Opinion: Limited Efficacy of Methylphenidate in Alleviating Fatigue Among Patients With Advanced Cancer

Amanda Brink, DNP, APRN, FNP-BC, AOCNP

Fatigue is among the most pervasive symptoms patients with cancer face, affecting them at every stage of their journey, including survivorship. The National Comprehensive Cancer Network describes cancer-related fatigue as “a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with functioning.” Unlike fatigue in healthy individuals, cancer-related fatigue often persists despite rest, making it a particularly challenging burden.¹

For oncology nurses, responding to a patient’s report of fatigue can be challenging. When there’s an identifiable cause, like anemia that can be treated with a blood transfusion, it can feel satisfying to address the issue in a tangible way. However, fatigue often lingers despite these interventions, leaving both patients and providers searching for relief.

Common interventions for cancer-related fatigue include stimulants like methylphenidate, modafinil, corticosteroids, and antidepressants, as well as erythropoietin for anemia. Nonpharmacologic approaches often recommended are exercise, cognitive behavioral therapy, and mind-body wellness practices such as yoga.¹ Although these interventions are frequently recommended, not all are backed by strong evidence, and some, like exercise, may not be feasible or realistic for all patients with cancer.

Efficacy of Methylphenidate in Alleviating Fatigue

Stone et al. carried out a randomized, double-blind, placebo-controlled clinical trial in patients with advanced cancer and fatigue of greater than 3 out of 10 on a numerical rating scale. Patients were randomly assigned in a 1:1 fashion methylphenidate or placebo.²

Participants were given either 5 mg tablets of methylphenidate or a placebo. Initially, participants took 1 tablet twice daily, with principal investigators adjusting the doses weekly based on each participant's perceived efficacy over a 6-week period. The maximum dosage allowed was 4 tablets 3 times a day (60 mg daily). After reaching the week 6 dose, participants continued this regimen for an additional 2 weeks (maintenance phase). Following the week 8 assessment, all participants gradually tapered their doses and discontinued completely for 1 week before the trial concluded at week 10.

Between June 29, 2018, and April 27, 2023, 162 participants were randomly assigned to the methylphenidate group or placebo, with 159 included in the analyses (mean age 63.7 years; 73 men, 86 women). After 6 weeks of dose titration, the median daily dose was 6 tablets (methylphenidate 15 mg twice daily). Similar proportions of participants in both groups perceived their treatment as effective (methylphenidate: 37.5%; placebo: 34%). The primary outcome analysis revealed a nonsignificant reduction in fatigue in the intervention group based on the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) scores (FACIT-F coefficient: 1.97 [95% CI, –0.95 to 4.90]; P = .186). Sensitivity analysis showed consistent results (FACIT-F coefficient: 2.05 [95% CI, –0.85 to 4.95]). No significant improvements were noted among subgroups stratified by baseline characteristics.

Nominally significant increases in FACIT-F scores (lower fatigue) were observed at various study weeks, with an overall reduction in fatigue over the 10-week period (2.20 [95% CI, 0.39 to 4.01]). The only notable difference between groups was in the Hospital Anxiety and Depression Scale (HADS) depression score at week 6, where the methylphenidate group had a nominal reduction (difference: –1.35; 95% CI, –2.41 to –0.30).

Regarding safety, there were no patterns indicating increased adverse effects in the methylphenidate group. A total of 25 serious adverse events occurred in 20 participants receiving methylphenidate compared to 25 serious adverse events in 16 placebo participants. No serious adverse events were linked to methylphenidate. Overall, while nominal benefits were noted, particularly regarding fatigue and depression, the primary outcome did not show significant improvement in fatigue levels associated with methylphenidate compared to placebo.

Nursing Considerations

In my experience caring for patients with advanced cancer and fatigue, I have managed several individuals on methylphenidate for symptom relief. In some cases, these patients have reported significant improvements in their fatigue after starting this regimen, suggesting a real benefit. However, many do not experience the same level of improvement, indicating that methylphenidate may not be effective for all and could potentially be tapered off.

It's important to note that the American Society of Clinical Oncology recommends against routinely prescribing methylphenidate to patients undergoing cancer treatment due to concerns about long-term side effects, potential interactions with other medications, and the risk of addiction.³ For those who, along with their provider, decide to try methylphenidate, the dosing regimen used in this clinical trial may be beneficial in optimizing the dose to assess whether the medication provides a tangible benefit.

Nurses play a crucial role in managing cancer-related fatigue by regularly assessing and monitoring patients' fatigue levels using standardized scales like the FACIT-F. Recognizing that fatigue is subjective and can vary widely among patients, interventions should be tailored to individual needs and preferences.

When appropriate, nurses can encourage light physical activity to enhance energy levels and improve overall well-being, and collaborating with physical therapists may further support these efforts. Additionally, nurses should remain open to discussing complementary therapies, such as cognitive behavioral therapy and mindfulness-based programs, which have demonstrated effectiveness in improving cancer-related fatigue³ and enhancing patients' quality of life. By considering these factors, nurses can provide comprehensive care that addresses the complex nature of cancer-related fatigue.

References

1. Thong MSY, van Noorden CJF, Steindorf K, Arndt V. Cancer-Related Fatigue: Causes and Current Treatment Options [published correction appears in Curr Treat Options Oncol. 2022 Mar;23(3):450-451. doi: 10.1007/s11864-021-00916-2]. Curr Treat Options Oncol. 2020;21(2):17. Published 2020 Feb 5. doi:10.1007/s11864-020-0707-5
2. Stone PC, Minton O, Richardson A, et al. Methylphenidate Versus Placebo for Treating Fatigue in Patients With Advanced Cancer: Randomized, Double-Blind, Multicenter, Placebo-Controlled Trial. J Clin Oncol. 2024;42(20):2382-2392. doi:10.1200/JCO.23.02639
3. Bower JE, Lacchetti C, Alici Y, et al. Management of Fatigue in Adult Survivors of Cancer: ASCO-Society for Integrative Oncology Guideline Update. J Clin Oncol. 2024;42(20):2456-2487. doi:10.1200/JCO.24.00541