Introduction
Sildenafil (Viagra®)
Vardenafil (Levitra)
Tadalafil (Cialis®)
Intracavernosal
Injection
Intraurethral
Suppository
Topical Agents
Vacuum Devices
Implants
Introduction: A common consequence of SCI is erectile
dysfunction (ED), defined by the National Institutes of Health as the
inability to achieve or maintain an erection sufficient for satisfactory
sexual activity. Because SCI disproportionately affects young men,
restoration of sexual function is a high priority, often listed ahead of
walking. Many approaches of varying effectiveness have been used to
asddress SCI-associated ED, including topical and intraurethral agents,
penile injections, vacuum-tumescence devices, penile implants, sacral
stimulators, and oral medications.
Reflex versus Psychogenic Erection: Because
the biology behind erectile function is complex, an in-depth
discussion is not possible. Basically, there are two types of erections:
reflex (produced by touch) and psychogenic (mentally induced). Each type
is controlled by different nerves and neurophysiology, and is affected
differently and in a contrasting fashion by injury level.
The ability to generate reflex erections depends on
the preservation of neural circuitry in the lower, sacral (S2-4)
spinal-cord segments. Hence, although there is less overall paralysis
from a sacral than a high-level injury, reflex-erection potential will
be more compromised. In contrast, the required sacral neural circuitry
is undamaged in higher injuries, preserving reflex erections.
Psychogenic erections (e.g., visual stimulation,
titillating talk, fantasies, sexual memories, seductive perfumes,
provocative music, etc) are mediated, in part, through the thoracic T-10
to lumbar L-2 spinal regions. Hence, individuals with injuries above
this level have lost the ability to generate psychogenic erections but
have maintained reflex-erection capacity. In contrast, although unable
to produce a reflex erection, those with a sacral injury have the neural
pathways necessary to mediate a psychogenic erection. Men with injuries
between the T10- L2 and S2-4 levels may retain both psychogenic and
reflex erections.
This synergistic situation is confounded with
incomplete injuries in which some function-controlling neurons still
transverse the injury site, often the situation even in those injuries
clinically classified as complete.
Erection Physiology: An erection develops
when cylindrical, sponge-like regions surrounding the penis become
filled with blood. Penile tumescence is initiated by nerve branches
releasing a key neurotransmitter called nitric oxide, which, in turn,
causes penile arteries to dilate, filling the sponge-like cavities with
blood. This process is mediated by the nitric-oxide-stimulated
production of a secondary messenger molecule called cGMP (cyclic
guanosine monophosphate). This molecule is especially important because
Viagra-like drugs inhibit its enzymatic degradation, letting it
accumulate and, in turn, promoting erection. So to speak, it is like
disabling the brakes on a cGMP-fueled car.
Sildenafil
(Viagra®): The development of popular oral drugs
over the past decade such as Viagra has greatly influenced how
SCI-related ED is tr
eated.
As mentioned above, Viagra inhibits cGMP degradation, therefore,
shifting the physiological balance more toward erection maintenance.
Often funded from the drug sponsor, studies have documented Viagra’s
SCI benefits:
1) Maytom (UK) et al carried out a two-part pilot
study in men with SCI-related ED (Spinal Cord, 37, 1999). In part
1, 27 subjects (age 18-55, sustaining injuries at least 1/2 years
earlier) received either Viagra or placebo. After a three-day washout
period to get the drug out of the system, the treatments were reversed.
Sixty-five percent had erections sufficient for penetration after taking
the drug compared with only 8% for the placebo. In Part 2, subjects were
randomized to receive either Viagra or placebo over a 28-day period.
Based on questionnaires, 75% and 8% of the Viagra- and placebo-treated
patients, respectively, indicated that treatment had improved their
erections. The study concluded that Viagra “is an effective,
well-tolerated oral treatment for ED in SCI subjects.”
2) In a somewhat similar but larger study, Giuliano
(France) and colleagues examined Viagra’s effects on 178 men with SCI,
who were injured at least six months before study recruitment (Ann
Neurol, 46(1), 1999). The subjects received either Viagra or a
placebo before sexual activity for six weeks. After a two-week washout
period, treatments were reversed. Evaluated by patient questionnaires
and feedback, 80% reported that Viagra improved sexual intercourse
compared with only 10% for placebo. The most common side effects were
headaches, flushing, and indigestion.
3) Schmid and colleagues (Switzerland)
prospectively studied the effects of Viagra in 41 men with SCI (Eur
Urol, 38(2), 2000). Ninety-three percent responded positively to
Viagra, obtaining a sufficiently rigid erection for sexual intercourse.
About 10% had side effects, such as headaches or dizziness
4) Green and Martin (Atlanta, GA, USA) studied
Viagra’s effects in 40 men with spinal cord dysfunction (both SCI and
MS) (NeuroRehabilitation, 15(2), 2000). Followed for up to two
years, erectile response improved from 4.9 to 7.8 on a scale of 1-10,
and 90% obtained erections sufficient for intercourse.
5) Ramos et al (Spain) studied Viagra’s safety and
efficacy in 170 men with SCI (Spinal Cord, 39, 2002). Assessed by
questionnaires, 88% of the subjects and 85% of their partners reported
improved erections as a result of the drug. The investigators concluded
that Viagra is an “effective, well-tolerated treatment for erectile
dysfunction caused by spinal cord injury, regardless of the cause,
neurological level, ASIA grade, and time since injury.”
6) One of Viagra’s side effects in neurologically
intact men is hypotension or low blood pressure. Because individuals
with higher level injuries are prone to hypotension, Ethans and
colleagues, (Manitoba, Canada) studied Viagra’s effects on blood
pressure in men with SCI (J Spinal Cord Med, 26(3), 2003).
Although blood pressure changed little in subjects with thoracic
injuries, it decreased significantly in those with cervical injuries.
The investigators recommend the drug be prescribed with caution.
7) Dr. Sureyya Ergin et al studied the
effects of Viagra on 50 men with SCI recruited at five centers in Turkey
(ref). Subjects averaged 39 years in age and had been injured at least
six months before recruitment. Approximately 58% had ASIA-A classified
complete injuries, and the remainder had incomplete injuries. The
subjects were randomized to receive either Viagra or placebo for six
weeks. This was followed by a two-week washout period in which nothing
was administered, i.e., ensuring the drug was out of the system.
Following this washout period, the treatments were reversed (i.e., a
crossover design). Based on subject feedback obtained by various
questionnaires and other mechanisms, the investigators concluded that
Viagra “produced higher levels of successful stimulation, intercourse
success, satisfaction with sexual life and sexual relationship, erectile
function, overall sexual satisfaction…”
Vardenafil (Levitra): Levitra is in the same
class of drugs as Viagra and promotes erectile potential through similar
physiological mechanisms.
In a large multi-center, double-blind study,
Giuliano et al (France) evaluated the effectiveness and tolerability of
Levitra in 418 men with SCI sustained at least six months before study
enrollment (Neurology, 66(2), 2006). Subjects were randomized to
receive either Levitra or an inactive placebo. Erectile function was
measured by questionnaires and diary questions concerning penetration,
maintenance of erection to completion of intercourse, and ejaculation.
All of these measures improved in the Levitra-treated group relative to
placebo. Side effects reported most often included headache, flushing of
the skin, nasal congestion, and dyspepsia (stomach Pain). The
investigators concluded Levitra “significantly improved erectile and
ejaculatory function and was generally well tolerated in men with
erectile dysfunction due to spinal cord injury.”
In a non-blinded study, Kimoto and colleagues
(Japan) treated 32 men with SCI with varying doses of Levitra (Int J
Urol, 13(11), 2006). The investigators concluded that drug was “well
tolerated and improved erectile function in patients with SCI.” Although
no serious side effects occurred, 22% of patients reported mild and
transient effects such as hot flushes and headaches.
In addition to improving erectile function, Levitra
seems to enhance bladder function in men with SCI as measured by a
variety of urodynamic assessments.
Tadalafil (Cialis®):
Cialis is yet another oral medication that works in a fashion similar to
Viagra or Levitra. However, unlike these other drugs, whose
effectiveness is limited to about four hours, long-lasting Cialis will
enhance erection potential for up to 36 hours.
Dr. Francois
Giuliano (France) and associates reported
the results of a double-blind study comparing erectile function,
measured by a number of parameters, in 186 subjects with SCI treated
with either varying doses of Cialis or a placebo control. Of these
individuals, 69% had complete injuries; 84% had thoracic, lumbar, or
sacral injuries; and 69% had moderate to severe ED.
Eighty-five percent of the Cialis-treated subjects
reported improved erections compared with only 19% for placebo-treated
subjects. Seventy-five percent of the Cialis-treated men were able to
penetrate their partner compared with only 44% before treatment; and 48%
reported successful intercourse compared with only 11% before treatment.
Headaches and urinary tract infections were the most common reported
side effects.
Dr. Giuseppe Lombardi (Italy) and
co-investigators followed 65 men with SCI who had been taking Cialis an
average of nearly 34 months. They reported a significant statistical
improvement in erectile function, sexual satisfaction, and overall
satisfaction…” and concluded that Cialis “represents an effective and
safe long-term option for SCI patients with ED.”
Intracavernosal Injection:
Erectile tumescence occurs when
cylindrical, sponge-like regions on each side of (corpus cavernosa) and
below the penis shaft become engorged with blood. Injection of certain
agents alone or in combination into one of the cavernous regions (i.e.,
the side of shaft) consistently produces rigid erections in men with
SCI-related ED. Basically, these substances enhance erection-promoting
blood flow into the penis. An occasional side effect is priapism, a
prolonged, often painful erection, in which the penis does not return to
its flaccid state within about four hours.
Alprostadil is identical to natural occurring
prostaglandin E1 (PGE1). Although originally isolated from
prostate secretions (hence, the name), prostaglandins are found in most
tissues and hormonally exert many physiological effects. Alprostadil
intracavernosal injections are marketed under various brand names,
including Caverject® (www.caverjectimpulse.com) and Edex®
(www.edex.com). Other substances used for SCI-related ED include
papaverine, a non-narcotic opiate; phentolamine, a drug used to treat
adrenal-gland tumors; and atropine. Combination products available
through compounding pharmacies, which create custom medications on a
doctor’s prescription, include Bimix (papaverine and phentolamine),
Trimix (Bimex plus alprostadil), and Quadmix (Trimix plus atropine).
Several studies have been carried out evaluating
the use of intracavernous injections to treat SCI-related ED, including
the following:
Beretta et al (Italy) treated 22 men with SCI with
intracavernous injections of papaverine, of whom, 20 obtained complete
penile rigidity (Acta Eur Fertil, 17(4), 1986). Seven had erections
lasting more than 300 minutes.
Sidi and colleagues (Minnesota, USA) treated 66
patients with SCI with intracavernous injections containing either
papaverine or a combination of papaverine and phentolamine (J Urol,
138(3), 1987). All 52 patients who completed the protocol “achieved
transient functional penile erections”; four suffered priapism requiring
treatment.
Earle et al (Australia) treated 22 men with SCI
with various intracavernosal agents, including papaverine, papaverine
plus phentolamine, or PGE1 (i.e., alprostadil) (Paraplegia,
30(4), 1992)). Nineteen responded to therapy. Twelve of 14 who
participated in a follow-up mail survey continued to periodically use
the drugs and reported satisfaction with their use.
Kapoor and colleagues treated 65 men with
paraplegia and 36 with quadriplegia with intracavernous papaverine. Of
these, 98 had erections sufficient for coital penetration (Paraplegia,
31(10), 1993)), and three had prolonged erections lasting more than four
hours.
Hirsch et al (Pennsylvania, USA) evaluated
intracavernous PGE1 (alprostadil) treatment in 27 men with neuropathic
erectile dysfunction (14 with SCI) (Paraplegia, 32(10), 1994).
“Quarterly monitoring up to 28 months demonstrated satisfactory erectile
rigidity and duration of erection.” No priapism was observed.
Zaslau and colleagues (New York, USA) treated 28
men with intracavernous injections containing a combination of
papaverine and prostaglandin E1 (alprostadil) (J Spinal
Cord Med, 33(12), 1999). Of those who completed the study, 85%
indicated that their erections were good or excellent, and 77% were
moderately or extremely satisfied with treatment. Average erection
duration was 43 minutes.
Intraurethral Suppository: Alprostadil can also be
administered by inserting a small medicated pellet in the urethral
opening (the passage from the bladder to the outside through which urine
flows). Absorbed by the urethral tissue, the medicine passes through to
the surrounding erectile tissue. This ED treatment is marketed under the name MUSE®, an acronym for
“medicated urethral system for erections” (www.muserx.net).
The method is less invasive and considered easier
for quadriplegics who may lack the hand function needed for
intracavernosal injections. To enhance erectile rigidity, it has been
used with a constrictor band at the base of the penis, which also limits
the systemic absorption of the drug into the rest of the body.
Studies suggest that the treatment is less
effective than the injections, and high doses of the drug were required
to produce sufficient tumescence. For example, Bodner and colleagues
(Ohio, USA) evaluated the ability of MUSE to treat ED in 15 patients
with SCI (Urology, 53(1), 1999). The investigators concluded:
“MUSE appears somewhat effective in creating erections; however, these
were less rigid erections than those obtained with intracavernosal
therapy and provided less overall satisfaction.”
Topical
Agents: A number of less-invasive, but less-effective,
topical agents enhance erectile potential. For example, Topiglan, which
is rubbed on the penis tip, contains alprostadil together with a
substance that increases skin absorption. Goldstein and colleagues
randomized 60 men with moderate to severe ED to receive either Topiglan
or a placebo gel (Urology, 57(2), 2001). About 40% of those who
received the active gel developed erections sufficient for vaginal
penetration compared with only seven percent of controls.
Several studies have been carried out evaluating
the effects of various topical agents in treating SCI-related ED,
including the following:
Sonksen and Biering-Sorensen (Denmark) studied the
erection-producing effects of placing nitroglycerin-containing plasters
on the penile shaft of 17 men with SCI (Paraplegia, 30(8), 1992).
(nitroglycerine is a vasodilator, i.e., a blood-flow-increasing
substance) All of these men had responded previously to intracavernous
papaverine injections sufficient for vaginal penetration. A positive
response was obtained in 12 of the men. Five were able to achieve
erections sufficient for vaginal penetration at home and preferred the
method over the previously used injections.
Beretta et al (Italy) examined the erectile
properties of minoxidal (another vasodilatory agent) topically applied
to the penile shaft in 15 men with SCI (Acta Eur Fertil, 24(1),
1993). Of the four who reported a positive erectile response, three
preferred to continue with this noninvasive treatment over
intracavernous injections.
Kim and McVary (Illinois, USA) evaluated the effect
of topically applied alprostadil on erection function in 10 men, nine of
whom had SCI (J Urol, 153(6), 1995). Blood flow in the arteries
serving the erection-producing cavernous tissue increased in 7 of the
10.
In a somewhat similar study, Kim and associates
(Illinois, USA) examined the effects of topically administered
papaverine gel in 20 men with ED, of whom 13 had SCI (J Urol,
153(2), 1995). The investigators concluded that “papaverine gel appears
to be safe and well tolerated… and increases blood flow to the penis.”
They also noted that the application of the gel to the genitalia
resulted in little systemic absorption and, as a result, less potential
to exert physiological effects in other parts of the body.
Renganathan and colleagues (India) compared the
effectiveness of intracavernous injections of papaverine with
nitroglycerin transdermal patches in treating ED in 28 men with SCI (Spinal
Cord, 35(2), 1997). Ninety-three percent of the subjects who
received an intracavernous injection of papaverine demonstrated a
complete erectile response compared with only 61% who used the
transdermal nitroglycerin.
Vacuum
Devices: Vacuum devices have been shown to enhance erections
in men with SCI-related ED. With these devices, a cylinder attached to a
vacuum pump is placed over the penis, and the resulting vacuum draws
blood into the penis, creating an erection. A constriction ring is then
temporarily placed around the penis base to maintain the erection. For
men with poor hand function, battery-operated devices are available. As
a non-pharmaceutical option for ED, vacuum devices can be used as a
backup for other approaches and more than once in a 24-hour period. The
devices have been evaluated in a number of SCI-focused studies:
Zazler and Katz (Virginia, USA) prospectively
examined vacuum-device effectiveness in 20 men with injuries ranging
from the cervical C-4 to lumbar L-2 level (Arch Phys Med Rehabil,
70(9), 1989). Subjects ranged in age from 21 to 65 (average: 40), had
been injured for at least a year, and had a steady sexual partner.
Evaluated by subject and partner questionnaires, all reported successful
vaginal intercourse after having used the device at least 20 times. The
majority indicated that intercourse quality was very good or excellent
compared to the previous best since injury. The investigators concluded
the device “was an effective, safe, non-invasive alternative for the
management of impotence secondary to cord injury.”
Heller et al (Israel) studied the use of such
devices in 30 subjects with chronic neurological impotence (Paraplegia,
30(8), 1992). After training at the clinic, 17 chose to use the device
at home, and 21 months later, 50% were still using it. Intercourse
frequency increased from 0.3 to 1.5 times a week.
Denil and associates (Michigan, USA) evaluated the
erection-promoting potential of vacuum devices in 20 men with
SCI-related ED (Arch Phys Med Rehabil, 77(8), 1996). At three
months, 93% and 83% of their female partners reported erection
sufficiently rigid for vaginal penetration (average duration 18
minutes). At six months, 41 and 45% of the men and women, respectively,
were satisfied with the device, with early rigidity loss the most common
complaint. Although minor side effects occurred often, including
petechiae (red spots under the skin caused by blood that has leaked from
the capillaries) and skin edema, none required treatment.
Penile
Implants: Both malleable and inflatable penile implants have
a relatively long history of use for SCI-related ED. With the former,
semi-rigid cylinders are implanted into erectile tissue; the device is
bent outward for sex and back toward the body for concealment. With a
two-piece inflatable device, inflatable cylinders are connected to a
ball-shaped pump locate in the scrotum, which, when squeezed, sends
fluid from the back of the cylinder to its mid-area, producing erectile
rigidity. When the middle of the penile shaft is bent, the fluid returns
to the cylinder base. In addition to the cylinders and scrotal pump, the
three-piece device includes a fluid reservoir located behind stomach
muscles.
In Spinal Cord Medicine: Principles and
Practices (2003), Elliot (British Columbia, Canada) notes:
“Men with SCI experience a much higher infection rate and erosion rate
with these devices when compared to nonneurological patients…Because
these devices are placed in the spongy tissue of the corpora cavernosal
bodies, much of the tissue is permanently destroyed. This precludes the
use of other erection enhancement techniques….”
In a review article focused on SCI-related ED,
Deforge and colleagues (Ontario, Canada) stated “Penile implants are
very satisfactory for those who do not have complications, but the
serious complication rate was consistently close to 10%. Furthermore,
patients who have an implant removed are likely to have damage to the
penile tissues that would make them nonresponsive to intracavernous
injections or vacuum devices.” (Spinal Cord, 44, 2006)
In a recently published study, Zerman et al
(Germany) reported the results of following 245 men (197 SCI) with
neurological impairment with ED, who had received implants between 1980
and 1996 (J Urol, 175, 2006). Fifty percent had a semi-rigid
device implanted, and the rest inflatable devices. The investigators
concluded “The implantation of a penile prosthesis is a safe procedure
for erectile dysfunction… in neurologically impaired. Based on technical
advances the complication rates significantly decreased during the
years.”
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