Efficacy of pharmacological treatments for fatigue associated with advanced disease

Fatigue in advanced disease such as cancer can be described as a subjective feeling of tiredness, weakness, or lack of energy. It is debilitating, impacting daily activity and quality of life, and continues to be a frequent challenge in palliative care. Underlying mechanisms are still not understood, which complicates its treatment. Although various pharmacological approaches have been examined, it has not been possible to recommend a specific treatment for fatigue based on scientific evidence. In this review, we aimed to identify substances that alleviate fatigue in advanced disease. We identified 22 studies for analysis, reporting fatigue treatment in 1632 participants, examining neurological diseases (multiple sclerosis (10), postpolio syndrome (1)), different types of cancer (6), HIV (4), and end-stage chronic lung disease (1). The identified therapeutic drugs can be considered as drugs interacting with the central nervous system, hormones, anti-inflammatory substances, or food supplement. Unfortunately, most studies included relatively small numbers of participants and research methodology was often heterogenous, resulting in weak and inconclusive data. Thus, based on the limited evidence, the authors still cannot recommend a specific drug for the treatment of fatigue in palliative care, although amantadine in multiple sclerosis and methylphenidate in cancer patients showed a superior effect. Interestingly, the literature search did not reflect the common clinical practice of using corticosteroids (drugs interacting with the immune system) for the treatment of fatigue in palliative care, since there was a lack of such studies. However, future research on psychostimulants and corticosteroids may be promising. In addition, consensus is needed concerning the measurement of fatigue in advanced disease (e.g. which scale should be used).

Authors' conclusions: 

Based on limited evidence, we cannot recommend a specific drug for treatment of fatigue in palliative care patients. Surprisingly, corticosteroids have not been a research focus for fatigue treatment, although these drugs are frequently used. Recent fatigue research seems to focus on modafinil, which may be beneficial although there is no evidence currently. Amantadine and methylphenidate should be further examined. Consensus regarding fatigue assessment in advanced disease is needed.

Read the full abstract...

In healthy individuals, fatigue is a protective response to physical or mental stress, often relieved by rest. By contrast, in palliative care patients fatigue can be severely debilitating, thereby impacting daily activity and quality of life, often with rest not counteracting fatigue. Fatigue frequently occurs in patients with advanced disease and modalities treating cancer often contribute or cause fatigue. Further complicating issues are its multidimensionality, subjective nature, and lack of a consensus definition of fatigue. Pathophysiology is not fully understood and evidence-based treatment approaches are needed.


The objective was to determine efficacy of pharmacological treatments on non-specific fatigue in palliative care. The focus was on patients at an advanced stage of disease, including cancer and other chronic diseases associated with fatigue, aiming to relieve fatigue. Studies aiming at curative treatment (e.g. surgical intervention for early breast cancer) were not included.

Search strategy: 

We searched EMBASE; Psych Lit, CENTRAL and MEDLINE to June 2009.

Selection criteria: 

We considered randomised controlled trials (RCTs) concerning adult palliative care with focus on pharmacological treatment of fatigue. The primary outcome had to be non-specific fatigue (or related terms such as asthenia).

Data collection and analysis: 

Results were screened and included if they met the selection criteria. If two or more studies were identified that investigated a specific drug in a population with the same disease, meta-analysis was conducted. In addition, comparison of type of drug investigated in a specific population as well as comparison of frequent adverse effects of fatigue treatment was done by creating overview tables.

Main results: 

More than 2000 publications were screened, and 22 met inclusion criteria. In total, data from 11 drugs and 1632 participants were analysed. Studies investigating amantadine, pemoline, and modafinil in participants with Multiple Sclerosis (MS)-associated fatigue and methylphenidate in patients suffering from advanced cancer and fatigue could be used for meta-analysis. Amantadine in MS and methylphenidate in cancer patients showed a superior effect. Most studies had low participant numbers and were heterogenous.