Review

Synthèse

Erectile dysfunction: management update

Luke Fazio, Gerald Brock

Abstract function of 52%, with 9.6% of respondents reporting com-
plete erectile dysfunction.5 In 2000 the overall prevalence
DRAMATIC ADVANCES IN THE MANAGEMENT of erectile dysfunction of erectile dysfunction in this study population was re-
have occurred over the past decade. Oral therapy with vasoactive estimated to be 44%.6 The Massachusetts study is impor-
agents has emerged as first-line treatment and has transformed tant because it is the first cross-sectional, community-
both the manner in which the public views erectile dysfunction based, random-sample multidisciplinary survey on the topic
and the way health care providers deliver care. Whereas an ex- and involved a significant cohort followed up for nearly a
tensive investigation was previously common in the management decade beyond the initial assessment. A survey of 3009 men
of erectile dysfunction, recent treatment guidelines promote a
aged 18–70 years from all regions of Canada revealed a
more minimalist, goal-oriented approach. In this article, we re-
similar prevalence of erectile dysfunction.7
view the physiology of erection, and the pathophysiology, diag-
nosis and clinical management of erectile dysfunction. We also
present the existing evidence for the efficacy of 3 phosphodi- Physiology of an erection
esterase inhibitors, the most widely used class of agents for erec-
tile dysfunction. Erection involves the integration of neural and vascular
functions. In essence, an erection occurs when blood flow
CMAJ 2004;170(9):1429-37
to the penis exceeds flow out of the penis. The cavernosal
arteries supply blood to the corpora cavernosa of the penis

E
rectile dysfunction can be defined as the inability to (through the pudendal artery); the emissary veins running
achieve or maintain a penile erection sufficient for through the tunica albuginea allow drainage. During erec-
satisfactory sexual performance.1 In the face of an tion, relaxation of trabecular smooth muscle results in in-
aging population, decreasing social stigma associated with creased blood flow to the corpora cavernosa and expansion
erectile dysfunction and an increasing availability of effec- of the sinusoids therein. This distension causes mechanical
tive oral therapy for its treatment, the number of patients compression of the emissary veins, which impedes their
presenting with this complaint has increased dramatically. ability to drain blood and thereby results in penile rigidity8
Current estimates describe 2–3 million Canadian men as (Fig. 1).
having significant recurring erectile difficulties. Recent re- Penile blood flow is controlled by the autonomic erec-
ports identifying a dramatic increase in rates of diabetes, in- tion centre, which provides parasympathetic (S2–S4) and
creased longevity and higher quality-of-life expectations by sympathetic (T12–L2) input to the pelvic plexus,8 including
“baby boomers” are all believed to be factors in a projected the cavernous nerves that innervate the cavernosal arteries
continued expansion of the patient population requesting and trabecular smooth muscle. These nerves are responsi-
medical help with sexual issues in the near future.2,3 Al- ble for the delivery of high local concentrations of nitric
though historically erectile dysfunction was a problem oxide to the trabecular smooth muscle, which results in
identified and treated by urologists, today primary care relaxation (Fig. 2). 9,10 Nitric oxide diffuses across the
physicians and other specialists write 80% of the prescrip- smooth-muscle membrane and activates guanylate cyclase
tions for sildenafil, the most popular drug used to treat the to produce cyclic guanosine monophosphate (cGMP); the
condition.4 biochemical cascade that ensues results in altered potassium
In this article, we review the epidemiology of erectile and calcium ion channel permeability; ultimately, the de-
dysfunction, the current understanding of its pathophysiol- crease in cytosolic calcium concentration causes smooth-
ogy and the evidence for the efficacy of oral therapy with muscle relaxation and increased regional blood flow.11,12
phosphodiesterase type-5 inhibitors, which has become the Phosphodiesterase enzymes (PDEs) regulate this pathway
DOI:10.1053/cmaj.1020049

first-line treatment of erectile dysfunction. by inactivating cGMP, which results in elevated cytosolic
calcium concentrations and smooth-muscle contraction.
Epidemiology of erectile dysfunction PDE type 5 is the most important isoenzyme in the cor-
pora cavernosa.13–15
The Massachusetts Male Aging Study surveyed 1709 The somatic motor nerve supply arises from the sacral
men aged 40–70 years in the greater Boston area between spinal cord, whose fibers join the pudendal nerve innervat-
1987 and 1989 and reported a prevalence of erectile dys- ing the bulbocavernosus and ischiocavernosus muscles, ac-

CMAJ • APR. 27, 2004; 170 (9) 1429

© 2004 Canadian Medical Association or its licensors

 Fazio and Brock

Central
Hypothalamus stimulation

Corpus
cavernosum Deep dorsal vein

Dorsal artery Dorsal nerve

Sympathetic nerve
fibers (T12-L2)
Parasympathetic nerve
fibers (S2-S4)
Pudendal
nerve FLACCID Deep dorsal vein
Genitofemoral Dorsal artery
nerve
Dorsal nerve

Circumflex
vein
Tunica
albuginea

ERECT

Sinusoid

Trabecular
smooth muscle
Corpus cavernosum

Cavernous artery Emissary vein (compressed)

Helicine arteries

Expanded sinusoids
Christine Kenney

Corpus spongiosum
Urethra

Fig. 1: Anatomy and mechanism of penile erection. The erection pathway can be triggered by direct genital stimulation and by
auditory and visual stimulation, which act in concert to increase penile blood flow. The penis has a highly specialized anatomical
structure that allows a massive increase in blood flow to be trapped within the inelastic layers surrounding the penis (the tunica
albuginea), which causes rigidity and expansion of the cavernosal smooth muscle.

1430 JAMC • 27 AVR. 2004; 170 (9)

 Erectile dysfunction

tive during ejaculation and climax. Adrenergic stimulation their effect on libido and sexual behaviour. Testosterone en-
is responsible for cavernous smooth-muscle contraction hances sexual interest and the frequency of sexual acts; it in-
and detumescence. Cholinergic nerves may contribute to creases the frequency of nocturnal erections but does not ef-
the erectile process through adrenergic inhibition as well as fect reflexogenic or psychogenic erections.19
by causing release of nitric oxide from the endothelium.16
Three mechanisms trigger these vascular changes: psy- Pathophysiology of erectile dysfunction
chogenic, reflexogenic and centrally originated (nocturnal
erections). Psychogenic erections occur through stimulatory Numerous factors can disrupt the normal physiologic
pathways (e.g., sound, smell, sight and touch) that travel mechanisms involved in erection (Table 1). Most cases of
from the spinal erection centres (T11–L2 and S2–S4) and in- erectile dysfunction were thought to be psychologically
duce a dopaminergic initiation of erection from the medial based, but it is now understood that most have an organic
pre-optic area.17 Reflexogenic erections, induced by direct cause, especially in older patients. In about 40% of men
genital stimulation, send ascending messages to the central over 50 years old, the primary cause of erectile dysfunction
erection centres and direct messages to the autonomic nu- is related to atherosclerotic disease.20 In this respect, risk
clei, which explains residual erectile activity in patients with factors are similar to those of cardiovascular disease. How-
upper spinal cord injuries. Nocturnal erections, initiated in ever, erectile dysfunction may also be related to psycholog-
the pontine reticular formation and amygdalae, are seen ical, neurological, hormonal, pharmacological and end-
during REM sleep and are believed to be caused by a rela- organ (penile) factors.
tive decrease in sympathetic inhibition with augmentation With respect to neurological causes, involvement of any
of the pro-erectile centres. nerve group, either central or peripheral, may lead to erec-
Despite considerable recent experimentation in animal tile dysfunction. Cerebral diseases lead to decreased sexual
models and human volunteers, information on the central interest, possibly through over-inhibition of spinal centres.
pathways of erection remains cursory at best.18 It is known Among patients with spinal cord injury, 95% of those who
that androgens play a predominantly modulating role by have upper motor neuron lesions are capable of reflexo-

Sexual
stimulation
Endothelial cell Stimulation
Inhibition

Smooth-muscle cell
Cavernous
nerve Ca2+
Endoplasmic
reticulum
Decreased
Ca2+
Nitric
oxide Guanylate cGMP-specific
cyclase protein kinase
Smooth-muscle
cGMP K+ relaxation (erection)
GTP
PDE-5
Ca2+
5' GMP K+
Christine Kenney

PDE-5 inhibitor
site of action

Fig. 2: Cellular perspective of the erection pathway. The signal (nitric oxide) is released from nerve endings or from
endothelial cells and activates a cascade reaction, which ultimately leads to an increased cellular concentration of
cGMP (cyclic guanosine monophosphate). This second messenger molecule induces a series of events that lead to
smooth-muscle relaxation through a reduction in the intracellular calcium ion concentration. The enzyme PDE-5
(phosphodiesterase type 5) reverses this effect by metabolizing the cGMP to GMP rapidly. The clinically important in-
hibitors of this enzyme (sildenafil, vardenafil and tadalafil) all act to promote smooth-muscle relaxation by their abil-
ity to allow cGMP to accumulate when nitric oxide is released, as is the case when sexual stimulation is present.

CMAJ • APR. 27, 2004; 170 (9) 1431

Fazio and Brock

genic erections, 25% of patients who have lower motor ated with a higher risk of erectile dysfunction. Obesity sta-
neuron lesions are capable of psychogenic erections, and tus was also associated with the condition (p = 0.006), with
more than 90% of patients who have incomplete lesions of baseline obesity predicting a higher risk regardless of fol-
either kind retain their erectile function.21 Direct injury to low-up weight loss. Smoking and alcohol consumption
the cavernosal nerve and blood supply commonly occurs were not found to be causally associated with the incidence
during therapy for prostate cancer; erectile dysfunction is of erectile dysfunction. The risk of the condition was
present to some extent in 80% of patients so treated, higher among men with lower education levels, diabetes,
whether by surgery or external beam radiation therapy.22 heart disease and hypertension.
Almost all antihypertensive medications have been im-
plicated in erectile dysfunction.23 The mechanisms vary Diagnosis
from central-acting sympatholytics, depression of libido as
well as higher blood pressure requirement to achieve erec- Just a decade or 2 ago, the routine evaluation of erectile
tion in atherosclerotic patients taking diuretics and vaso- dysfunction consisted of an exhaustive biochemical screen-
dilators. The role of smoking in causing erectile dysfunc- ing panel, psychological assessments and occasional vascu-
tion remains a source of controversy. A recent consensus lar testing. This approach was justified as reasonable at the
group analysis failed to document a direct link to erectile time, because the treatment options available were invasive.
dysfunction. However, smoking seems to amplify other risk In contrast, current recommendations for management rely
factors, such as hypertension and coronary artery disease.24 on history-taking and basic screening tests. The Canadian
Martin-Morales and colleagues25 have shown an increased Urological Association has recently developed an algorithm
risk of erectile dysfunction among smokers (odds ratio for the management of erectile dysfunction that supports
[OR] 2.5). Systemic diseases are also associated with erec- this approach.28
tile dysfunction. This is often multifactorial, as in diabetes The most important component of diagnosing erectile
and renal failure.26 Given the role of androgens in the phys- dysfunction is obtaining a complete medical and sexual his-
iology of erections, it is not surprising that many hypo- tory. It is important to distinguish the condition from other
gonadal men do not experience erectile dysfunction per se. sexual dysfunctions, such as premature ejaculation and loss
Low serum testosterone levels may be primary or sec- of libido. Several formalized sexual questionnaires, such as
ondary to another condition, such as hyperprolactinemia or the IIEF (Internation Index of Erectile Function) and
hypothyroidism. Regardless of the mechanism, the result is EDITS (Erectile Dysfunction Inventory of Treatment Sat-
primarily a loss of libido, although many hypogonadal men isfaction), allow one to detect the presence and grade the
retain their ability to obtain erections.27 severity of erectile dysfunction. The complete IIEF is com-
The rich database of the Massachusetts Male Aging posed of 15 questions; an abridged 5-item version, called
Study has allowed important insights to be gained into a the sexual health inventory for men (SHIM), has been de-
variety of risk factors for erectile dysfunction, both psy- veloped and validated.29 Allowing a patient to complete
chosocial and physical. A submissive personality was associ- such a questionnaire before his first clinical encounter may
produce a more comfortable clinical environment.30 The
duration of the problem, time of onset and degree of pa-
Table 1: Causes of erectile dysfunction tient and partner concern should also be elucidated. The
Causes Examples circumstances surrounding erectile dysfunction may be
helpful in determining whether a situational or nonorganic
Aging
factor is involved. Sudden onset, maintenance of nocturnal
Psychological disorders Depression, anxiety
erections, presence of psychological problems and concur-
Neurological disorders Cerebral diseases, spinal cord injury, spinal
disease, peripheral neuropathy, pudendal rent major life events or relationship issues may be associ-
nerve injury ated with nonorganic erectile dysfunction.31 Concurrent
Hormonal disorders Hypogonadism, hyperprolactinemia, medical illnesses and any medications the patient may be
(depresses libido) hyper- or hypothyroidism, Cushing’s taking should be reviewed. Erectile dysfunction is often a
syndrome, Addison’s disease component of generalized medical illness and may repre-
Vascular disorders Atherosclerosis, ischemic heart disease, sent the initial presentation of cardiovascular disease or dia-
peripheral vascular disease, venous
incompetence, cavernosal disorders
betes. The history may also reveal certain reversible or
Medications Antihypertensives, antidepressants
modifiable risk factors, such as tobacco use or inadequate
(depresses libido), estrogens and anti- diabetes control.
androgens (depresses libido), digoxin The physical examination should focus on the vascular,
Habits Marijuana use, alcohol abuse, narcotics neurological and endocrine systems.28,31 Testes size should
use, cigarette smoking be noted and the penis shaft examined to rule out a penile
Other diseases Diabetes mellitus, renal failure, deformity (Peyronie’s disease). With respect to laboratory
hyperlipidemia, hypertension, chronic investigations, recommendations vary,30,31 and investigations
obstructive pulmonary disease
should follow clinical suspicion of specific disorders. He-

1432 JAMC • 27 AVR. 2004; 170 (9)

 Erectile dysfunction

moglobin A1c and serum glucose may be measured to detect PDE-5 is an enzyme found in trabecular smooth muscle.
occult diabetes, and a lipid screen performed to assess the It catalyzes the degradation of cGMP, which results in an
presence of dyslipidemia. Hormonal screening is contro- elevated cytosolic calcium concentration and smooth-
versial; however, it is reasonable to measure testosterone muscle contraction (Fig. 2). PDE-5 inhibitors, therefore,
levels in the face of erectile dysfunction combined with loss block this biochemical pathway to promote erection.
of libido.28 Patients in whom hyper- or hypothyroidism is Eleven subtypes of PDEs have been described, with 30
suspected should have their thyroid-stimulating hormone isoenzymes mediating a variety of physiologic actions
level checked.30 throughout the body.32 PDEs exhibit enormous functional
A number of specialized investigations exist for the eval- diversity; at present, our understanding of PDE types 1 to 6
uation of erectile dysfunction but need not be part of the are considerably better than our understanding of PDE
routine evaluation. The penile brachial index involves mea- types 7 to 11.
suring penile pressure and comparing it with arm pressure. All 3 of the PDE-5 inhibitors are metabolized by the cy-
It has limited clinical utility because the data are based on tochrome P-450 3A4 enzyme. Sildenafil and vardenafil
superficial and deep penile arterial pressure, whereas erec- share similar pharmacokinetic properties (Table 2). Both
tile function depends on the deep arteries exclusively. Du- have been shown in clinical trials to improve the ability to
plex ultrasonography allows for refined assessment of the attain and maintain erections when taken 1 hour before sex-
penile circulation. The information it provides, however, is ual activity (Table 3). Since sildenafil was introduced, exten-
operator dependent and rarely alters patient management. sive clinical experience has been gained with prescriptions of
Selective pudendal arteriography combined with intracav- it to more than 20 million patients. Vardenafil has distin-
ernous injection of a vasoactive drug should be limited to guished itself by demonstrating efficacy in patients who
the small group of patients who are candidates for penile have previously undergone radical prostatectomy for local-
revascularization surgery. These patients include nonsmok- ized prostate cancer (a group that had been difficult to treat
ing men less than 40 years old with a history of pelvic because of nerve and vascular injury secondary to surgery)
trauma who have sustained a penile arterial disruption.30 and in patients with diabetes.34,35
Tadalafil differs from sildenafil and vardenafil in its
chemical structure and its lack of inhibition of PDE type 6.
Treatment Tadalafil exhibits a prolonged half-life of 17.5 hours, and
the time to peak concentration is about 2.0 (range 0.5–12.0)
Oral therapy hours in healthy volunteers.37 Among men with erectile
dysfunction, a significantly higher percentage of attempts
The use of oral therapy has long been preferred over in- at sexual intercourse were successful up to 24–36 hours af-
vasive procedures such as injection therapy for erectile dys- ter use of tadalafil compared with placebo.37,40,41 The phar-
function. We review the pharmacology, efficacy and side macokinetics of tadalafil is not clinically influenced by food
effects of the newest agents available for oral therapy: the or alcohol intake, or by intrinsic factors such as diabetes, or
PDE-5 inhibitors sildenafil, vardenafil and tadalafil. renal or hepatic impairment.41

Table 2: Pharmacokinetic characteristics of PDE-5 inhibitors used in the treatment of erectile

dysfunction
Parameter Sildenafil Vardenafil Tadalafil

Oral dose, mg 100 20 20

Median time to peak concentration,
min 60 40–60 120
Half-life, h 3–4 4–5 17.5
Maximum concentration, µg/L 411 17 378
Area under the erectile curve, µg · h/L 1691 67 8066
Volume of distribution, L 105 208 63
Food interaction Yes with high-fat Minimal with low-fat None
foods; possible with foods; delay in time to
low-fat foods peak concentration
with high-fat foods
Alcohol interaction None None None
Age > 65 yr Half-life ↑ Half-life ↑ Half-life ↑
Dose adjustment Dose adjustment Dose adjustment
may be needed may not be needed may not be needed
Note: PDE-5 = phosphodiesterase type 5.

CMAJ • APR. 27, 2004; 170 (9) 1433

Fazio and Brock

Adverse events 6884 patient-years of drug use and 543 patient-years of

placebo use, found that the incidence of myocardial infarc-
The primary concern with oral therapy for erectile dys- tion was low in both the treatment and placebo groups
function has centred on cardiovascular-related adverse (0.80 and 1.11 per 100 patient-years respectively) and that
events.42 Because PDE-5 inhibitors promote vasodilation, the rates did not differ significantly between the 2 groups.
they inherently have the potential to cause hypotension. Among more than 4000 patients in clinical studies of
The concern has been greatest in elderly patients with pre- tadalafil, the incidence of myocardial infarction in the treat-
existing cardiovascular disease. ment group was 0.39 per 100 patient-years, as compared
Mittleman and colleagues,43 in a review of 53 open-label with 1.1 per 100 patient-years in the placebo group.44
and double-blind trials of sildenafil representing a total of All PDE-5 inhibitors are contraindicated in men who

Table 3: Results of clinical trials of oral PDE-5 inhibitor therapy for erectile dysfunction (ED)
Results
No. of PDE-5
Trial patients Patients inhibitor Outcome measures Drug Placebo p value Comments

Stark 601 Men with mild Vardenafil Erectile function scores Drug therapy stopped in 0.7%
33
et al to severe ED Successful intercourse to 4.8% of patients because of
secondary to attempts > 70% 40% < 0.001 adverse events
various causes

Brock 440 Men who Vardenafil % with improved erections Efficacy measured after 12 wk
34
et al underwent (based on global-assessment of therapy
radical question)
prostatectomy • 10-mg dose 59.4% 12.5% < 0.0001
for localized • 20-mg dose 65.2% 12.5% < 0.0001
prostate cancer

Hellstrom 805 Men > 18 yr Vardenafil IIEF scores Multicentred, randomized,

35
et al with ED lasting • 5-mg dose 17.79 14.84 < 0.0385 double-blind trial; 506 of original
> 6 mo • 10-mg dose 21.2 14.84 < 0.0005 1311 patients not included in
• 20-mg dose 21.83 14.84 < 0.0005 analysis, mostly because of
protocol violation (< 2
intercourse attempts per wk)

Goldstein 452 Men with Vardenafil % with improved erections Multicentred, double-blind,
36
et al diabetes (type (based on global-assessment placebo-controlled trial
1 or type 2) question)
• 10-mg dose 57% 13% < 0.0001
• 20-mg dose 72% 13% < 0.0001
Successful intercourse
attempts (among patients
with erections sufficient for
penetration)
• 10-mg dose 49% 23% < 0.0001
• 20-mg dose 54% 23% < 0.0001

Brock 1112 Men with mild Tadalafil Normal erectile function Drug was well tolerated and
37
et al to severe ED scores 59% 11% < 0.001 effective across various causes,
secondary to age groups and degrees of ED
various causes % of intercourse attempts severity; dyspepsia and
that were successful 75% 32% < 0.001 headache were most common
adverse events

Fink 6659 Meta-analysis Sildenafil % of intercourse attempts Drug effective across various
38
et al of 27 trials; that were successful 57% 21% –* subgroups and degrees of ED
mean age of severity
patients 55 yr; At least 1 successful
mean duration intercourse during
of ED 4.8 yr treatment 83% 45% –†

Carson 2667 Meta-analysis Sildenafil Multiple parameters: IIEF Overall efficacy of < 0.02 to No specific characteristic
39
et al of 11 double- score, questions 3 and 4 of drug v. placebo not 0.0001 predicted absolute failure with
blind, placebo- IIEF erectile function reported; however, sildenafil
controlled domain questions, global significant improve-
trials efficacy question and ment with drug seen in
patient log of sexual activity all subgroups
Note: IIEF = International Index of Erectile Function.
*Weighted mean difference between drug and placebo groups 33.7 (95% confidence interval [CI] 29.2–38.2).
†Relative benefit increase with drug 1.8 (95% CI 1.7–1.9).

1434 JAMC • 27 AVR. 2004; 170 (9)

 Erectile dysfunction

use or may need to use nitrates. These drugs potentiate the Currently, it is believed that a metabolite of testosterone,
vasodilatory effect of organic nitrates and nitric oxide dihydrotestosterone, enhances the production of nitric ox-
donor drugs.45 The effect on systemic blood pressure, how- ide, thereby producing the clinical effect.58
ever, in both normotensive and hypertensive men tends to Several other, more invasive options exist for patients
be clinically nonsignificant when sildenafil is used alone or who do not respond to PDE-5 inhibitor therapy or in
in conjunction with other antihypertensive agents.46 Tha- whom it is contraindicated. Alprostadil (prostaglandin E1)
dani and colleagues47 reported that use of vardenafil did not causes smooth-muscle relaxation and subsequent vasodila-
affect exercise tolerance among men with stable coronary tion by acting on adenylate cyclase to increase the intracel-
artery disease.47 lular cyclic adenosine monophosphate (cAMP) concentra-
Other adverse events associated with oral PDE-5 in- tion. Prostaglandin E1 may be administered intraurethrally,
hibitor therapy appear to be few (Table 4). In clinical trials where it is absorbed and transported throughout the erec-
the rates of discontinuation of the drug because of adverse tile bodies. The reported efficacy of intraurethral alpros-
events was low (< 5%) for all of 3 drugs, with few or no tadil therapy is variable. Padma-Nathan and colleagues59 re-
cases of priapism.37,53,55,56 Extra caution should be taken for ported a response rate of 65.9%. Fulgham and associates60
patients who are expected to have reduced clearance of the noted improvement in 30% of patients; however, this study
drug. This group includes men who have severe hepatic or has been criticized for inadequate dose titration.61 The most
renal insufficiency, men over 65 years old and men taking common side effect of intraurethral alprostadil therapy is
drugs that inhibit the cytochrome P450 3A4 enzyme (e.g., local penile pain caused by drug-mediated sensitization of
cimetidine, erythromycin and ketoconazole).57 For these nerve fibres.60
patients it is prudent to start with smaller doses of medica- Vasoactive drugs may also be injected intracavernosally.
tion and build up gradually. For sildenafil, it is our experi- Such therapy represents an important second-line therapy
ence that a starting dose of 50 mg is safe and effective for for erectile dysfunction. It is the most effective pharmaco-
all men. logic treatment but has a high dropout rate because of the
The potential effects of prolonged PDE-5 inhibition on associated pain and apprehension involved. Phentolamine
spermatogenesis were evaluated by Hellstrom and col- is an α-blocker that was used in initial studies; its efficacy is
leagues55 in a large cohort of men given daily doses of 10 poor, but it may be used in combination with other agents.
and 20 mg of tadalafil who were followed up for 6 months. Papaverine is a nonspecific PDE inhibitor and was the first
They found no significant effect of the drug on reproduc- effective intracavernosal therapy for erectile dysfunction.
tive hormones or sperm parameters. Currently, intracavernosal alprostadil therapy is preferred;
it is more effective than other agents and produces fewer
Alternative treatments side effects. In a comparison study comparing alprostadil, a
papaverine–phentolamine combination and papaverine
If erectile dysfunction is determined to be secondary to a alone, rates of success (ability to achieve and maintain an
hypogonadal state, often after an unsuccessful trial of PDE- erection) of 72%, 61% and 31% were reported respective-
5 inhibitors, exogenous testosterone therapy is indicated. ly.54 No patients in the alprostadil group experienced pri-

Table 4: Adverse events reported in studies comparing PDE-5 inhibitors with placebo
Group; % of patients
Sildenafil Vardenafil Tadalafil
Adverse event (25–100 mg) Placebo (5–20 mg) Placebo (2.5–20 mg) Placebo

Headache 14–30 4–6 6.8–15.3 3.9 7–21 6

Flushing 13–27 1–2 10.2–11.3 0.7 1–5 2
Dyspepsia 2–16 1–2 0.7–6.7 0 1–17 2
Rhinitis or nasal
congestion 1–11 2 2.8–7.3 3.3 4–6 4
Nausea 1–6 1 NR NR NR NR
Dizziness NR NR NR NR NR NR
Visual disturbance 0–11 ≤2 < 1–2 0 0.1 0
Back pain 0–6 2 NR NR 3–9 5
Myalgia NR NR NR NR 1–7 2
Yawning NR NR NR NR NR NR
Somnolence NR NR NR NR NR NR
Pharyngitis NR NR NR NR NR NR
Note: NR = not reported.
Source: Dula et al,48 Bukofzer et al,49 Montorsi et al,50 Carson et al,39,51 Goldstein et al,52 Porst et al,41,53,54 Hellstrom et al35,55 and Brock et al.37

CMAJ • APR. 27, 2004; 170 (9) 1435

Fazio and Brock

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I NSTITUTE
rate (Viagra) on blood pressure in normotensive and hypertensive men. Urol- A five level credit program exclusively for
ogy 2002;59:747-52. physicians designed to develop superior leadership
47. Thadani U, Smith W, Nash S, Bittar N, Glasser S, Narayan P, et al. The effect and management skills
of vardenafil, a potent and highly selective phosphodiesterase-5 inhibitor for the
treatment of erectile dysfunction, on the cardiovascular response to exercise in Approved for RCPSC, CFPC, CCHSE credits
patients with coronary artery disease. J Am Coll Cardiol 2002;4;40(11):2006-12.
48. Dula E, Bukofzer S, Perdok R, George M; Apomorphine SL Study Group.
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and with 4 mg apomorphine SL in male erectile dysfunction. Eur Urol May 30-June 1 / June 2-4 Ottawa, ON
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Int J Impot Res 2001;13(Suppl 3):S40-4. PMI III/IV
50. Montorsi F, McDermott TE, Morgan R, Olsson A, Schultz A, Kirkeby HJ, et
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dysfunction of various etiologies. Urology 1999;53:1011-8.
51. Carson CC, Burnett AL, Levine LA, Nehra A. The efficacy of sildenafil citrate PMI Refresher
(Viagra) in clinical populations. An update. Urology 2002;60(Suppl 2B):12-27. Oct. 22-24 Vancouver, BC
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53. Porst H, Rosen R, Padma-Nathan H, Goldstein I, Giuliano F, Ulbrich E, et A practical, cost effective and focused training opportunity
al. The efficacy and tolerability of vardenafil, a new, oral, selective phosphodi- held on-site for medical leaders and managers
esterase type 5 inhibitor, in patients with erectile dysfunction: the first at-
home clinical trial. Int J Impot Res 2001;13(4):192-9. FOR INFORMATION:
54. Porst H. [Prostaglandin E1 in erectile dysfunction] [article in German]. tel 800 663-7336 or 613 731-8610
Urologe A 1989;28:94-8. x2319 (PMI) or x2261 (In-house PMI)
55. Hellstrom WJ, Overstreet JW, Yu A, Saikali K, Shen W, Beasley M Jr, professional_development@cma.ca
Watkins VS. Tadalafil has no detrimental effect on human spermatogenesis
or reproductive hormones. J Urol 2003;170(3):887-91.
56. Saenz de Tejada I, Anglin G, Knight JR, Emmick JT. Effects of tadalafil on
erectile function in men with diabetes. Diabetes Care 2002;25(12):2159-64.

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