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Sexual and Reproductive Health

Phosphodiesterase Type 5 Inhibitors (PDE5i) and Other Oral Agents

Erection is initiated by smooth muscle relaxation of the corpora cavernosa (erectile bodies) of the penis and depends on the nitric oxide-cyclic guanosine monophoshpate [cGMP] pathway. The PDE5i are selective inhibitors of type 5 (cGMP specific) phosphodiesterase, which in turn delay breakdown of cGMP, prolonging and enhancing the erectile response. Apomorphine is a dopamine-receptor agonist important in the control of sexual functioning, whereas 4–aminopyridine is a K+ channel-blocking agent noted for increasing neurotransmitter release at neuronal sites and enhancing conductivity in demyelinated axons. Most clinicians recommend that men with SCI, regardless of their level of injury, be offered a trial of PDE‐5 inhibitors (Rizio et al. 2012).

Author Year;
Country
Score
Research Design
Total Sample Size
Methods Outcome
Khorrami et al.
2010;
Iran
RCT
Level 1
PEDro=9
N=105
Population: 105 men with SCI who had
neurogenic erectile dysfunction; all with
paraplegia; mean age 47.6 (range 40-55);
divided into those with upper motor neuron
(UMN) injuries (n=72) and those with lower
motor neuron (LMN) injuries (n=33).
Treatment: Sildenafil 50mg 45min before
start of sexual intercourse, increased to
100mg if not effective, for treatment group
(n=45 from UMN and n=14 from LMN);
placebo for control group (n=27 from UMN
and n=19 from LMN).
Outcome Measures: International Index of
Erectile Function (IIEF5) questionnaire; if
subject scored more than 15 points on the
IIEF5, then treatment considered effective, if
less than 15 then inadequate.
1. 37 (82%) of the 45 UMN participants who took
sildenafil had a favourable response,
compared to 7 (26%) of the 27 placebo UMN
participants.
2. 4 (28.5%) of the 14 LMN participants who took
sildenafil had a favourable response,
compared to 5 (26%) of the 19 LMN
participants who had placebo.
3. Side effects include headache (n=8), flushing
(n=4) and gastro-intestinal discomfort (n=3).
Giuliano et al. 2008;
USA
RCT
Level 1
PEDro=9
N=418
Population: 418 men with SCI over 18 yrs old
with resulting erectile dysfunction for over 6
months, and in a stable heterosexual
relationship for over 1 month, randomized to
vardenafil (n=207) or placebo (n=211).
Treatment: Vardenafil (placebo for controls)
for 12 weeks; dosage for the first 4 weeks was
10mg, and subsequently adjusted individually
to 20 or 5mg.
Outcome Measures: Success of ejaculation;
International Index of Erectile Function (IIEF)
scores; Global Confidence Question (GCQ);
Psychological General Well-Being Index
(PGWBI); Centre for Epidemiological Studies
– Depression (CES-D) score; Rosenberg
Self-Esteem Score (RSES); Mental Health
Summary of the SF-36 Health Survey.
1. Success rate of ejaculation was significantly
higher in the vardenafil group compared to
control (19% vs. 10%).
2. The IIEF orgasmic function domain score
(questions 9 and 10) increased from 2.9 to 4.0
in vardenafil group, compared to 3.0 to 3.4 in
control.
3. The GCQ score increased from 2.5 to 3.5 in
the vardenafil group, compared to from 2.6 to
2.9 in control (significant difference).
4. No significant difference between vardenafil
and control groups in the PGWBI, the CES-D,
RSES, or SF-36 mental health domain scores
before and after treatment.
Ergin et al. 2008;
Turkey
RCT with crossover
Level 1
PEDro=8
N=50
Population: 50 men with SCI, over 19 yrs old,
with associated erectile dysfunction but had
some psychogenic or reflexogenic erectile
function.
Treatment: 50mg of sildenafil (placebo for
controls) 1 hr before sexual activity, for 6
weeks; this was followed by a 2-week
washout period, after which the patient was
switched to the alternate treatment for another
6 weeks.
Outcome Measures: International Index of
Erectile Function (IIEF); Life-Satisfaction
Check List (LISAT-8); Erectile Dysfunction
Inventory of Treatment Satisfaction (EDITS);
Global Efficacy Assessment questionnaire.
1. Sildenafil produced greater improvements than
placebo in following areas: satisfaction with
sex life and sexual relationship (IIEF questions
13 and 14), EDITS score, erective function
and overall sexual satisfaction.
2. No difference between the 2 groups with
regard to total IIEF scores.
3. No difference between the 2 groups with
regard to intercourse satisfaction or sexual
desire.
4. No reports of AD symptoms in patients
undergoing treatment.
5. Participants with incomplete injuries showed
improvement in 7/11 measures whereas
participants with complete injuries showed
improvement in 3/11 measures.
Derry et al. 1998;
UK
RCT
Level 1
PEDro=8
Initial N=27
Final N=26
Population: 27 men, treatment n=12,
placebo n=14; Age: mean 32-34 yr; Injury
level: T6-L5, AIS: A-D but must have partial
reflexogenic erection to vibrostimulation.
Treatment: Randomized to receive 50mg of
sildenafil or placebo not more than 1/day,
approx 1 hr before sexual activity.
Outcome Measures: Efficacy and safety of
sildenafil, sexual function questionnaire.
1. 75% on sildenafil and 7% on placebo
reported that treatment improved erections.
2. Significant improved satisfaction with sex life
reported by sildenafil group.
3. Mean number of grade 3-4 erections was
1.8/wk for sildenafil group, 0.4/wk for placebo
patients.Effect Sizes: Forest plot of standardized mean differences (SMD ± 95%C.I.) as calculated from pre- and post-intervention data.
Giuliano et al. 2007;
France
RCT
Level 1
PEDro=7
N=186
Population: 186 men with SCI; Age: mean
38 yrs, range 18-66; Level of injury: cervical
15.6%, thoracic 62.0%, lumbosacral 22.3%;
Impairment grade: 69% AIS A; Erectile
dysfunction (ED) at least 6 months.
Treatment: Tadalafil 10-20mg for 12 wks or
placebo, 1 tablet 1 hr before each attempt at
intercourse, not more than 1 dose/day, at
wks 4 and 8 dose maintained or titrated
up/downwards (10 or 20mg).
Outcome measures: International Index of
Erectile Function (IIEF)/Erectile Function
(EF) domain, Sexual Encounter Profile
(SEP), adverse events.
1. IIEF/EF: Tadalafil group improved (13.5 to
22.6) compared to placebo group (13.0 to
13.6).
2. Tadalafil group compared to placebo reported
greater mean per-patient percentage of
successful penetration attempts (75.4% vs
41.1%), greater percentage improved
erections (84.6% vs 19.5%), and greater
ejaculatory frequency.
3. Adverse events: headache (8.5% vs 4.5%)
and UTI (7.7% vs 6.8%).
Giuliano et al. 1999;
UK
RCT (cross-over)
Level 1
PEDro=7
N=178
Population: 178 men, Age: mean 38 yrs,
Impairment: 53% complete.
Treatment: Sildenafil 25, 50, or 100mg or
placebo, 1hr before sexual activity for 6
weeks followed by a 2-week washout before
cross-over.
Outcome Measures: Efficacy and safety of
oral sildenafil, International Index of Erectile
Function (IIEF), event log data.
1. IIEF: 83% reported improved erections with
sildenafil vs. 12% on placebo.
2. Ability to achieve & maintain erection,
satisfaction of sexual intercourse, &
satisfaction of sexual relationship with partner
significantly improved with sildenafil over
placebo.
3. Ejaculation and orgasm frequency improved
in sildenafil group over placebo.
Maytom et al. 1999;
UK
RCT
Level 1
PEDro=7
N=27
Population: 27 men; Age: range 21-49 yrs;
Impairment grade: AIS A (n=14), B (n=3), C
(n=5), D (n=5); Level of injury: T6-L5.
Treatment: Single dose sildenafil 50mg or
matching placebo (part I) in random order
followed by at least a 3 day washout period
before cross-over treatment (part II) for 28
days.
Outcome Measures: Efficacy and safety of
sildenafil, duration & rigidity of erections, self report diary data.
1. Part I: 65% had erections (defined as >60%
rigidity) on sildenafil, 8% with placebo.
2. Part II: 75% on sildenafil & 7% on placebo
reported improved erections.
3. Sexual Satisfaction: the sildenafil group were
more satisfied with their sex lives.
Potter et al. 1998;
USA
Population: 26 men; Age: mean 40.6 yrs;
Injury level: C4-T12, tetraplegia (n=19), paraplegia (n=10), incomplete.
Treatment: Fampridine-SR or placebo
12.5mg for first week, 17.5 mg for 7 days, 1
week washout before cross-over.
Outcome Measures: Safety and efficacy of
oral Fampridine-SR, patient satisfaction,
quality of life, sensory and motor scores,
Ashworth.
1. No significant results related to sexual
function.
2. 5 fampridine-SR patients reported erection
improvement; however 4 placebo patients
also reported erection improvement.
Cardenas et al.
2014
US and Canada
RCT
PEDro=6
Study SCI-F301
N=213
Study SCI-F302
N=204
Population: Patients with incomplete chronic
SCI from two identical double-blinded,
placebo-controlled studies (SCI-F301 and
SCI-F302), from 45 and 33 centres,
respectively, in the US and Canada. Both
patient populations were balanced at
baseline rendering comparability of patient
populations. SCI-F301: Placebo
(n=98): Mean age: 40.1 yr; Gender:
males=85, females=13. Fampridine-SR
(n=114): Mean age: 41.6 yr, Gender:
males=100, females=14.
SCI-F301: Placebo (n=100): Mean age: 40.5
yr. Fampridine-SR (n=103): Mean age: 41.3
yr.
Intervention. Patients were randomly
assigned to either fampridine-SR 25 mg or
placebo, twice daily for 2 wk in addition to a 2
wk titration, 12 wk of stable dosing, 2 wk of
downward titration and 2 wk of untreated
follow-up. Within treatment groups, patients
were further stratified by concomitant
antispasmodic medication within the two
treatment groups.
Outcome Measures: Ashworth Spasticity
Scale (AS) scores for bilateral knee flexors
and extensors, Subject Global Impression
(SGI), Penn Spasm Frequency Scale (SFS),
International Index of Erectile Function (IIEF),
Bowel and Bladder assessments, Sexual
function.
1. There were no significant between-treatment
differences except for an improvement
among men treated with fampridine-SR on
two IIEF domains, erectile function (p=0.016)
and orgasmic function (p=0.032) in SCIF301
Cardenas et al.
2007;
USA
RCT
Level 1
PEDro=6
N=91
Population: 72 men (19 female) with SCI;
Injury level: C4-T10, AIS C-D; Age: mean 38-
42 yrs, range 19-67; Time since injury at
least 1 yr.
Treatment: Fampridine-SR 25mg 2 times
per day or fampridine-SR 40mg 2 times per
day for 8 wks (2-wk dose titration, 4 wks at
fixed target dose, 2-wk downward titration) or
placebo.
Outcome Measures: International Index of
Erectile Function (IIEF), adverse events.
1. IIEF: non-significantly improved scores for
fampridine-SR 25mg and 40mg 2 times per
day vs placebo.
2. Erection frequency: significantly improved for
fampridine-SR 25mg group vs placebo.
3. Adverse events: fampridine-SR 40mg:
increased incidence of abdominal pain,
dizziness, insomnia, paresthesia,
nervousness, and anxiety vs placebo;
fampridine-SR 25mg: increased incidence of
pain vs placebo.
Del Popolo et al.
2004;
Italy
RCT
Level 1
PEDro=6
N=30
Population: 30 men, Age: range 21-60 yrs;
Injury level: cervical (n=9), above T10 (n=6),
below T10 (n=10); Time since injury: 6-12
months.
Treatment: Randomized to sildenafil (4
doses 50mg) or tadalafil (4 doses 10 mg). To
attempt intercourse on 4 separate occasions:
within 4h of 1st tablet, 12h of 2nd tablet, 24h
of 3rd and 24-36h after 4th tablet. Cross-over
after 2 wk wash-out.
Outcome Measures: Safety, time/duration
effectiveness, Sexual Encounter Profile.
1. Tadalafil allowed normal sexual functioning
up to 24hr post dosing compared to sildenafil.
Giuliano et al. 2006;
USA
RCT
Level 1
PEDro=6
N=418
Population: 418 men, treatment n=207,
placebo n=211; Age: range 18-80 yrs; Injury
level: below T12 (n=94), at or above T12
(n=307).
Treatment: Randomized to 12 wks of
vardenafil (10mg for the first 4 wks) or
placebo. 1 tablet 1 hr before each attempt at
intercourse, not more than 1/day. At wks 4
and 8, dose maintained or titrated increasing
or decreasing 1 step (to 5 or 20 mg).
Outcome Measures: Efficacy and tolerability
of vardenafil, Erectile Function Domain
Scores (from International Index of Erectile
Function), Sexual Encounter Profile.
1. EF domain scores in the vardenafil group
improved significantly (22.0 from 11.6)
compared to the placebo group (13.5 from
12.1).
2. Over 12 weeks of treatment, mean perpatient penetration (76% vs 41%),
maintenance (55% vs 22%), and ejaculation
success rates (19% vs 10%) on vardenafil
were significantly greater vs the placebo
group.
Hultling et al. 2000;
Australia
RCT (cross-over)
Level 1
PEDro=6
N=178
Population: 178 men with SCI; Age: mean
38 yrs, range 19-63 yrs.
Treatment: Sildenafil upward and downward
titration with variable dose of 25mg 1hr presexual activity to a maximum of 100mg.
Doses adjusted by 25mg/wk during 6-wk
period. Randomized to 6-wk flexible dosing,
2 wk washout, then 6-wk placebo or vice
versa.
Outcome Measures: Efficacy of sildenafil
citrate, IIEF (Q13,14), Medical Outcomes
Survey, SF-12, Psychological General WellBeing Index.
1. Increase in overall satisfaction with sex life
(49% over baseline).
2. Sexual relationship with partner (increased
34% over baseline) with sildenafil.
3. “Impact of erectile problems” assessing
emotional distress improved 23% above
baseline.
Tuzgen et al. 2006;
Turkey
RCT
Level 1
PEDro=6
N=60
Population: 60 Men with SCI; Age: mean
35.2 yrs, range 25-45; Impairment: AIS A
(n=28), AIS B (n=8), AIS C (n=7), AIS D
(n=17); Mean time since injury: 53.5 months.
Treatment: Sildenafil 25mg or sildenafil
50mg for 4 wks, 1 hr before sexual activity.
Outcome measures: International Index of
Erectile Function (IIEF) – Erectile Function
(EF), Intercourse Satisfaction (IS), Overall
Satisfaction (OS), Orgasmic Function (OF),
and Sexual Desire (SD); adverse events.
1. Improved reflexogenic erectile response in
both groups.
2. Significant improvement in erections,
frequency of sexual intercourse, satisfaction,
enjoyment, sexual desire, overall sex life,
sexual relationship, and self-confidence in
erections at both the low and the high
dosage.
3. There were no significant differences
between the low dose and the high dose
groups. .
4. There were 13 and 16 adverse events
recorded in the low dose and high does group
respectively. Main adverse events: headache,
dyspepsia and rash.
Hultling 1999;
Sweden
RCT
Level 1
PEDro=5
N=178
Population: Men with SCI and partner; Age:
mean 30 yrs, range 19-63 yrs.
Treatment: Sildenafil flexible-dose 25-
100mg (on demand) for 6 wks (cross-over
with 4-wk washout period).
Outcome measures: ability to have
intercourse, partner perception of ability to
achieve erection and ability to maintain
erection.
1. Men: improved ability to achieve erections
and to have intercourse was reported by 83%
and 80% of men, respectively, compared to
the placebo group with 10% reporting
improvements.
2. The number of successful attempts at
intercourse improved in the sildenafil group.
3. Partner perception: improved ability to
achieve and maintain erections with sildenafil.
Yildiz et al. 2011;
Turkey
Prospective, oneway crossover,
dose-controlled
study
Level 2
N=31
Population: Men with erectile dysfunction
secondary to SCI.
Treatment: Day 1- Group 1: visual and
auditory sexual stimulus (VASS) Group 2:
VASS with 25 mg of intracavernosal
papaverine; Group 3: after a wash-out period
of papaverine on day 2, VASS with 50mg oral
sildenafil on day 5.
Outcome Measures: Peak (PSV) and end
diastolic velocity (EDV) using penile color
Doppler ultrasound.
1. There was a statistically higher PSV with
papaverine (45.31(11.37)) or with sildenafil
(41.59(15.55)) compared to control
(22.25(7.54)).
2. There was no statistically significant difference
between the PSV and EDV values of the
papverine and sildenafil groups.
Lombardi et al.
2009a;
Italy
Pre-post
Level 4
N=103
Population: 103 men with SCI and erectile
dysfunction (mean age 39)
Treatment: Tadalafil 10mg for 4 weeks;
participants whose IIEF (ED) score were still
less than 26 were treated with Tadalafil 20mg
for 4 weeks; participants who responded well
to the treatment (n=74) continued treatment
and were included in a 6-month follow up.
Outcome Measures: International Index of
Erectile Function (IIEF15); Sexual Encounter
Profile (SEP) question 2 and 3.
1. 38 out of 103 participants responded to 10mg
of Tadalafil.
2. 36 participants subsequently responded to
20mg of Tadalafil.
3. 9 patients dropped out of the follow-up due to
various reasons.
4. There was a statistically significant
improvement in erectile function, sexual
satisfaction, and SEP2-3 scores in the follow up group.
5. There was no significant difference in
ejaculatory function.
Lombardi et al.
2009b;
Italy
Pre-post
Level 4
N=113
Population: 113 participants with SCI and
with erectile dysfunction (ED), median age 39
(range 21-67), mean time since injury 39
months (range 6-74 months); 74 participants
had injury level above T12, and 70 were AIS
A.
Treatment: Sildenafil 50mg, increased to
sildenafil 100mg for non-responsive
participants.
Outcome Measures: Sexual Encounter
Profile Questions 2 and 3 (SEP2 and SEP3);
International Index of Erectile Function
(IIEF15) erectile domain score; both scales
were used for Phase 1, and only IIEF15 was
administered for Phase 2 (follow-up every 6
months for 10 years).
1. 75 participants reached an erectile domain
score of at least 26 and answered “yes” for
75% of the time or more for SEP2 and 3; of
these participants 48 responded to 50mg of
sildenafil while the rest had increased to
100mg.
2. In responsive participants, the IIEF15 erectile
domain score increased from 16-18 to above
25.
3. 34 of the 75 responsive participants stayed for
Phase 2 of the study; erectile domain scores
remained stable at above 25 for the duration of
the 10-year follow-up.
Soler et al. 2009;
France
Pre-post
Level 4
N=14
Population: Men who sustained an abnormal
prolonged erection or priapism following an
intracavernous injection of prostaglandin E1 to
induce erection.
Treatment: Oral midodrine following the
failure of 30 minutes of cooling procedures
using ice or ether, or penile vibrator
stimulation.
Outcome measures: evaluation of penile
rigidity at 30 minutes, and 1, 3 and 6 hours
post treatment.
1. All patients returned to flaccid penile state
within 30-45 min after midodrine
administration.
2. Oral midodrine well tolerated with few side
effects and without increasing incidence of AD.
3. Complete erection could be induced again 6
months later by intracavernous injection in all
treated patients.
Moemen et al.
2008;
Egypt
Pre-post
Level 4
N=60
Population: 60 men with SCI and erectile
dysfunction, at least 6 months post-injury,
randomized into 3 groups of 20 (A, B, C).
Treatment: Group A took sildenafil 50mg
before sexual activity for 1 month; Group B
were given intracorporal injection (ICI, 10
mg/ml prostaglandin E1 or 0.5 ml trimix) for 1
month and then took sildenafil for 1 month;
Group C used vacuum constriction device
(VCD) for 1 month and sildenafil for 1 month.
Outcome Measures: International Index of
Erectile Function – erectile function domain
(IIEF-EF); Global Efficacy Assessment
Questionnaire (GAQ); Hormonal Profile.
1. The improvement in the IIEF-EF score was
90% in all groups after sildenafil, 90% in
Group B after ICI, and 70% in Group C after
VCD.
2. Improvement in erection reached 100% in all
groups according to the GAQ, but ability to
penetrate reached 90% after sildenafil, 90%
after ICI, and 70% after VCD.
3. There was a significant increase in
testosterone in all groups after sildenafil
treatment.
4. Participants in Group B reported that ICI
resulted in more rigid erections than sildenafil,
but 14 of the 20 participants preferred
sildenafil due to easier administration; no
participants in Group C was satisfied with VCD
and preferred either ICI or sildenafil.
Soler et al. 2007;
France
Pre-post
Level 4
N=240
Population: Men with SCI; Age: mean 32.6-
36.2 yrs; tetraplegia (n=78), paraplegia
(n=145), cauda equine (n=17); Impairment:
AIS A (n=197), AIS B (n=19), AIS C (n=18),
AIS D (n=6); Mean time since injury 91.5-
112.4 months.
Treatment: Sildenafil (50-100mg, n=120),
tadalafil (10-20mg, n=66), and vardenafil (10-
20mg, n=54) depending on efficacy/tolerability, follow-up at 3 months.
Outcome measures: Quality of erection;
duration of erection; International Index of
Erectile Function (IIEF) – Erectile Function
(EF), Intercourse Satisfaction (IS), Overall
Satisfaction (OS), Orgasmic Function (OF),
and Sexual Desire (SD); adverse events.
1. Good rigidity reported by 85% (sildenafil),
74% (vardenafil), and 72% (tadalafil) of the
patients.
2. Mean duration of erection: 34 min (sildenafil),
28 min (vardenafil), 26 min (tadalafil).
3. IIEF: improved global and domain (EF, IS,
and OS) scores for all groups; improved
orgasmic function and ejaculation for
sildenafil group.
4. Initial dose sildenafil (50mg) effective in 55%,
whereas vardenafil and tadalafil (10mg)
ineffective in over 70%.
5. Adverse events: mild; 15% on sildenafil
(headache, flushing, dizziness, dyspepsia);
14% on vardenafil (headache, dizziness); 6%
on tadalafil (headache, back pain).
Kimoto et al. 2006;
Japan
Pre-post
Level 4
N=32
Population: 32 men with SCI; Age: mean
37.5 yrs, range 20-64; Level of injury: T12-
lumbar (n=10), cervical-T11 (n=22); Time
since injury at least 6 months.
Treatment: Vardenafil 10mg for 12 wks or
vardenafil 10mg for 4 wks and then 20mg for
8 wks.
Outcome measure: International Index of
Erectile Function (IIEF)/Erectile Function
(EF), success in penetration, success in
maintaining erection during intercourse.
1. IIEF/EF: Improved in both the 10/10mg group
(12.2 to 25.0) and the 10/20mg group (10.3 to
22.5); the 10/20mg group increased 5.0
points following up-titration.
2. Success in penetration: 10/20mg group: 56%
at 4 wks, 76% at 8 wks, 83% at 12 wks;
10/10mg group: 88% at 4-12 wks.
3. Success in maintaining erection: 10/20mg
group: 43% at 4 wks, 62% at 8 wks, 69% at
12 wks; 10/10mg group: 81% at 4-12 wks.
Gans et al. 2001;
USA
Pre-post
Level 4
N=17
Population: 17 men with SCI; Age: mean
40.3 yrs, range 25-58; Injury level: cervical
(n=4), thoracic (n=12), lumbar (n=1).
Treatment: Sildenafil 25mg (dose increased
in 25mg increments as needed), mean(SD)
follow up of 5.3(2.2) months.
Outcome measures: International Index of
Erectile Function (IIEF) (abridged version),
questions on aspects of sexual function.
1. IIEF scores improved significantly compared
with baseline or previous therapies.
2. Of the 17 men, 94% recommended sildenafil
to others.
3. One patient discontinued treatment due to
hypotension.
Schmid et al. 2000;
Switzerland
Pre-post
Level 4
N=41
Population: 41 men with SCI; Age: mean
36.5 yrs, range 20-63; Injury level: paraplegia
(n=33, 23 incomplete, 10 complete),
tetraplegia (n=8, 7 incomplete, 1 complete);
Time since injury: mean 5.9 yrs, range 0.5-
26.
Treatment: Sildenafil 25-100mg as needed.
Outcome measures: International Index of
Erectile Function (IIEF) – Erectile Function
(EF) and Intercourse Satisfaction (IS),
response rate, ideal dose, adverse events.
1. Improved erections (grade 3-4) permitting
sexual intercourse reported by 38 (93%) men.
2. 58% of men achieved good erectile function
with sildenafil 50mg, 37% required 75-100mg,
and 5% required only 25mg.
3. EF (9.2 to 25.5) and IS (4.5 to 10.5)
significantly improved after sildenafil therapy.
4. Men with preserved reflexive or psychogenic
erection responded well to sildenafil, while
men without integrity of either sacral or
thoraco-lumbar segments due to ischemic
damage did not have a successful response.
5. Adverse events: 10% suffered side effects
such as headache, dizziness or flushing.
Ohl et al. 2015;
USA
Retrospective
Analysis
Level 5
N=248
Population: 248 men (≥ 18 years, mean
age=37.7 years) with traumatic spinal cord
injuries (≥ 6 months duration, 136/248
complete SCI) and erectile dysfunction
attributed to SCI and in a stable heterosexual
relationship (≥ 6 months).
Treatment: Participants were randomized and
treated sequentially with sildenafil and
placebo in two treatment phases. The starting
dose was 50 mg, taken one hour before
sexual activity. Subsequent dose adjustments
to 100 mg or 25 mg based on patients’
tolerability during the 6 week treatment phase.
Outcome Measures: The International Index
of Erectile Function (IIEF) questions and
percent successful attempts at intercourse
were analyzed for sildenafil vs. placebo using
analysis of covariance (ANCOVA) models.
1. Average changes from baseline to week 6 in
the IIEF Q3 (frequency of penetration), Q4
(maintaining erection after penetration), and
Q9 (frequency of ejaculation) scores
significantly improved with sildenafil vs.
placebo (all P<0.01).
2. Treatment preference for sildenafil vs placebo
was 96% vs 4% in the overall population
(P<0.001).
3. The most common all-cause adverse events
with sildenafil were headache (16.1%) and
urinary tract infection (UTI) (11.6%)

Discussion

Over 2000 men with SCI have been investigated in 14 RCTs and 9 prospective case series (pre-post) studies using oral agents for ED. The evidence supports the use of PDE5i as the first-line of treatment in men with ED secondary to SCI. Sildenafil (Viagra®) being the first available PDE5i has been more frequently studied to date than either vardenafil (Levitra®) or tadalafil (Cialis®). Meta-analysis of case-series reports of sildenafil efficacy have shown a random effects pooled estimate of 79% success (with 95% CI from 68-90%) improving erectile function (EF) sufficient for intercourse at home (DeForge et al. 2006). Ergin et al. (2008) found that sildenafil was effective for improving erective function regardless of completeness of injury however the treatment showed wider impacts among individuals with incomplete injuries. Khorrami et al. (2010) found that sildenafil was more effective in upper motor neuron (UMN) versus lower motor neuron (LMN) injuries, with the latter being no more effective than that found with placebo.

In addition, in a cost-utility study of ED treatments in men with SCI (Mittmann et al. 2005), sildenafil has been shown to be preferred to non-oral treatments, as well as a cost-effective option with a calculated total annual cost of CAN $1,530 and incremental cost-utility ratio less than CAN $20,000 per QALY. Results from 3 large RCTs (Giuliano et al. 200620072008), as well as several case-series studies (Kimoto et al. 2006Morgentaler et al. 2006Soler et al. 2007), have shown similar efficacy for vardenafil and tadalafil compared to placebo, with reported improvements in erectile function (~10 points gain in IIEF/EF scores), success in penetration (~75%), maintenance and duration of erection (25-30 mins) and successful attempts at intercourse (~50-60%).

Only one small RCT (n=28) has directly compared the efficacy of different oral treatments in men with SCI (Del Popolo et al. 2004), comparing sildenafil (50mg) and tadalafil (10mg) in a randomized, blinded, cross-over design with washout. In this study, tadalafil significantly increased the percentage of successful intercourse attempts at 24 hours post dosing (68%), compared to sildenafil (18%). The increased duration of action of tadalafil, providing for more spontaneous rather than planned “on-demand” sexual activity, has also been noted as a benefit by other authors (Giuliano et al. 2007Soler et al. 2007). Of interest, in the study by Del Popolo et al. (2004), two out of 5 patients not responding to sildenafil did respond to tadalafil, both having LMN incomplete lumbar lesions. Two newer studies with higher subject numbers (Khorrami et al. 2010Ergin et al 2008) have expanded on the effectiveness of PDE5i depending on completeness of injury and whether it is UMN or LMN. There is also lack of effectiveness of PDE5i where there is extensive ischemic damage involving both thoraco-lumbar and sacral cord segments (Schmid et al. 2000). In general though, a lesion above the sacral spinal tract and a higher reflexive erection are predicable favorable parameters for a positive response to all PDE5i (Lombardi et al. 2009aSoler et al. 2007Schmid et al. 2000Sanchez Ramos et al. 2001). It appears that efficacy is maintained with the use of PDE5i over time, and tachphylaxis (a decrease in the response to a drug after repeated doses over a short time period) is rare (Lombardi et al. 2009b).

The importance of correct dose titration has been emphasized by various studies, with over 50% of patients responding to sildenafil at a dose of 50 mg (Soler et al. 2007) and even as low as 25mg in some (Tuzgen et al. 2006), whereas around 50-70% of patients will require the higher dose (20mg instead of 10mg) of vardenafil and tadalafil (Giuliano et al. 20062007Soler et al. 2007Lombardi et al. 2009a). Kimoto et al. (2006) reported a 5-point increase in IIEF/EF score following up-titration of Vardenafil from 10 to 20mg. Soler et al. (2007) reported a significant improvement in ejaculation and orgasm only in the group taking sildenafil, while others (Giuliano et al. 2006) have reported overall improvement in ejaculatory function with vardenafil (19% compared to 10% in placebo), particularly in those with incomplete lesions (29% compared to 15%). A recent study (Lombardi et al. 2009a) on tadalfil failed to show a significant improvement in the ejaculatory and orgasmic parameter, however, the improvement in IIEF to > 26 (normal) was apparent in the majority of the men with SCI in the study. With the long acting tadalafil, over 80% of subjects on either 10 or 20 mg of tadalafil were able to achieve successful intercourse within 24 hours of taking the drug, and approximately 65% were still able to have successful intercourse after 24 hours had passed (however the percentage of men attempting intercourse within versus after 24 hours were approximately 67% versus 33% respectively).

Headache (8-15%) and flushing (3-14%) were noted to be the most common side effects for men with SCI using PDE5i, followed by dyspepsia, nasal congestion, dizziness, visual disturbances and infrequently back pain. Urinary tract infection was also found to be a common adverse event, along with headache, in one sildenafil study (Ergin et al. 2008). Priapism and symptoms of dysreflexia are not reported in the SCI population after PDE5i use (Maytom et al. 1999Giuliano et al. 1999Gans et al. 2001). Despite some concerns, cases of symptomatic hypotension requiring withdrawal of medication have rarely been reported with PDE5i (Gans et al. 2001Giuliano et al. 2006Lombardi et al. 2009a). Garcia-Bravo et al. (2006) noted that patients with neurological impairment above T6 level had often been systematically excluded from earlier studies due to potential risks of autonomic dysreflexia and, more particularly, concern about inducing hypotension. This small study demonstrated significant reductions in blood pressure in individuals with a higher SCI lesion (n=12) compared to patients with neurologic levels below T5 (n=10) up to 4 hours after taking sildenafil (50mg dose). Although a maximum drop of 26mmHg (mean change of 17.5mmHg) in systolic and 17mmHg (mean 11mmHg) in diastolic BP was observed, none of these patients with high-level SCI reported hypotensive symptoms. Although not a primary question in their study, Sheel et al. (2005) also noted a significant hypotensive effect of sildenafil being present in a group of 8 subjects with tetraplegia. Data supports an adequate tolerance of sildenafil in men with high-thoracic level paraplegia. However, despite a general absence of clinical reports of symptomatic postural hypotension associated with other PDE5i use, these studies suggest that men with tetraplegia may be at risk of significant hypotension during orthostatic challenges and some caution should be exercised in this group after taking PDE5i.

Three studies (2 RCTs and 1 case series) have trialed oral medications other than PDE5i for men with SCI. In a RCT assessing safety and efficacy of fampridine-SR in persons with established incomplete SCI (AIS grades C or D), Cardenas et al. (2007) reported strong trends for improved IIEF scores and increased erection frequency and firmness, ability to maintain erections and levels of sexual desire for fampridine-SR compared to placebo groups. However, adverse events were frequently reported, including pain, dizziness, insomnia, nervousness, paresthesia and one seizure, with 24% of patients discontinuing this trial, particularly those taking higher dose (40mg b.i.d.) of fampridine-SR. This study used considerably higher doses of fampridine-SR than an earlier exploratory trial (Potter et al. 1998) in 26 men with incomplete SCI, and reported statistical improvement in Global Assessment of Patient Satisfaction, but only five patients (19%) reported stronger, more frequent and better sustained erections. Apomorphine, a relatively successful medication in men without SCI, was used for 22 men with SCI and noted to have an overall low rate of response for erectile dysfunction, with 41% experiencing side effects (headache, nausea, tiredness) (Strebel et al. 2004).

Conclusion

There is level 1a evidence (from 9 RCTs, excluding 2 reporting outcomes of a previous trial: Derry et al. 1998Giuliano et al. 1999Hultling et al. 2000Del Popolo et al. 2004Giuliano et al. 2006; Tuzgen et al. 2006; Giuliano et al. 2007Ergin et al. 2008Khorrami et al. 2010) that supports the use of PDE5i as a safe and effective treatment for erectile dysfunction in men with SCI.

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