The PDE5 inhibitors: Viagra, Levitra, and Cialis

Approved by the FDA in 1998, sildenafil (Viagra) revolutionized the way we think about — and treat — erectile dysfunction (ED), largely because it is effective and easy to use. In 2003, the FDA approved two closely related drugs, vardenafil (Levitra) and tadalafil (Cialis). Five years later, in January 2008, low-dose Cialis for daily use came onto the market, creating an option that — theoretically, at least — makes having sex a possibility without advance planning.All three drugs work in a similar fashion, by affecting the normal physiology of the penis. In particular, they block PDE5, an enzyme that breaks down the erection-producing chemical cyclic guanosine monophosphate. This enables the penis to fill with blood and to stay erect long enough for intercourse. Of course, it’s important to realize that none of these drugs is an aphrodisiac. You must feel sexually aroused in order for them to work.The main differences between the three drugs have to do with timing: how quickly they begin to work, and how long their effects last (see Table 4). The biggest divide lies between Cialis for daily use, which keeps a steady supply of the drug in the bloodstream, and the as-needed dosing offered by the original form of Cialis, as well as by Levitra and Viagra. Among the nondaily pills, Levitra may start working slightly faster than Viagra (within a half-hour instead of an hour) although the FDA says that like Viagra, it should be taken about an hour before sexual activity. Some studies suggest that Levitra may help some men who don’t respond to Viagra. And while some doctors are skeptical about this claim, there’s no harm in trying Levitra or Cialis if Viagra doesn’t work for you.

Cialis stays active in the body much longer than the other drugs. Viagra and Levitra last about four to five hours (and sometimes up to 12 hours). But with Cialis, the window of opportunity ranges from 24 to 36 hours, which is why it’s sometimes called “the weekend drug.” The low-dose daily option aims to allow a man to be prepared for sex anytime (see “Why take a daily ED pill?”). Another difference among the three drugs is that while Viagra’s action may be delayed or impaired when taken with food (especially high-fat foods), that’s not the case with Levitra or Cialis.

Table 4: Comparing the treatments

Therapy Onset of action Duration of effectiveness Advantages Disadvantages Approximate cost
sildenafil (Viagra) 30–60 minutes 4–5 hours Oral medication, very effective (about 70%), few side effects Cannot be used by men taking nitrates or those with unstable cardiovascular disease About $15–$20 per dose
vardenafil (Levitra) 15–30 minutes 4–5 hours
tadalafil (36-hour Cialis) 30–45 minutes 24–36 hours
tadalafil (Cialis for daily use) Steady low dose in bloodstream Any time sexual arousal occurs Oral medication. According to one small study, effectiveness varies depending on dose (2.5 mg or 5 mg) and level of ED, ranging from 27% for severe ED to 82% for mild ED. Same as above About $4–$5 per day
yohimbine (Yocon) 2–3 weeks with daily use As long as therapy continues Oral medication, somewhat effective (40%), a good option for men who cannot use Viagra and related drugs Side effects include insomnia, increased heart rate and blood pressure, nervousness About $0.27–$0.54 per day
alprostadil injections (Caverject, Edex) 5–20 minutes 30–60 minutes Highly effective (about 80%), few side effects Requires training; injections unpleasant for many men; may cause penile pain or painful sustained erections $43–$49 per dose
alprostadil pellets (MUSE) 5–15 minutes 30–60 minutes Moderately effective (about 30%) Requires training; may cause penile pain, usually mild; may cause dizziness $30–$36 per use
vacuum pump Immediate Until the band placed at base of penis after using the vacuum pump is removed Highly effective (about 80%), no serious side effects Requires training; cumbersome and awkward; may cause penile numbness or bruising $160–$425 per device (a one-time cost)
penile band (Actis, Erecxel) Immediate While in use Effective when used properly, helpful for men with venous leakage who cannot sustain an erection May be awkward to use $4–$16 per band (reusable)

Success rates

Because Viagra has been available the longest, there’s more research available on this drug. Pooled data involving studies of 6,659 men have shown that Viagra helped 83% of men have intercourse at least once. On the other hand, Viagra is not a panacea. A 2001 study of its long-term effectiveness, published in The Journal of Urology, reported a somewhat lower overall success rate (69%). The success rates for Levitra and 36-hour Cialis are similar to those for Viagra (59% and 69%, respectively).Not as much information is available on the effectiveness of the daily Cialis pill. One small study found that effectiveness varies depending on dose — 2.5 milligrams (mg) or 5 mg — and level of ED:

  • severe ED: 27% (2.5 mg) to 33% (5 mg)
  • moderate ED: 56% (2.5 mg) to 61% (5 mg)
  • mild ED: 73% (2.5 mg) to 82% (5 mg).

It’s worth noting that effectiveness of placebo was 57% for mild ED, 27% for moderate ED, and 9% for severe ED.Viagra has proved beneficial for many men with ED resulting from spinal cord injuries. In one study, 83% of such men who took Viagra had improved erections. But for men with diabetes or advanced heart disease, the drug helped only about half of the time. The response was even lower — about 30% — for men who have had a radical prostatectomy.

ED and the single man

In addition to the psychological and medical issues facing all men with ED, men without long-term partners who wish to be sexually active face their own set of questions and concerns.

If you’re in this situation, you may wonder how much to tell a new sexual partner. There is no right or wrong answer. It depends on how much you’re comfortable revealing and, to some extent, on which therapy you’re using. For example, if you’re taking a pill, you don’t have to reveal as much as you would if you’re using one of the other treatments.

If treatment is successful, you may not have to say anything about your ED, even if you develop a steady relationship with someone. But if the problem recurs periodically, you may want to discuss it with your partner. The best time to do this is usually not when sexual intimacy is actively under way, but rather during a quiet, private time when you are feeling at ease with each other.

Tell your partner about your condition and what you know about its causes. Discuss the types of treatment, if any, that you are using. Answer any questions your partner has and, when the time for sexual intimacy arises, take it slowly. You may find that having discussed the subject improves your sexual experience.

 

Side effects

So far, the risks and side effects of these three drugs seem to be roughly the same. They all work by relaxing smooth muscle cells, which widens blood vessels — primarily in the penis, but also in other parts of the body. The most common side effect is a headache, which occurs in about 16% of users (see Figure 7). Other reactions include flushing, upset stomach, nasal congestion, and urinary tract infections. But when the drugs are used properly, these side effects are relatively mild, and most disappear after a few hours. In rare cases, some men experience temporary, mild visual problems — mainly a blue tinge to the vision, but also increased sensitivity to light and blurriness. However, men with retinitis pigmentosa, a rare eye disease, should be very cautious about using these medications.

In 2005, reports linked Viagra use to another rare eye disease, nonarteritic anterior ischemic optic neuropathy, which can lead to blindness. However, fewer than 50 possible cases were reported as of 2006, compared with the millions of men who have used erectile drugs without problems. Still, these reports serve as a reminder to men over 50 to get regular eye check-ups and to check with a physician about any unusual vision problems that occur after taking a PDE5 inhibitor drug.

Sudden hearing loss is another rare side effect documented as a possible risk of PDE5 inhibitors. In 2007, the FDA noted that this type of hearing loss was almost always one-sided. At that time, it had proven temporary in about one-third of the cases.

Figure 7: Side Effects of Viagra

Side effects of Viagra

 

Drug Interactions

Within several hours after a man takes a PDE5 inhibitor drug, his blood pressure tends to drop slightly: the top (systolic) number dips 8 to 10 millimeters of mercury (mm Hg), while the bottom (diastolic) number goes down by 5 to 6 mm Hg. So it’s very important to avoid taking these drugs with medications that contain nitrates, which also lower blood pressure. Interactions between these two types of drugs can cause life-threatening drops in blood pressure. (The nitrates and nitrites found in food don’t pose a problem.) Men who take long-acting nitrates, including isosorbide dinitrate (Isordil, Sorbitrate, and others) and isosorbide mononitrate (Imdur, Ismo, and others) or who use nitroglycerine patches or paste should not take PDE5 inhibitor drugs. And they should not use short-acting, under-the-tongue tablets or a spray form of nitroglycerine within 24 hours of taking either Viagra or Levitra. For Cialis, the ban extends to 48 hours.

Men who take medications known as alpha blockers should be cautious about taking PDE5 inhibitors. These drugs, which include doxazosin (Cardura), terazosin (Hytrin), and tamsulosin (Flomax), are used to treat BPH and high blood pressure. If you take an alpha blocker, ask your doctor before taking any PDE5 inhibitor. For example, Viagra shouldn’t be taken within four hours of taking an alpha blocker.

Yet another common medication that interacts with PDE5 inhibitors is cimetidine (Tagamet), used to treat severe heartburn and stomach ulcers. Tagamet slows the breakdown of these drugs, which can effectively double the level of Viagra, Levitra, or Cialis in the bloodstream. Because of this, men who take Tagamet should start with a lower dose of a PDE5 inhibitor. No adverse effects from taking the drugs together have been reported, but the risk of side effects such as headache or flushing may be higher.

Why take a daily ED pill?

Cialis comes in a version designed to be taken daily, for continuous effect. If you are contemplating using a daily pill for ED, discuss these and other essential issues with your doctor:

  • How often do you have sex? If it’s two or more times a week, a daily pill might be a reasonable choice, since the drug continually circulates in your bloodstream.
  • How important is spontaneity? Taking a daily pill clears the flight path for sex at any given time if you’re among those for whom the drug is effective (remember, just like other ED drugs, it won’t work for every man). On the other hand, the 36-hour window offered by the nondaily version of Cialis might offer quite enough spontaneity.
  • How important is cost? While the manufacturer suggests that a 30-day supply of daily Cialis should cost approximately the same as eight pills of 36-hour Cialis a month, there’s no way to enforce this. Check your insurance policy and local pharmacies for price information.
  • What other medications do you take? Men taking nitrate medications are advised not to take any of the ED drugs. Ask your doctor if any medications or supplements you take might interact unfavorably with the daily ED pill, including blood pressure drugs, alpha blockers, antifungal drugs, and HIV drugs.
  • Have side effects of your current ED pill been bothering you? Taking a daily low-dose pill may reduce side effects, though it may reduce effectiveness as well (see “Success rates”). In studies, the most common daily pill side effects were headache, muscle pain, dyspepsia, and back pain.
  • How much alcohol do you drink? Drinking until intoxicated isn’t a good idea anyway, but men taking Cialis for daily use risk inducing a worrisome drop in blood pressure if they drink too much. The same is true for conventional ED drugs, but since these are shorter-acting, this may be less of an issue.

At this writing, Cialis is the only ED pill that comes in a low-dose form for daily use. The starting dose is 2.5 milligrams (mg); if that fails to work, the daily dose can be bumped up to 5 mg. Splitting Levitra or Viagra pills to get a lower dose would be ill-advised since no data are available on safety or effectiveness.

 

Other Considerations

The PDE5 inhibitors are expensive (about $15–$20 per pill), but many health insurance plans (including Medicare) cover them, although most have a limit of four pills per month. Perhaps even more important considerations are the sometimes complicated and unexpected challenges that these medications may present to your sexual relationship. Some partners who’ve grown comfortable in a relationship without intercourse may need time to shift gears, if the drug is successful. Use of these drugs may raise other issues for couples. Should you tell your partner before or after you’ve started taking it? Will this put pressure on your partner to have sex? Should you take the medication and just hope your partner will be in the mood? The best way to address these questions is to talk about them with your partner. Particularly if you’re in an established relationship, your partner should know that you have a prescription for one of the drugs, and the two of you can decide together how and when to use it.

Who leads ED drug sales?

Viagra, introduced in 1998, was the pioneer in the ED drug market and the only ED medication available for five years. When challengers came on the market in 2003, Viagra’s strong name recognition, brand loyalty, and longer history kept it at the top of the ED drug heap. According to the most recent data available from the makers of the three ED medications, Viagra continues to outsell its competitors, but the margin is growing smaller, with Cialis nipping at its heels.

While Viagra experienced a 2% dip in sales in 2009 and a 2% rebound in 2010, Cialis sales grew by 8% in 2009 and 9% in 2010. That growth is due in part to the aggressive marketing campaigns that have made Cialis, like Viagra, a household name. But two other factors may be even more important: Cialis is the only drug available for daily use, and it is effective much longer than its competitors — allowing for an erection to occur anytime in the period of 24 to 36 hours after taking the drug, compared with four to five hours for Viagra and Levitra.

The sales figures are staggering, with both Viagra and Cialis selling in the billions of dollars worldwide in 2010 (see Figure 8): Viagra sold $1.934 billion worth, and Cialis hit the $1.699 billion mark. Levitra lags significantly behind. Its parent company, Bayer, provides sales figures in euros, not dollars. For 2010, Levitra recorded sales of €429 million (which, using the conversion rates at the time of this printing, was the equivalent of $614 million).

With the patent for Viagra expiring in the United States in 2012, that drug will soon face competition from generic drugs. That has industry insiders speculating that Viagra’s reign as king of the ED market may be coming to an end, with Cialis taking over the throne.

Figure 8: Annual Sales of Viagra, Cialis, and Levitra

Annual sales of Viagra, Cialis, and Levitra

Viagra and Cialis both sold in the billions of dollars from 2008 to 2010 (the most recent year for which the data are available), while Levitra trails with hundreds of millions in sales.

*Editor’s note: Converted from euros based on rates from July 2011

Source: Annual reports of Eli Lilly and Co., Pfizer, and Bayer.

 

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