Dec 6, 2002
By Todd Zwillich
A debate has begun among researchers about whether Pfizer's impotence drug Viagra (sildenafil) might be associated with instances of aggressive behavior and sexual violence.
One researcher has concluded that doctors should begin warning Viagra users about the possibility of psychological and emotional side effects. But other scientists, as well as officials at Pfizer, reject the claim as unsound.
In July of this year, Dr. Harold A. Milman, a toxicologist based in Rockville, Md., published a report in the Annals of Pharmacotherapy examining more than 12,000 reports of adverse events in men who took Viagra.
More than 270 of the reports, collected and archived by the US Food and Drug Administration (FDA), detailed psychological side effects, including dizziness, disorientation and amnesia. The drug was also listed as a suspect in 22 reports involving aggression, 13 involving rape, and six involving murder, according to Dr. Milman's article.
FDA officials said that they have no plans to change Viagra's labeling in light of Dr. Milman's report. But one top agency official said that the study was important to scientific debate about the drug.
"[The report] had a lot of information that hadn't been pulled together in one place before," Dr. Bernard Schwetz, FDA's senior advisor for science, said in an interview.
Dr. Milman acknowledged that the adverse-event reports are anecdotal evidence. "But it's clear that these men are behaving abnormally," he told Reuters Health.
The theory that the drug may cause aggression has formed the basis of the so-called "Viagra defense," a claim made by half a dozen defendants since 1998 that the drug caused them to commit violent crimes. Dr. Milman was hired as an expert witness in one such case.
The Viagra defense has not been successful so far, but an Israeli court did mention in a 1999 ruling against a rapist that the drug had played a role in the attack.
Viagra causes erections by working directly on the blood vessels of the penis, not through actions in the brain. Clinical studies in more than 8,000 men showed that the drug caused central nervous system effects in less than 2% of users, none of whom became violent or disoriented, according to Pfizer.
"I'm not saying Viagra causes anything, but there is evidence to suggest an association," said Dr. Milman, who noted that he is not an expert in Viagra's biological mechanisms. He spent 18 years as a senior advisor at the US Environmental Protection Agency and 10 as a cancer-drug expert at the National Institutes of Health.
Scientists don't consider adverse-event reports to be hard evidence of a causal link between a drug and an event. The reports don't always show which other drugs patients were taking or note the state of health they were in when taking the medication.
"You could take any product and connect individuals who use it with certain behaviors. I think it's a coincidence," said Geoff Cook, a Pfizer spokesman. "We don't think there is any credible medical evidence linking Viagra with violent or aggressive behavior."
Still, adverse-event reports are often used as a way to flag side effects in the general population that may have been missed during clinical studies. Effects that fail to show up in several thousand test subjects have a better chance of being noticed when millions of people have taken a drug.
Dr. Milman cited research in his report showing that sildenafil can enter the brain and that the drug could affect biological pathways in parts of the brain controlling sexual responses and aggression.
In interviews, other scientists rejected a link to aggressive behavior. "To me, it is an extremely remote hypothesis," said Dr. Raymond C. Rosen, a professor of psychiatry and medicine at the University of Medicine and Dentistry of New Jersey.
Dr. Rosen and Northwestern University toxicologist Dr. Kevin E. McKenna wrote to the Annals of Pharmacotherapy this month challenging Dr. Milman's article.
Dr. Rosen told Reuters Health that there is no clinical evidence in humans that the biological pathways affected by Viagra can cause aggression or violence. He said that no patient he has ever evaluated has shown such symptoms.
"Changing anything clinically or legally because of this is stretching the point totally beyond credibility," said Dr. Rosen, who is recognized as a leading expert in sexual dysfunction. He noted that he has served in the past as a paid consultant for Pfizer.
Dr. McKenna acknowledged that sildenafil could affect parts of the brain that control sexual behavior, including the hypothalamus and parts of the medulla. But studies in mice show that the drug would probably make aggression less likely, not more likely, he said.
Dr. Milman said his paper was intended to encourage more scientists to look directly at whether Viagra can cause problems. "There are a lot of question marks," he said.
On that point, Dr. McKenna agreed. "I still believe behavioral effects
of sildenafil should be studied more closely," he said.
© 2002 Reuters Ltd