Anybody who watched the recent World Series between the Red Sox and the Cardinals got a pretty good education in Viagrology, Levitrology, and Cialisology. Between footage of men shopping at Victoria's Secret and couples soaking in outdoor tubs, it was a challenge to fit in a few double plays and home runs.

Sex sells, and promising better sex really sells, to the tune of nearly $2 billion in yearly sales for Viagra (sildenafil) alone. Five years after Viagra's approval, both Levitra (vardenafil), and Cialis (tadalafil) were approved within months of each other in 2003.

By now, most of us have become familiar with the circuitous mechanism of action of these agents. They are all phosphodiesterase type 5 (PDE-5) inhibitors. To get an erection, you release nitric oxide (NO) into the bloodstream, which in turn stimulates cGMP to cause smooth muscle relaxation in the walls of the penile artery, allowing blood into the penis and subsequent erection. PDE- 5 breaks down cGMP; inhibit it and you keep levels high, and therefore keep the erection-producing blood flowing. The process in women works similarly, in that clitoral smooth muscle relaxes, allowing artery inflow and clitoral tumescence.

All three of the PDE-5I's are very effective at helping men to achieve erection, regardless of the cause of the original erectile dysfunction, with reported response rates of 70-80% (N Engl J Med 1998; 338:1397). Do they work for women? Yes, to some degree. A recent study enrolled 200 postmenopausal women with "sexual arousal disorder" in a double-blind placebo-controlled study. Half received Viagra for 12 weeks, half placebo. Viagra significantly improved sexual sensation in these women, with the marked exception of those with the primary diagnosis of "hypoactive sexual desire" (J Urol 2003; 170:2333-2338). Thus, it appears that Viagra enhances sexual pleasure in women as in men, but that it does little to reverse a lack of libido.

How well do PDE-5I's work for those patients in whom we're most likely to use it, namely, patients with antidepressant-associated sexual dysfunction (AASD)? Very well, at least for men. In a study of 90 men on SSRIs who reported AASD, half were assigned to flexible-dose Viagra and half to placebo. After six weeks, 59% of men in the Viagra group reported "much/very much improved" sexual functioning, vs. only 6% of those in the placebo group. Most of these patients were taking 100 mg by the end of the study (JAMA 2003; 289: 56-64).

Many psychiatrists have noticed clinically that while PDE-5I's help many patients with AASD achieve an erection, the very common complaint of delayed ejaculation often persists. Based on anecdotal experiences that high dose PDE-5I's seem to help cure this problem, researchers at Columbia University conducted an open label study of high dose Viagra for persistent ejaculatory delay associated with antidepressants. Patients were told to start with low dose (25 mg) Viagra, and to keep increasing the dose until they got a response. Of 21 men who began in the trial, four responded to doses from 25 to 100 mg, which is the point where most of us would close up the prescription pad. After a few patients dropped out, there were 10 patients left with persistent ejaculatory delay. Nine of them responded to Viagra in the 150-200 mg range. Side effects were minimal, even at double the FDA-recommended maximum dose of 100 mg (J Clin Psychiatry 2003; 64:721-725).

Table: PDE-5 Inhibitor Comparison Chart



Patients who tell you that PDE-5Is don't work for them may be using them incorrectly. According to urologists, 40-55% of apparent Viagra non-responders are converted to responders by simple patient education (J Urol 2003; 170: 2356-2358). Key elements of this instruction include: 1. Make sure the dose is adequate-- if 50 mg of Viagra doesn't work (or 10 mg of Levitra or Cialis), go immediately up to 100 mg (or 20 mg for the others); 2. Make sure the patient is timing the dose properly--at least 30 minutes and not more than 4 hours before sex, unless you're prescribing Cialis, the "weekender"; 3. Sexual stimulation is required before erection can occur; 4. Take Viagra and Levitra on an empty stomach to maximize absorption; 5. Keep trying, as results improve after several attempts.

So which of the Big Three should you be prescribing for your patients? At this point, there are no published comparative studies of efficacy, side effects, or metabolic features. There is some buzz that Levitra may be absorbed better after a meal than Viagra, and that it may kick in a few minutes more quickly.

They have similar side effects, with a couple of possible exceptions: Cialis causes back pain in some patients (not listed prominently in either Viagra or Levitra inserts) but appears to be less likely to induce flushing than the others. All are contraindicated with nitrates. While it's not a great idea to combine any PDE-5Is with doxazosin, it's completely contraindicated with Cialis. The major differences are in dosing and pharmacokinetics, all of which are listed in the chart on this page.

The only head-to-head data are three published studies sponsored by Lilly/ICOS, all of which are studies of patient preference, rather than efficacy or other inherent qualities of the drugs. All three studies report that, given the choice between taking Cialis or Viagra in a double-blind protocol, most patients prefer Cialis, because of the long duration of action and the lack of a fatty meal effect (European Urology 2004; 45:499-509; Clin Ther 2003; 25:2724-37; Clin Ther 2003; 25:2709-23.) The longer half-life is a clear advantage, except for patients who are prone to one of the nuisance side effects of PDE-5Is. After all, a 36-hour headache will take the mood right out of most patients, no matter how much nitric oxide in their cavernosa.

TCR VERDICT: They all work, but Cialis lasts six times longer.