COVER STORY

IMPROVING INTIMACY

More drugs that rival Viagra are coming to treat the unspoken condition of sexual dysfunction

Getting people to talk about their sexual problems is not easy, to say the least. This may be why so few people seek treatment. That's a shame, considering there are tens of millions of Americans needlessly grappling with some form of sexual dysfunction. Effective treatments for these problems are currently available, and many more are on the way.

The numbers

In 1999, the Journal of the American Medical Association published the results of a survey on sexual dysfunction. Among respondents aged 18 to 59, 43% of the women and 31% of the men reported having at least one form of sexual dysfunction. The biggest problem in women was low sexual desire (22%), followed by problems with arousal (14%) and painful intercourse (7%). Premature ejaculation was the most prevalent problem for men (21%), while erectile dysfunction (ED) and low desire were reported with equal frequency (5% each).

The American Foundation for Urologic Disease (AFUD) estimated 20 million men in the United States suffer from ED, while only 5%-10% of these men seek treatment. "It's still a very difficult topic for men to discuss," said Jody Hammerman, a spokeswoman for AFUD.

Erectile dysfunction

In 1992, a National Institutes of Health conference produced a consensus statement on impotence. It was at this conference that renaming the disorder as "erectile dysfunction" was suggested. As for treatment, participants agreed that pinpointing the causes of ED is the first step. From there, treatment can be tailored to each patient by targeting the disorder's root. For example, untreated diabetes or hypertension, psychological problems, and polypharmacy can all be addressed to help correct ED.

If erectile problems remain, further treatment can begin. In 1992, treatment options were a bit more limited, and long-term efficacy was reported to be low, while noncompliance was high. Although a few oral and topical medications had been used to treat ED (e.g., yohimbine), most of them had not been approved by the Food & Drug Administration for this purpose, and the consensus panel discouraged their use.

The panel concluded that, aside from psychotherapy, there were only three types of effective treatment available: intracavernosal injections, vacuum devices, and surgery.

Intracavernosal injection therapy has been quite effective but not overly popular. It involves injecting one or more vasodilators, such as papaverine, prostaglandin E₁, or phentolamine, into the corpora of the penis. Side effects include priapism, hypotension, pain, and fibrosis around the injection site.

Vacuum devices have also been effective for some men and with a lower incidence of side effects. However, patients complained about their interfering with spontaneity. Surgical options include local vascular surgery and penile prostheses. Risk of infection, failure of the devices, and decreased efficacy over time have limited the use of these procedures.

Since the NIH conference, some advances have been made. In 1997, a new drug company, VIVUS, began marketing a formulation of alprostadil (MUSE) for ED. The drug is contained in a urethral suppository inserted with a prefilled applicator. Alprostadil is a vasodilator, and, when administered transurethrally, it increases blood flow to the penis, allowing erection to occur. According to VIVUS, onset of action is within five to 10 minutes, and duration is 30-60 minutes.

MUSE was fairly well received by patients, said Tom F. Lue, M.D., a urologist at the University of California, San Francisco, and an expert spokesman on sexual dysfunction for the American Urological Association (AUA). The problem is that it's an indirect approach. With intracavernosal injection, he said, patients achieve an 80% success rate, while the rate with MUSE is 40%.

Ira Sharlip, M.D., also a urologist at UCSF and an expert for the AUA, is president of the Sexual Medicine Society of North America. He said MUSE "can be effective, but the percentage of patients who have a good response is less than those who respond well to sildenafil."

The approval of sildenafil (Viagra), Pfizer's now clichéd "little blue pill," was a major milestone in ED treatment. All of the urologists interviewed for this article reported a marked increase in the number of patients seeking treatment after sildenafil reached the market. This is particularly important because ED can be a symptom of other disorders, such as diabetes and hypertension, that often go undiagnosed and untreated.

"Few drugs have gotten the attention Viagra has," said Geoffrey Cook, a spokesman for Pfizer. The subject of TV jokes and commercials starring Bob Dole, Viagra quickly became a household name. Then Web sites began selling the drug. While they obtained the drug from licensed wholesalers, most of them bypassed conventional and legal prescribing and dispensing procedures.

Although Pfizer couldn't shut down these Web sites, it has worked with authorities to help get rid of some of them. It has also addressed the issue on its Viagra site, www.viagra.com. Patients are advised to see a physician for diagnosis and a prescription and to check with state pharmacy boards to determine which on-line pharmacies are licensed to sell Rxs.

All this attention hasn't been bad for Pfizer, and Cook said the company is very pleased with sales. Still, the discrepancy between the number of men estimated to have ED and the number of men who have actually tried the drug has left many speculating as to the reason. Is it lack of satisfaction with the drug? Or is it because each pill costs nearly $10 and most insurance plans don't cover it?

While sildenafil may not be quite as effective as vasodilator injections, with an efficacy rate of 60%-65%, it is more effective than alprostadil, said Lue. And the oral route is definitely more appealing to patients. "Our research has shown that cost isn't really a barrier," Cook said. While $10 may seem a lot to pay for one pill, "it's less than going to the movies." As for the insurance plans, "they're coming around slowly," he said.

Sexual dysfunction is different from other disorders because it requires only as-needed treatment, and many patients may not need it very often. Another difference is that sexual function is an integral part of each patient's relationship with his or her partner. If a man has had ED for a long while, starting up a sexual relationship again may take some time and adjustment. This could explain why sildenafil Rxs may not be refilled as often as expected.

Still, there have been some problems with sildenafil, from the mild to the severe. Most notably, several deaths have been associated with the drug. The majority of patients ex-periencing fatal or serious adverse events already had cardiovascular risk factors before starting sildenafil. The labeling for the drug urges cautious use in patients with cardiovascular disease. Unfortunately, many patients with ED also have cardiovascular disease. "Ultimately, ED is one form of vascular disease," said Sharlip. Other factors, such as smoking and certain drugs, usually aggravate problems rather than cause them.

Because sildenafil is primarily metabolized by cytochrome P-450 enzymes, primarily the 3A4 subtype, it interacts with several drugs; that is, any drug that inhibits or induces these enzymes can significantly alter levels of sildenafil. Erythromycin, cimetidine, ritonavir (Norvir, Abbott), and saquinavir (Invirase, Roche) have all produced increased levels of the drug; ketoconazole and itraconazole would be expected to do the same. In addition, sildenafil use is contraindicated in patients taking nitrates (nitroglycerin, isosorbides) because it potentiates the hypotensive effects of these drugs.

It's no surprise, then, that several rivals for sildenafil are in development. Like sildenafil, tadalafil, TA-1790, and vardenafil are in-hibitors of phosphodiesterase type 5 (PDE5). By inhibiting PDE5, these drugs enhance the activity of nitric oxide on smooth muscle, causing relaxation of vessel walls. Because nitric oxide is released locally upon sexual stimulation, theoretically the PDE5 inhibitors will work only in conjunction with sexual stimulation.

The makers of these drugs are already touting benefits over sildenafil in hopes of nabbing a chunk of the ED market. For example, in clinical studies, absorption of sildenafil was slowed by food, while Lilly ICOS' new drug, tadalafil (Cialis), was not. Other trials have demonstrated that tadalafil has a much longer duration of action than sildenafil (24 hours versus four hours) and may possibly take effect faster. The onset of sildenafil was 30 minutes to two hours (average one hour) during clinical studies, while that for tadalafil was as fast as 16 minutes, with most men responding within 30 minutes.

"Actually, some of the results with Cialis have been remarkable," said Gerald Brock, M.D., associate professor at the University of Western Ontario. Brock has been one of the investigators in the tadalafil studies. "Men want to take a pill that's going to let them be normal again," he said. "This pill does it more than any other pill I've worked with."

Bayer has conducted several studies to illustrate superiority of its PDE5 inhibitor, vardenafil, over sildenafil. One study concluded that Bayer's drug is more effective in producing erections in rabbits. Other studies have found the drug is effective in patients with different etiologies and severities of ED, and in patients taking antihypertensives. Recently, a study of patients receiving a series of vardenafil doses followed by one dose of nitroglycerin found no interaction with the nitrate. However, the study population was small (18 men aged 40 to 65 years), and none of them had cardiovascular disease.

VIVUS' contestant is TA-1790. Like Bayer, the company has tested the nitrate interaction. So far, preclinical study results show that the drug, when coadministered with nitrates, decreases blood pressure less than sildenafil. VIVUS also believes the drug may not cause the visual disturbances that have been observed with other PDE5 inhibitors. The company is also preparing a transurethral form of TA-1790 for patients who cannot tolerate the oral form.

With three years of market experience and many completed studies, Pfizer expects to do well against the competition. As for the claims made by other manufacturers, "We feel that more noise is likely to grow the market," said Cook. The firm continues to test sildenafil in different populations. In fact, results of a study in patients taking selective serotonin reuptake inhibitors (SSRIs) were presented late last year. They indicated both safety and efficacy in this population.

Other drugs in the works

The PDE5 inhibitors aren't the only drugs in development for ED. ALIBRA is a combination of alprostadil and prazosin created by VIVUS. The company submitted a New Drug Application in 1999, then withdrew it in 2000. The firm will say only that it is still analyzing the data and expects to present the results within a year.

TAP Pharmaceutical Products is working on a few drugs for sexual dysfunction. LGD2226 is a selective androgen receptor modulator (SARM) for the treatment of several disorders, including male and female sexual dysfunction. FR229934 is a PDE5 inhibitor. Apomorphine (Uprima) is a centrally acting drug for ED.

Many other drugs, designed to attack the problem from different receptors, are all in early development for ED. Although much of the media attention has focused on ED, there are other male sexual disorders, such as premature ejaculation. VIVUS is testing VI-0134, an oral therapy for this disorder. The idea is that men can take the drug prior to sex to prolong the time to ejaculation. The drug is still in phase I studies.

Female sexual arousal disorder

Treating sexual dysfunction in women is quite different from treating it in men, although some of the same drugs are being studied. For example, VIVUS has developed a formulation of alprostadil (ALISTA) specifically for women. The drug is applied topically to produce genital engorgement and induce arousal. While some experts may argue that women require a more complex combination of psychological and biological therapies, others believe that VIVUS' tactic may work.

"It could possibly affect physical satisfaction and desire," said Jan Hastings, Pharm.D. An assistant professor of pharmacy practice at the University of Arkansas for Medical Sciences College of Pharmacy, she specializes in women's health. Although she hasn't studied alprostadil and doesn't know whether the drug will be effective, "the theory behind how it works is sound," she said.

In fact, VIVUS recently completed phase II trials on alprostadil, and the results were promising. When used by women diagnosed with female sexual arousal disorder (FSAD), alprostadil produced significant increases in arousal and patient satisfaction with arousal. The company plans to begin at-home trials of the drug early this year. NexMed is also working on a similar formulation of alprostadil.

For some women, sexual dysfunction may arise from a syndrome called androgen insufficiency. One study measured the ability of DHEA (dehydroepiandrosterone) to correct this disorder. The researchers concluded that, while more studies are needed, the drug appeared to be effective. DHEA increased levels of androgens in most women, and these women reported improved sexual function.

Another investigational drug, PT-141, is a nasal spray in development at Palatin Technologies Inc. By stimulating melanocortin receptors in the brain, the drug appears to increase arousal. Preclinical studies indicated the drug was effective in female rodents. While it may seem difficult to estimate arousal in rodents, researchers have identified a variety of "precopulatory sexual behaviors," which they measured before and after administration of PT-141. The drug increased these behaviors and the rodents' desire for intercourse. Palatin hopes to have the same success in humans and plans to begin phase II trials in men and women by early this year.

As promising as these new drugs may be, Hastings pointed out that current therapies might also be helpful. For example, if a woman is menopausal, painful sex may be caused by decreased vaginal secretions. This can be effectively treated with hormone replacement therapy or topical creams (either hormonal or lubricating). Topicals containing estrogen decrease the thinning of vaginal walls and increase lubrication.

For many women, Hastings said the cause might be the drugs they are taking. "Depression rates are high, and a lot of the medications used to treat depression can also [cause sexual problems]," she said. "Prozac [fluoxetine, Lilly] seems to have gotten the most press on this." This may be because fluoxetine has been on the market longer than other SSRIs.

The SSRIs can cause female anorgasmia and decreased desire. Hastings suggested switching to a different drug within the class. Each drug may behave differently in each patient, and some SSRIs appear to decrease libido more than others. Also, "it has been shown that length of treatment plays a role in it," she said. If a different SSRI doesn't solve the problem, switching to another antidepressant may be in order. "Wellbutrin [bupropion, GlaxoSmithKline] is one that has a lower incidence of sexual side effects," she added.

With depression, sometimes it is difficult to determine the real cause: depression or the drugs used to treat it. "You can also try a drug-free holiday for a month," said Hastings. The dose may need to be tapered down, especially with fluoxetine. Some patients may find they don't need the drug at all. Other patients have restarted a drug after a holiday, or six months on another drug, and found it no longer caused sexual problems. "You can't predict who will experience these side effects," she said.

Anticholinergics, which dry secretions, can also cause sexual discomfort. "Antihistamines are probably the worst culprits," said Hastings. While taking an antihistamine for three or four days isn't a problem, chronic use can cause vaginal dryness and, hence, painful intercourse.

Getting the word out

Still, the greatest barrier to treatment seems to be patients' unwillingness to discuss their sexual problems with their physicians. Some patients are embarrassed, said Sharlip, some don't know whom to see, and some simply aren't interested in seeking treatment. To illustrate the reluctance to discuss ED, Brock asked an audience of about 150 healthcare professionals if anyone had ever experienced sexual dysfunction. None of them raised a hand. However, when given the chance to respond by anonymous keypad entry, the result was 30%, "which is about what I'd expect," said Brock.

Many organizations are working to increase awareness and decrease embarrassment regarding sexual dysfunction. The AFUD began International Impotence Education Month in November 1997. The foundation has also added an "Ask the Expert" section to its Web site, and the response has been tremendous, according to Hammerman.

The Consortium for Improvement in Erectile Function (CIEF) was founded last year, with help from Lilly, to educate healthcare professionals. The Sexual Medicine Society of North America also works to educate healthcare professionals and encourage research. Medem, a medical information site for patients, provides many links to sexual dysfunction article sites at its member organizations (the American College of Obstetricians and Gynecologists, the American Medical Association, and so on).

Once patients do receive treatment, another problem seems to be incomplete education and follow-up. "Most men probably want to get their prescription and get out of the doctor's office as fast as they can," Cook explained, and, therefore, they may not get the education they need from their physician. For example, patients receiving sildenafil should know that the drug produces an erection only in conjunction with sexual stimulation.

Pharmacists can help by explaining proper use and side effects of medications and by screening for drug interactions. Many pharmacies have created private counseling areas, which would be especially helpful in working with sexual dysfunction patients.

Jillene Magill-Lewis, R.Ph.

Drugs that may cause or precipitate sexual dysfunction

Anticholinergics
Antidepressants, particularly SSRIs
Antipsychotics
Benzodiazepines
Beta-adrenergic antagonists
Ethanol
H₂ antagonists
Illicit drugs (amphetamines, cocaine)
Narcotic agonists
Nitrates
Thiazide diuretics

Drugs in development for sexual dysfunction

Helpful Web sites

• Sexual Medicine Society of North America: www.smsna.org

• Medem: www.medem.com

• Consortium for Improvement in Erectile Function: www.erectilefunction.org

• NIH consensus statement on impotence: http://text.nlm.nih.gov/nih/cdc/www/91txt.html

• American Foundation for Urologic Disease Inc.: www.afud.org

• American Urological Association: www.auanet.org/index_hi.cfm

 

Jillene Lewis. IMPROVING INTIMACY. Drug Topics 2002;2:33.