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Patient-Controlled Methylphenidate for the Management of Fatigue in Patients With Advanced Cancer: A Preliminary Report

Eduardo Bruera, Larry Driver, Elizabeth A. Barnes, Jie Willey, Loren Shen, J. Lynn Palmer, Carmelita Escalante

From the Departments of Palliative Care and Rehabilitation Medicine, Anesthesiology, General Internal Medicine, and General Internal Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and the Toronto-Sunnybrook Regional Cancer Center, Toronto, Canada.

Address reprint requests to Eduardo Bruera, MD, Department of Palliative Care and Rehabilitation Medicine, The University of Texas M.D. Anderson Cancer Center, Unit 8, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: ebruera{at}mdanderson.org.

	ABSTRACT

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Purpose: To assess the effects of patient-controlled methylphenidate for cancer-related fatigue.

Patients and Methods: In this prospective open study, 31 patients with advanced cancer and fatigue who scored 4 on a scale of 0 to 10 received methylphenidate 5 mg by mouth every 2 hours as needed for 7 days (maximum, 20 mg/d). Multiple symptoms were assessed daily; the primary end point, fatigue, was measured using the 0 to 10 scale, and the Functional Assessment for Chronic Illness Therapy–Fatigue (FACIT-F) was performed at baseline, day 7, and day 28.

Results: The following mean (± standard deviation) scores for 30 assessable patients improved significantly between baseline and day 7: fatigue (0 to 10 scale), 7.2 ± 1.6 v 3.0 ± 1.9 (P < .001); overall well-being (0 to 10 scale), 4.5 ± 2.2 v 2.8 ± 2.1 (P < .001); fatigue (FACIT-F) subscore, 17.5 ± 11.3 v 34.7 ± 10.0 (P < .001); functional well-being, 14.4 ± 5.9 v 18.3 ± 6.6 (P < .001); and physical well-being, 13.5 ± 6.4 v 21.4 ± 5.0 (P < .001). Anxiety, appetite, pain, nausea, depression, and drowsiness all improved significantly (P < .05). All patients took afternoon or evening doses, and 28 patients (93%) took three or more doses daily. All patients chose to continue taking methylphenidate after 7 days of treatment. No serious side effects were reported.

Conclusion: These preliminary results suggest that patient-controlled methylphenidate administration rapidly improved fatigue and other symptoms. Randomized controlled trials are justified.

	INTRODUCTION

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FATIGUE IS one of the most common and devastating symptoms associated with advanced cancer. Its frequency ranges from 60% to 90%, depending on the diagnostic criteria used.¹ Cancer-related fatigue is defined as an unusual, persistent, subjective sense of tiredness that is related to cancer or cancer treatment and interferes with usual functioning.² Cancer fatigue is a multidimensional syndrome.³ Severe cancer-related fatigue has a number of major contributing factors, including cancer cachexia, depression, pain, treatment with opioid and other medications, anemia, different antineoplastic treatments, and deconditioning.³ Some contributing factors, such as anemia and medications, can occasionally be corrected, but most factors that contribute to cancer-related fatigue have no specific treatments. Medications capable of improving the subjective symptom of fatigue might be useful, but none are currently available.

Methylphenidate is a mild psychostimulant that has been used for the management of attention deficient and hyperactivity disorder⁴ and for depression, particularly in geriatric patients.⁵ In patients with cancer, methylphenidate has been used successfully to manage opioid-induced sedation,^6,7 cognitive failure associated with brain tumors,⁸ and depression.^4,9

In one randomized controlled trial, methylphenidate significantly improved fatigue in ambulatory patients with HIV, compared with placebo.¹⁰ In another study, methylphenidate improved interferon-induced fatigue in 12 ambulatory patients with melanoma.¹¹ A pilot study of 14 assessable patients with advanced cancer found that methylphenidate at a dose of 5 to 10 mg/d significantly improved fatigue after 7 days.¹²

No studies of methylphenidate in patients with fatigue associated with advanced cancer have evaluated fatigue using validated instruments and global assessments of efficacy. In addition, studies of methylphenidate for the management of fatigue and other symptoms have consistently used a fixed-dose regimen, usually limited to administration in the morning and at lunchtime. In our experience, patients present with fatigue at variable times of the day. Methylphenidate has the advantage of a short half-life and thus might be able to provide clinical improvement in fatigue during the second half of the day without causing significant anxiety or residual insomnia.

The purpose of this preliminary open study was to establish the efficacy and safety of patient-controlled self-administration of methylphenidate for the management of cancer-related fatigue.

	PATIENTS AND METHODS

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Patients
Patients seen in the Palliative Care Outpatient Clinic and the Pain Clinic at our institution were approached for participation in this study. Inclusion criteria were as follows: presence of fatigue scored as 4 on a scale of 0 to 10 (0 = no fatigue, 10 = worst possible fatigue) during the last 24 hours for a minimum of 4 days; absence of significant dementia and delirium defined as a score of 24 (highest score, 30) in the Mini-Mental State Exam;¹³ no major (> 25%) dose change of opioids for at least 48 hours before study entry if the patient was taking opioids; hemoglobin level of at least 10 within 2 weeks of enrollment of the study; no major contraindications to methylphenidate, including hypersensitivity; no history of significant arterial hypertension or cardiac disease; no presence of glaucoma, severe anxiety disorders, or substance abuse; and no administration of monoamine oxidase inhibitors, tricyclic antidepressants, clonidine, psychostimulants, concurrent steroids, or other medications specifically for fatigue. Exclusion criteria were a history of seizures or uncontrolled CNS disease, and significant hepatic or renal dysfunction. The University of Texas M.D. Anderson Cancer Center Institutional Review Board approved the protocol, and all patients provided written informed consent.

Methods
Patients who agreed to participate in the study were given a 7-day supply of 5-mg methylphenidate tablets. They were directed to use one 5-mg tablet as needed every 2 hours for patient-described significant fatigue. Patients were allowed to take a maximum of four tablets per day. Patients were asked to record in a daily diary the time methylphenidate was taken and the fatigue rating (on the 0 to 10 numerical scale) before taking methylphenidate and 2 hours later. Patients were advised that taking methylphenidate within 2 hours of bedtime might cause insomnia.

Patients were contacted daily by a research nurse by telephone (or in person for inpatients). The nurse ensured that the daily diaries were being completed and asked questions related to side effects. To assess the diurnal variation of fatigue, patients were asked to rate the intensity of their fatigue four times a day (before meals and in the evening), using a numerical scale of 0 to 10, and were asked about any triggers that exacerbated fatigue. Patients were also asked to rate their drowsiness, ability to sleep at night, pain, depression, and nervousness, using a numerical scale of 0 to 10.

Patients were asked to return to the clinic or were contacted by telephone on day 8 for a final evaluation. A pill count was performed at that evaluation to verify the diaries. Patients were off study on day 8 after the final assessment was completed. At that point, patients were given the option of continuing methylphenidate for the management of their fatigue or discontinuing the medication. Patients who elected to continue methylphenidate were provided with a free drug supply for 4 weeks. Additional follow-up took place either with the patients’ primary physicians or in the Palliative Care Clinic. A final week-4 assessment was conducted in person or by telephone by a research nurse.

Assessments
The following demographic information was collected from the patient charts: age, sex, primary disease, cancer treatment during the last year, and concurrent medications.

The primary end point, fatigue, was measured on a 0 to 10 point scale. Fatigue was also assessed using the Functional Assessment for Chronic Illness Therapy–Fatigue (FACIT-F) measurement system.¹⁴ Multiple symptoms were assessed using Edmonton Symptom Assessment Score (ESAS).¹⁵ These tools have been validated in cancer patients.^14,15 The FACIT-F and ESAS were administered at baseline, on day 8, and at the end of 4 weeks of follow-up.

Patients’ ability to sleep at night was assessed using a 0 to 10 numerical scale to rate difficulty falling asleep, restfulness in the morning, and overall problems with sleep. The overall importance of lack of sleep was rated on a scale of 1 (not important) to 7 (of great importance). These tools have been used before in the assessment of insomnia.¹⁶ The assessments were administered at baseline, on day 8, and at the end of 4 weeks of follow-up.

A side effect recording sheet was administered daily and at the end of 4 weeks. It included all major known side effects, such as slurred speech, restlessness, involuntary movements, behavioral changes, dizziness, insomnia, anorexia, skin rash, vertigo, and tachycardia.

Fatigue, pain, drowsiness, sleep at night, depression, and nervousness were assessed daily using 0 to 10 numerical scale. National Cancer Institute toxicity criteria were used for scoring the severity of detected side effects.

On day 8, patients were asked to rate the overall usefulness of the medication on a scale of 1 (not beneficial) to 7 (greatly beneficial). In addition, they were asked to choose from the following statements: "I felt better," " I felt no different," and "I felt worse." Finally, patients were asked to reply yes or no to the statement, "I wish to continue this medication."

Statistical Analysis
Our primary end point was defined as fatigue measured on a 10-point scale. We planned to enroll 30 patients onto this study. A previous study by our group involving 28 patients with chronic pain caused by cancer who were treated with methylphenidate found a 26-point improvement (on a 100-point scale) in subjective activity levels after 3 days.⁶ Standard deviations (SDs) associated with the premedication and postmedication scores were no greater than 29 (on a 100-point scale). With the assumption that a change in fatigue measurement from baseline to day 3 was comparable with a change after 2 hours, and assuming an SD of 3 (for our 10-point scale), entering 30 patients onto the study allowed us to declare differences as large as or larger than 2 points between scores before and after taking methylphenidate with a two-sided significance level of 0.01% and 80% power. A difference of 2 points was considered a clinical success based on the generally accepted clinically meaningful difference of one-half SD change for symptom assessment and quality-of-life measures. Given that we used similar tools in a similar population and observed SDs of 29 or less using a 100-point scale, this would be equivalent to an SD of 2.9 on a 10-point scale. We conservatively chose a value of 2 rather than a value of 1.45 in estimation of effect size of one-half SD for sample size calculations.

Descriptive statistics are presented and scores are reported as means ± SDs. We compared variables at baseline versus days 7 and 28 using a paired t test if the data were normally distributed and used a sign test otherwise. We also compared the daily timing of fatigue scores separately at days 1 and 7 using an analysis of variance and a test for linear trend. Because many statistical tests were performed, we consider that statistical significance has been shown by P value .005 instead of the usual value of .05.

	RESULTS

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A total of 40 patients were approached to participate in this study; four patients refused, and five patients were not eligible. Thirty-one patients provided written, informed consent and were admitted onto the study, but one patient was not assessable because the patient had to undergo a surgical procedure during the first week of treatment.

The characteristics of the remaining 30 assessable patients are summarized in Table 1. All patients had hemoglobin levels of 10 within 2 weeks of admission to the study. All patients had normal thyroid function, as defined by normal thyroid stimulating hormone values.

Figure 1 shows that the intensity of fatigue decreased progressively from breakfast to evening both on days 1 and 7. We found that there were significant differences in the reporting of fatigue at different times of the day for both days 1 and 7 (P = .0023 and P = .0008, respectively), and that there was a significant linear trend for fatigue to decrease over time for both days (P = .0003 and P < .0001, respectively).

View larger version (32K): [in this window] [in a new window]   Fig 1. Mean intensity of fatigue throughout the day during days 1 and 7 of methylphenidate treatment.

The overall mean intensity of fatigue (0 to 10 scale) before and after methylphenidate was 5.1 ± 1.7 and 3.2 ± 2.1, respectively (P < .001). The mean intensity of fatigue was 5.3 ± 2.0 before and 3.2 ± 2.1 after methylphenidate when the drug was taken during the morning (before and including 1:00 PM; P < .001) and 4.8 ± 1.7 before and 3.1 ± 2.3 after methylphenidate when the drug was taken in the afternoon (after 1:00 PM; P < .001).

Twenty eight of 30 patients (93%) had improved fatigue (defined as a decrease of > 2 on a 0 to 10 scale) by day 7. Twenty-eight patients (93%) took three or more methylphenidate tablets daily, and all 30 patients (100%) took afternoon or evening doses. Overall, the day 7 assessment (better, same, or worse) was better in all 30 patients (100%; P < .0001) who received the drug, compared with chance alone. The overall importance of the difference was 5 or greater (1 = no benefit, 7 = greatly important) in 20 of 30 patients (67%). All patients chose to continue methylphenidate for a period of 4 weeks.

To assess the side effects, we compared the baseline side-effect scores with the scores during the first 7 days of therapy. Patients were considered to have one or more side effects if the reports of any side effects increased from baseline. Two patients reported increased restlessness, one patient reported increased dizziness, two patients reported increased anorexia, one patient reported a 2-day self-resolved skin rash, one patient reported intermittent vertigo for 2 days, and one patient reported self-resolved tachycardia for 3 days.

Nine patients were not available for follow-up at day 28: two had died as a result of progressive disease, two were terminally ill and unable to answer questions, two were lost to follow-up after returning back to their communities, two did not take additional medication, and one refused to answer, owing to billing disagreements. In none of the cases was methylphenidate toxicity believed to contribute to the patients dropping out of the study, either during the first week or during the 4-week follow-up phase.

	DISCUSSION

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Our results showed that patient-controlled methylphenidate improved fatigue, a number of other symptoms, and overall quality of life; patients also chose to continue treatment for an additional 4 weeks. Our results confirm results from previous studies involving patients with HIV,¹⁰ patients receiving interferon for melanoma,¹¹ and patients undergoing palliative care.¹²

In our patient population, fatigue was the most severe symptom on entry onto the study (Table 2). Although previous studies have shown significant improvement in symptoms such as depression,^4,9 the observed improvement in fatigue was probably not a function solely of depression because on inception, our patient population complained of a much higher baseline intensity of fatigue than other symptoms (Table 2). In the future, randomized controlled trials will need to stratify patients according to the presence or absence of depression to better characterize response to methylphenidate independently of its demonstrated mood effects.

Our study has a number of limitations. Fatigue is a subjective symptom and as such can be appropriately tested only in double-blind trials. Our study cannot rule out the possibility of a strong placebo effect; the nonspecificity of the benefits might increase the possibility that the effects are due partly to placebo effect. However, the robust response for an observation period of 1 week followed by 4 weeks of treatment, with maintained overall symptom improvement and satisfaction, suggests that these results were genuine symptomatic effects. Finally, our study was not able to establish whether methylphenidate affected fatigue directly or indirectly by influencing other symptoms, such as depression, drowsiness, or anxiety.

Our findings (Fig 1) suggest that patients experienced consistent improvement in their fatigue level throughout the day. Fatigue intensity before breakfast reflects fatigue before the first methylphenidate dose of the day. These findings suggest that methylphenidate had a cumulative effect during the day. We cannot exclude the possibility of circadian variation in the severity of fatigue in these patients because of the absence of a placebo control.

Methylphenidate had a remarkable effect on the overall quality-of-life scores. Other drugs that affect fatigue, such as erythropoietin, also affect quality-of-life scores.¹⁷ However, because methylphenidate appears to affect multiple symptoms, it is not possible with this small number of patients to establish the relationship between fatigue and overall quality-of-life improvement. Randomized controlled trials will be required to better characterize this response.

Methylphenidate is a psychostimulant with potential negative effects on appetite, anxiety, and insomnia. Our results show that this drug did not worsen but in fact significantly improved these three symptoms (Table 2). Our results suggest that randomized controlled trials can include patients with these symptoms. Given that methylphenidate can significantly improve arousal,^6,7 it is likely that the improvement in insomnia is related to a substantial decrease in the number of micronaps and to restoration of better circadian function. This hypothesis should be studied in future prospective studies of insomnia.

All 30 patients chose to continue taking methylphenidate, and in all cases, the patients took the drug during the afternoon or evening. Our results suggest that patients were able to appropriately titrate their methylphenidate to their symptom distress. This modality of administration of methylphenidate has been used successfully in a palliative care program in Denmark (L. Pedersen, personal communication, 1998). Our results suggest that methylphenidate can be used safely in doses that are higher than the usual starting doses of 2.5 to 5.0 mg bid, and that afternoon or evening doses of immediate-release methylphenidate do not detrimentally affect anxiety or insomnia. Randomized controlled trials should be conducted on this modality of administration for the management of cancer-related fatigue. Given that there currently are no effective symptomatic treatments for fatigue,^3,18 these randomized controlled trials comparing methylphenidate with placebo can be ethically justified.

The majority of patients enrolled onto our study continued to use methylphenidate for up to 4 weeks. These patients continued to self-administer their methylphenidate up to a maximum of four doses per day, with no significant dose increase and continued symptomatic response. This appears to be different from the use of methylphenidate for opioid-induced sedation, for which patients frequently develop a substantial tolerance.^6,7 This finding suggests that methylphenidate may work against fatigue by a mechanism of action that is different from simple arousal and may be more like the mechanism in patients with attention deficit (and hyperactivity) disorder, in which the development of tolerance is rare.¹⁹

We conclude that in this pilot study, methylphenidate appeared to have a significant and sustained effect on fatigue and quality of life, and that double-blind placebo-controlled trials are justified.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	NOTES

 
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 2, 2003.

	REFERENCES

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2. Mock V, Atkinson A, Barsevick A, et al: NCCN practice guidelines for cancer-related fatigue. Oncology 14:151–161, 2000[Medline]

3. Barnes EA, Bruera E: Fatigue in patients with advanced cancer: A review. Int J Gynecol Cancer 12:424–428, 2002[CrossRef][Medline]

4. Rozans M, Dreisbach A, Lertora JJ, et al: Palliative uses of methylphenidate in patients with cancer: A review. J Clin Oncol 20:335–339, 2002[Abstract/Free Full Text]

5. Homsi J, Walsh D, Delson KA: Psychostimulants in supportive care. Support Care Cancer 8:385–397, 2000[CrossRef][Medline]

6. Bruera E, Brenneis C, Chadwick S, et al: Methylphenidate associated with narcotics for the treatment of cancer pain. Cancer Treat Rep 71:67–70, 1987[Medline]

7. Bruera E, Miller MJ, MacMillan K, et al: Neuropsychological effect of methylphenidate in patients receiving a continuous infusion of narcotics for cancer pain. Pain 48:163–166, 1992[CrossRef][Medline]

8. Meyers CA, Weitzner MA, Valentine AD, et al: Methylphenidate therapy improves cognition, mood and function of brain tumor patients. J Clin Oncol 16:2522–2527, 1998[Abstract]

9. Homsi J, Nelson KA, Sarhill N, et al: A phase II study of methylphenidate for depression in advanced cancer. Am J Hosp Palliat Care 18:403–407, 2001[Abstract/Free Full Text]

10. Breitbart W, Rosenfeld B, Kaim M, et al: 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 161:411–420, 2001[Abstract/Free Full Text]

11. Schwartz AL, Thompson JA, Masood N: Interferon-induced fatigue in patients with melanoma: A pilot study of exercise and methylphenidate. Oncol Nurs Forum 29:1045, 2002 (abstr)

12. Sugawara Y, Akechi T, Shima Y, et al: Efficacy of methylphenidate for fatigue in advanced cancer patients: A preliminary study. Palliat Med 16:261–263, 2002[Free Full Text]

13. Folstein MF, Folstein S, McHugh PR: "Mini-Mental State": A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198, 1975[CrossRef][Medline]

14. Cella DF, Tulsky DS, Gray G, et al: The functional assessment of cancer therapy scale: Development and validation of the general measure. J Clin Oncol 11:570–579, 1993[Abstract/Free Full Text]

15. Chang VT, Hwang SS, Feuerman M: Validation of the Edmonton symptom assessment scale. Cancer 88:2164–2171, 2000[CrossRef][Medline]

16. Bruera E, Fainsinger RL, Schoeller T, et al: Rapid discontinuation of hypnotics in terminal cancer patients: A prospective study. Ann Oncol 7:855–856, 1996[Abstract/Free Full Text]

17. Turner R, Anglin P, Burkes R, et al: Epoetin alfa in cancer patients: Evidence-based guideline. J Pain Symptom Manage 22:954–965, 2001[CrossRef][Medline]

18. Bruera E, Ersnt S, Hagen N, et al: Effectiveness of megestrol acetate in patients with advanced cancer: A randomized, double-blind, crossover study. Cancer Prev Control 2:74–78, 1998[Medline]

19. Thompson S, Leigh L, Christensen R, et al: Immediate neurocognitive effects of methylphenidate on learning-impaired survivors of childhood cancer. J Clin Oncol 19:1802–1808, 2001[Abstract/Free Full Text]

Submitted June 30, 2003; accepted September 8, 2003.

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