The female overdose problem is one of the few health issues the CDC is working on that are clearly getting worse, said Dr Thomas Frieden, director of the Centers for Disease Control and Prevention, which compiled the data.
"Mothers, wives, sisters and daughters are dying at rates that we have never seen before," he said.
For many decades, the overwhelming majority of US overdose deaths were men killed by heroin or cocaine. But by 2010, 40 per cent were women, most of them middle-aged women who took prescription painkillers.
The CDC found that the number and rate of female prescription drug overdose deaths increased about fivefold 1999 to 2010. Among men, overdose deaths rose about 3½ times.
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Overall, more men still die from overdoses of painkillers and other drugs; there were about 23,000 such deaths in 2010, compared with about 15,300 for women.
Men tend to take more risks with drugs than women, and often are more prone to the kind of workplace injuries that lead to their being prescribed painkillers in the first place, experts say.
Studies suggest that women are more likely to have chronic pain, to be prescribed higher doses, and to use pain drugs longer than men.
Some research suggests women may be more likely than men to "doctor shop" and get pain pills from several physicians, CDC officials said.
But many doctors may not recognize these facts about women, said John Eadie, director of a Brandeis University program that tracks prescription-drug monitoring efforts across the United States.