Tuesday, May 2, 2006
The Journal of Clincal Oncology has published a randomized, double-blinded, placebo-controlled trial of methylphenidate for cancer related fatigue from Eduardo Bruera and colleagues at MD Anderson. It was, unfortunately, a wash.
About 100 cancer patients were randomly assigned to methylphenidate (5mg tabs, taken q2hours per patients' wishes, up to 20mg a day) or identical placebo. Per the authors, this provided adequate power to detect a difference between the groups, based on the findings from a preliminary study they did several years ago. There is no mention of opioid use in the article--it wasn't an exclusion criterion--so presumably many of these patients were on opioids and had some amount of opioid-associated fatigue as well. The primary outcome was fatigue at day 8 based on the FACIT-F subscale of the FACIT quality of life scale. After 8 days patients could continue on open-label methylphenidate and data was collected for a total of 36 days. During the 8 day study period patients received daily phone-calls from a nurse. Patients took an average of ~10mg of methylphenidate a day.
The good news: methylphenidate was well-tolerated and didn't cause sleep disturbance or a higher rate of drop-out. Patients on methylphenidate had a significant improvment in fatigue at day 8 (and 36 for those who stayed on it). The magnitude of the improvement was approximately 3 on a 0-10 scale (baseline fatigue was ~7/10 in both groups...10 being bad).
The bad news: placebo was equally effective at day 8--patients had the same amount of improvement.
What does this mean?
It could mean 1) methylphenidate truly is no better than placebo for cancer associated fatigue, 2) the daily nurse calls were such a powerful intervention for fatigue that it overshadowed any effect from the methylphenidate, 3) one actually needs a longer period of follow-up to identify a difference (this counters clinical experience in which methylphenidate begins to work quite quickly), or 4) effective doses are higher than previously suspected. Another question is could the problem be one of patient selection--in this study the patients were a relatively unselected group of people at MD Anderson with cancer, fatigue, and without a few exlusion criteria (no severe anemia, anxiety disorders, etc.). Maybe responders to methylphenidate have occult depression and are responding to the anti-depressive effects of the drug. Anyway this is beginning to sound like the desperate thoughts of someone who has felt methylphenidate has helped many of his patients, which it did, but perhaps only through the gentle sugar-pill kiss of the placebo effect. The authors acknowledge many of these interpretations and one hopes they continue their research to address these. If not, on to modafinil, which I have yet to use.
Pain Medicine has an interesting article about the history of using electrical stimulation to modulate chronic pain. It is really, really fascinating (the Romans used contact with the torpedo fish for gout pain as early as 15 C.E.) and a recommended read.