Abstract: For this update, we screened 1645 publications of which 45 met the inclusion criteria (20 additional studies to the previous reviews). In total, we analysed data from 18 drugs and 4696 participants. There was a very high degree of statistical and clinical heterogeneity in the trials and we discuss the reasons for this in the review. There were some sources of potential bias in the included studies, including a lack of description of the methods of blinding and allocation concealment, and the small size of the study populations. We included studies investigating pemoline and modafinil in participants with multiple sclerosis (MS)-associated fatigue and methylphenidate in patients suffering from advanced cancer and fatigue in meta-analysis. Treatment results pointed to weak and inconclusive evidence for the efficacy of amantadine, pemoline and modafinil in multiple sclerosis and for carnitine and donepezil in cancer-related fatigue. Methylphenidate and pemoline seem to be effective in patients with HIV, but this is based only on one study per intervention, with only a moderate number of participants in each study. Meta-analysis shows an estimated superior effect for methylphenidate in cancer-related fatigue (standardised mean difference (SMD) 0.49, 95% confidence interval (CI) 0.15 to 0.83). Therapeutic effects could not be described for dexamphetamine, paroxetine or testosterone. There were a variety of results for the secondary outcomes in some studies. Most studies had low participant numbers and were heterogeneous. In general, adverse reactions were mild and had little or no impact. Based on limited evidence, we cannot recommend a specific drug for the treatment of fatigue in palliative care patients. Fatigue research in palliative care seems to focus on modafinil and methylphenidate, which may be beneficial for the treatment of fatigue associated with palliative care although further research about their efficacy is needed. Dexamethasone, methylprednisolone, acetylsalicylic acid, armodafinil, amantadine and L-carnitine should be further examined. Consensus is needed regarding fatigue outcome parameters for clinical trials.

Plain-language summary: We searched the literature in April 2014 and found 45 randomised controlled trials for this update of the review. We analysed data from 4696 participants who received treatment for their fatigue. The trials dealt with neurological diseases (such as multiple sclerosis (753 participants), post-polio syndrome (58) and Parkinson's disease (19)), different types of cancer (3223), HIV/AIDS (514), end-stage renal disease (56), multi-type advanced disease in hospice patients (30), amyotrophic lateral sclerosis (28) and end-stage chronic lung disease (15). There was weak evidence for the efficacy of amantadine, pemoline and modafinil in reducing fatigue in patients with multiple sclerosis. There was also weak evidence for the efficacy of carnitine and donepezil for cancer-related fatigue. One small trial showed that people with HIV/AIDS and fatigue seemed to benefit from treatment with methylphenidate or pemoline. There was some low-quality evidence from small trials that methylphenidate, a stimulant drug that improves concentration, is effective for the management of cancer-related fatigue. There was no information about dexamphetamine, paroxetine or testosterone. Previous studies have shown that erythropoietin and darbepoetin, drugs that improve anaemia (a shortage of red cells or haemoglobin in the blood), are also effective for cancer-related fatigue. However, due to safety concerns and side effects shown by more recent studies, erythropoietin and darbepoetin should no longer be used. Therefore, we excluded these drugs from this review update. Overall, most side effects of the investigated drugs seemed to be mild. Based on limited evidence from small studies, the evidence does not support the use of a specific drug for the treatment of fatigue in palliative care. Future trials should measure fatigue in advanced disease using comparable and standardised measures.