Department of Psychiatry, UCSD

Fifteen epidemiologic studies have associated hypnotic drugs with excess mortality, especially excess cancer deaths. Until recently, insufficient controlled trials were available to demonstrate whether hypnotics actually cause cancer. The U.S. Food and Drug Administration (FDA) Approval History and Documents were accessed for zaleplon, eszopiclone, and ramelteon. Since zolpidem was used as a comparison drug in zaleplon trials, some zolpidem data were also available. Incident cancers occurring during randomized hypnotics administration or placebo administration were tabulated. Combining controlled trials for the 4 drugs, there were 6190 participants given hypnotics and 2535 given placebo in parallel. Restudy of on-line FDA files led to somewhat altered counts of incident cancers, which are currently being checked against an FDA case review. FDA files revealed that all 4 of the new hypnotics were associated with cancers in rodents. Three had been shown to be clastogenic. Combining these new randomizing trials provided equivocally- significant data that new hypnotics cause cancer. Together with the epidemiologic data and laboratory studies, the available evidence signals that new hypnotics may increase cancer risk. Due to limitations in available data, further review of case files for these trials and confirmatory research is needed.