Gabapentin reduces hot flashes in men receiving androgen deprivation therapy

North Central Cancer Treatment Group researchers based at Mayo Clinic in Rochester, Minn., have discovered that low doses of a drug used to prevent epileptic seizures and to treat nerve pain caused by shingles substantially reduces hot flashes in patients who are undergoing anti-hormonal treatment, or androgen-deprivation therapy, for prostate cancer.

In presenting results of a 223-patient, placebo-controlled Phase III clinical trial at the 2007 annual meeting of the American Society of Clinical Oncology (http://www.asco.org/portal/site/ASCO), Mayo Clinic investigators report that the drug gabapentin reduced the frequency and the intensity of hot flashes by up to 46 percent in men receiving androgen deprivation therapy. The men who received gabapentin reported fewer side effects than those receiving a placebo tablet, the researchers say.

Many men undergoing androgen deprivation therapy suffer debilitating hot flashes, but until now the only therapeutic agents proven to provide relief are androgen-originating hormones, some of which can actually fuel their cancer. So any symptom relief these men get comes with worry about new cancer growth.

"To my knowledge, this is the first nonhormonal treatment of hot flashes in men, where results from a placebo-controlled trial are positive enough to support that a nonhormonal medication can be used to help some of our patients," says the study's lead investigator, Mayo Clinic oncologist Charles Loprinzi, M.D.

He adds that hot flashes in patients receiving androgen-deprivation therapy can be quite severe. Overall, between 60 percent and 80 percent of these patients suffer from hot flashes, Dr. Loprinzi says, and in this clinical trial, about 40 percent of participants had hot flashes for longer than nine months and a similar percentage reported having at least 10 hot flashes a day.

Because gabapentin works on the central nervous system, its function may be similar to some antidepressants that are prescribed to reduce hot flashes in women entering menopause, he says. "But we don't understand exactly how any of these drugs work to reduce hot flashes," says Dr. Loprinzi.

Gabapentin (trade name Neurontin) was approved by the Food and Drug Administration to treat epileptic seizures in 1994, and pain from shingles in 2002.

The ability of gabapentin to reduce hot flashes was first detected when it was being used for other reasons. Since then, several clinical trials testing gabapentin in women found that a dose of about 900 milligrams a day decreased hot flashes by about half -- the same dose and a similar degree of effectiveness discovered in Dr. Loprinzi's clinical trial.

Men participating in this study had a mean age of 70, and suffered with hot flashes occurring at least 14 times a week. They were randomized into four groups. Over 28 days, one group was given placebo pills, another received a 300 mg/d (milligrams a day) tablet of gabapentin, a third group received an escalating dose of gabapentin that reached 600 mg/d, and the fourth group's dose reached 900 mg/d. The study was blinded: physicians and patients did not know which pills contained the active agent.

Using a scale from 1 to 4, patients recorded the daily number of mild, moderate, severe, and very severe hot flashes. Researchers found that median hot flash frequency and score decreased between 22 percent to 27 percent in the placebo group, 23 percent to 30 percent in the 300 mg/d group, 32 percent to 34 percent in the 600 mg/d group, and 44 percent to 46 percent in the 900 mg/d gabapentin arm.

The highest dose used in the study was less than one-third of the dose that can be used to treat epileptic seizures, Dr. Loprinzi says, leaving room for possible improvements in effect against hot flashes with an increase in dosage. His research team may explore that idea in the future.

Women can develop hot flashes during menopause because of the suddenness with which their ovaries stop producing estrogen. Similarly, a sudden loss of testosterone in men, from androgen deprivation therapy, can also result in hot flashes. (Testosterone is part of a class of compounds known as androgens, which are largely steroid hormones. This class of compounds also includes the precursors to estrogen.) In general, men don't develop hot flashes because their production of steroid hormones gradually tapers off as they age, Dr. Loprinzi says. But the dramatic decrease in testosterone with prostate cancer treatment can cause hot flashes.

The moderate ability of gabapentin to reduce hot flashes is less than hormonal therapies provide, he adds. But many prostate cancer patients don't use hormonal treatments because of fear that their hormone-sensitive cancer will recur, he says, or because some therapies, such as estrogen, produce unwanted side effects, such as growth of breast tissue.

"This [gabapentin] provides an immediate clinical option that has not been previously available for treatment of hot flash side effects, and it is a welcome one," Dr. Loprinzi says.