major depression treated for three weeks after response or to a maximum of six weeks. Therapeutic response in terms of depression was seen in 46%. Only 6% response was seen in those within six weeks of death, and this was termed vital exhaustion. Women were more likely to respond (50% vs. 12%). We, therefore, investigated the possible effects of female sex and time until death on response to treatment across BFI, average MQOL, and MQOL subscales, and they were not found to be significant. Our results show that it is not possible to extrapolate the demonstrated improvement from psychostimulants in one symptom (e.g., depression, opioid-induced somnolence) 7 to another superficially similar one (fatigue) in hospice patients. Our results also have not demonstrated any particular subgroup of hospice patients who would be more likely to respond than others. The transient response seen on day 2 of this study may be related to a short-lived effect of commencing psychostimulants, but as this improvement was not sustained or reflected in better quality of life or functional status, it is unlikely that the use of dexamphetamine for the day-to-day management of fatigued hospice patients is clinically useful. Like several of the other trials, 5e11,13,14 our results show that palliative care patients can tolerate the medication at the doses used, which may encourage other researchers who want to use the medication for other indications or try higher doses in this population. As the patients studied here were very unwell, with fatigue that was likely to be of multifactorial etiology, it is possible that further research on cancer-related fatigue in patients earlier in their cancer illness or those with treatmentinduced fatigue may respond differently. There has recently been a Phase II study of methylphenidate for fatigue in women with a recent past history of breast cancer that suggests that this may well be the case. 25 Given the transient early response, other investigators may want to study different dosing regimens (e.g., immediately before an important life event). In conclusion, these results suggest that dexamphetamine may not be superior to placebo for the management of cancer-related fatigue in palliative care patients. Acknowledgments The authors acknowledge the assistance in data collection of Mrs. Fiona Boyd and Mrs. Karen Collins. They also thank their colleagues and patients in the Palliative Care Unit at Hollywood Private Hospital for their support. Dr. Auret developed the research proposal and was chief investigator during the study period; he wrote the first draft of the article and

9 Vol. 37 No. 4 April 2009 Dexamphetamine for Fatigue in Advanced Cancer 621 interpreted the results. Mr. Bulsara contributed to study design, and Dr. Bremner performed the statistical analysis and wrote part of the Methods section. Professor Schug contributed toward proposal development and interpretation of results and edited the final manuscript. References 1. Ahlberg K, Ekman T, Gaston-Johansson F, Mock V. Assessment and management of cancerrelated fatigue in adults. Lancet 2003;9384: 640e Vogelzang NJ, Breitbart W, Cella D, et al. Patient, caregiver and oncologist perceptions of cancer related fatigue: results of a tripart assessment survey. The Fatigue Coalition. Semin Hematol 1997;34(3):4e Morrow GR, Abhay RS, Roscoe JA, Hickok JT, Mustian K. Management of cancer-related fatigue. Cancer Invest 2005;23:229e National Cancer Institute. Fatigue. Modified 17/10/07. Available at: Accessed November Breitbart W, Rosenfeld B, Kaim M, Funesti-Esch J. A randomized, double-blind, placebo-controlled trial of psychostimulants for the treatment of fatigue in ambulatory patients with human immunodeficiency virus disease. Arch Intern Med 2001;161(3):411e Wagner GJ, Rabkin R. Effects of dextroamphetamine on depression and fatigue in men with HIV: a double-blind, placebo-controlled trial. J Clin Psychiatry 2000;61(6):436e Wilwerding MB, Loprinzi CL, Mailliard JA, et al. A randomised crossover evaluation of methylphenidate in cancer patients receiving strong narcotics. Support Care Cancer 1995;3(2):135e Macleod AD. Methylphenidate in terminal depression. J Pain Symptom Manage 1998;16(3): 193e Sarhill N, Walsh D, Nelson KA, et al. Methylphenidate for fatigue in advanced cancer: a prospective open-label pilot study. Am J Hosp Palliat Care 2001; 18(3):187e Homsi J, Walsh D, Nelson KA, Legrand S, Davis M. Methylphenidate for depression in hospice practice: a case series. Am J Hosp Palliat Care 2000; 17(6):393e Homsi J, Nelson KA, Sarhill N, et al. A phase II study of methylphenidate for depression in advanced cancer. Am J Hosp Palliat Care 2001; 18(6):403e Olin J, Massand P. Psychostimulants for depression in hospitalized cancer patients. Psychosomatics 1996;37(1):57e Bruera E, Driver L, Barnes EA, et al. Patient-- controlled methylphenidate for the management of fatigue in patients with advanced cancer: a preliminary report. J Clin Oncol 2003;21(23):4439e Bruera E, Valero V, Driver L, et al. Patientcontrolled methylphenidate for cancer fatigue: a double-blind, randomized, placebo-controlled trial. J Clin Oncol 2006;24(13):2073e Rozans M, Dreisbach A, Lertora JJ, Kahn MJ. Palliative uses of methylphenidate in patients with cancer: a review. J Clin Oncol 2002;20(1):335e Dalal S, Melzack R. Potentiation of opioid analgesia by psychostimulant drugs: a review. J Pain Symptom Manage 1998;16(4):245e Homsi J, Walsh D, Nelson KA. Psychostimulants in supportive care. Support Care Cancer 2000;8: 385e End-of-Life Physician Education Resource Center. Psychostimulants in palliative care. Available at: Accessed May Mendoza TR, Wang XS, Cleeland CS, et al. The rapid assessment of fatigue severity in cancer patients: using the Brief Fatigue Inventory. Cancer 1999;85(5):1186e Cohen SR, Mount BM, Bruera E, et al. Validity of the McGill Quality of Life Questionnaire in the palliative care setting: a multi-centre Canadian study demonstrating the importance of the existential domain. Palliat Med 1997;11:3e Taylor AE, Olver IN, Sivanthan T, Chi M, Purnell C. Observer error in grading performance status in cancer patients. Support Care Cancer 1999;7:332e Schwartz AL, Meek PM, Nail LM, et al. Measurement of fatigue: determining minimally important clinical differences. J Clin Epidemiol 2002;55(3): 239e Massand P, Pickett P, Murray GB. Psychostimulants for secondary depression in medical illness. Psychosomatics 1991;32(2):203e Little KY. D-Amphetamine versus methylphenidate effects in depressed inpatients. J Clin Psychiatry 1993;54(9):349e Hanna A, Sledge G, Mayer M, et al. A phase II study of methylphenidate for the treatment of fatigue. Support Care Cancer 2006;14(3):210e215.