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Sexual and Reproductive Health

Intracavernosal Injections (ICI) Utilizing Penile Medications

An intracavernosal (or intracavernous) injection is an injection into the base of the penis. This is often used to administer medications including alprostadil (prostaglandin E1 (PGE1)), Bimix (a combination of papaverine and phentolamine), and Trimix (a combination of papaverine, phentolamine and PGE1), to treat erectile dysfunction in adult men. This treatment can generate an erection in patients with SCI by direct cavernosal vasorelaxation, therefore bypassing the neurotransmission signals (release of nitric oxide from the nerve endings) requisite to initiate erection. Self‐administration is an issue for the subset of SCI patients with poor hand function (Ibrahim et al. 2016).

Author Year; Country
Score
Research Design
Total Sample Size
Methods Outcome
Renganathan et al. 1997;
India
RCT
Level 1
PEDro=4
N=28
Population: 28 men, Age: range 16-60
yrs.
Treatment: Randomized to transdermal
nitroglycerine or intracavernous injection
of papaverine, two week washout, crossover.
Outcome Measures: Effectiveness of
transdermal nitroglycerin vs.
intracavernous injection of papaverine.
1. Erectile index for papaverine was
significantly higher than that of
nitroglycerine.
2. 93% who received papaverine had a
complete response vs. 61% who received
nitroglycerine.
3. 32% of patients had complications with
papaverine vs 21% with nitorglycerine.
Yildiz et al. 2011;
Turkey
Prospective, one-way
crossover, dose-controlled
study
Level 2
N=31
Population: Men with erectile dysfunction
secondary to SCI.
Treatment: Control: Received visual and
auditory sexual stimulus (VASS).
Treatment1- VASS with 25 mg of undiluted
intracavernosal papaverine. Treatment 2 –
Same participants as treatment 1, followed
by 72 hour washout period and VASS with
50 mg of oral sildenafil on day 5.
Outcome Measures: Peak systolic
velocity (PSV), end diastolic velocity
(EDV) for each cavernous artery.
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.
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 hrs
post treatment.
1. All patients returned to flaccid penile state
within 30-45 min after midodrine
administration.
2. Oral midodrine was 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. 90% of people in all groups showed
improvement of erection as measured by
IIEF-EF after sildenafil. 90% showed
improvement 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 participants preferred
sildenafil due to easier administration; no
participants in Group C was satisfied with
VCD and preferred either ICI or sildenafil.
Zaslau et al. 1999;
USA
Pre-post
Level 4
N=37
Population: 37 men, Age: mean 43.7
years, range 24-72 yrs, Level of injury:
C3-L4.
Treatment: Intracavernosal injection (ICI)
of papaverine & prostaglandin E1 (PGE1);
Dosage was titrated until satisfactory
erection obtained.
Outcome Measures: Safety & efficacy of
intracavernosal injection therapy,
satisfaction.
1. 28 patients (76%) responded to injection.
2. 21% ejaculated during >50 % of sexual
encounters.
3. At 3 months: 77% were moderately or
extremely satisfied with therapy.
4. 85% rated their intracavernosal injection –
produced erections as good or excellent.
5. 60% on intracavernosal injection reported
almost always or always being able to
have successful intercourse.
Tang et al. 1995;
Republic of China
Post-test
Level 4
N=15
Population: Men with SCI; Age: mean
38.5 yrs, range 25-50; Injury level:
cervical (n=1), thoracic (n=6), lumbar
(n=8); Time since injury: mean 6.3 yrs.
Treatment: Intracavernosal Prostaglandin
E1 (IC PGE1) 5μg (up to 20μg) until full
erection lasting 20 minutes.
Outcome measures: Schramek grade of
erection, blood pressure, heart rate.
1. All men achieved a rigid (grade 5)
functional erection lasting at least 20 mins
(mean 59.1 min), except 1 found to have
venogenic impotence.
2. Grade of erection improved significantly
post-treatment.
3. No significant dosage effect of PGE1 in
the difference between pre- and post
treatment.
4. No systemic side effects or other
complications, however, 2 men
complained of pain at injection site.
Hirsch et al. 1994;
USA
Pre-post
Level 4
N=27
Population: 27 men (14 SCI, 7 multiple
sclerosis, 6 discogenic disease); Age:
(SCI) mean 31.5 yrs, range 22-39.
Treatment: Intracavernosal Prostaglandin
E1 (IC PGE1) 2.5μg initially, increased in
2.5μg increments, with a mean
maintenance dose of 6.2 μg.
Outcome measures: Continued home use
or cessation of PGE1 at 28 months
and reasons for cessation.
1. Rate of voluntary cessation in men with
SCI at 28 months was 43%.
2. Main reason for voluntary cessation
among men with SCI was urinary
diversion, adrenal tumor, loss of interest,
insurance difficulties.
3. Self-administered IC PGE1 was safe and
efficacious, with all patients completing
protocol reporting excellent rigidity and no
discontinuations due to inadequate
erectile response or pain.
Costa et al. 1993;
France
Pre-post
Level 4
N=12
Population: Men with SCI; Age: mean 34
yrs, range 25-43; Injury level: C6-L1;
Impairment: complete; Previous
successful treatment with intracavernosal
injection (ICI) of 20mg moxisylyte.
Treatment: ICI of 20mg moxisylyte
diluted in 0.4, 0.8, 1.2, and 2.0 ml solvent.
Outcome measure: Rigidity of penis at 5-
10-15-20-30 min after injection,
abdomino-penile angle, penis length, and
circumference of penis at same times,
duration of erection, blood pressure (BP),
heart rate (HR), adverse events.
1. Penile rigidity, abdomino-penile angle,
length, circumference, and duration of
erection were unaffected by
dilution/change in volume of solvent.
2. Mean maximal values for rigidity ranged
from 2.33-2.58/3 and lasted between 47-
62.5 min.
3. No priapism or prolonged erections were
noted.
Kapoor et al. 1993;
India
Post-test
Level 4
N=101
Population: 101 men with SCI; Age:
range 20-51 yrs; Injury level: C4-L4, 65
paraplegia, 36 tetraplegia.
Treatment: Intracavernosal injection (ICI)
of papavarine hydrochloride.
Outcome Measures: Erectile rigidity,
duration of erection.
1. Satisfactory erection sufficient for
penetration was possible in 98 patients.
2. 78 participants had good erection within
10 minutes, 13 within 20 minutes, 7
within 30 minutes.
3. Older patients required higher dose.
4. Erections lasted from < 1 hour to >4
hours.
Bodner et al. 1992;
USA
Post-test
Level 4
N=58
Population: 58 men; Age: range 19-68
yrs; Injury level: cervical (n=19), thoracic
(n=32), lumbar (n=17); Impairment grade:
44 complete, 14 incomplete, 19 cervical,
32 thoracic, 17 lumbar, (53%) dropped
out.
Treatment: 7.5mg papaverine, titrated to
dosage that produced adequate erection,
evaluated every week during titration
period, then every 2 months.
Outcome Measures: Erectile rigidity,
complications.
1. Rigid erections in 45 patients (90%).
2. 53% of participants dropped out of
program, usually after 1st injection or
during titration period.
3. Main complication was prolonged erection
necessitating aspiration and epinephrine
injection.
Earle et al. 1992;
Australia
Post test
Level 4
N=22 (14)
Population: Men with SCI; Age: mean
35.2 yrs, range 20-45; Injury level: cervical
(n=3), thoracic (n=8), lumbosacral (n=3).
Treatment: Intracavernosal self-injection
(ICI) of papaverine 2-20mg or papaverine
40mg + phentolamine 0.5 mg or
prostaglandin E1 1-20μg.
Outcome measures: Achieve erection,
patient acceptance (continued use of
method), partner satisfaction and
complications.
1. Full erection was achieved by 19 out of
22 men.
2. Out of 14 men who took part in survey, 12
reported continued use and satisfaction
with self-injection (8 using papaverine, 1
using, papaverine + phentolamine and 3
using prostaglandin E1).
3. Partners of men with SCI responded
positive in half of the cases. Two men
stopped ICI due to partner disapproval.
4. Complications included blood in urethra,
prolonged erection and bruising at
injection site.
Sidi et al. 1987;
USA
Post-test
Level 4
N=66
Population: 66 men with SCI, Age: range
18-61 yrs.
Treatment: Intracavernosal injection of
papaverine hydrochloride and
phentolamine mesylate (n=22), papaverine
hydrochloride alone (n=44).
Outcome Measures: Erection quality.
1. 52 participants had functional erections.
2. In response to plain papaverine 20/30
responded with functional erections.
3. 4 participants had sustained erections
that had to be drained.
4. 71% continued to use method.
Beretta et al. 1986;
Italy
Post-test
Level 4
N=22
Population: 22 men, Age: range 18-52
yrs.
Treatment: 20-30mg papaverine.
Outcome Measures: Effectiveness of
papaverine.
1. 20/22 participants were able to achieve
an erection with complete rigidity with a
mean duration of 4.1 hrs.
2. 20 participants who were successful at
intercourse were offered training in self
injection, but only 10 accepted.
3. 7/22 lasting >5 hrs controlled with
ethilefrine and aspiration of corpus.

Discussion

The technique of penile intracavernosal injection (ICI) of vasoactive medications, such as papaverine, phentolamine and PGE1 alone or in combination, has been used to treat ED in men with SCI for over 20 years. Despite this, there is only one RCT study (Renganathan et al. 1997) in this area, comparing administration of intracavernosal papaverine with transdermal nitroglycerin. Patients who received ICI of papaverine were statistically more likely to have a complete response (erection) than those patients who received nitroglycerine (93% vs 61%).

Results from other non-RCTs support greater efficacy of ICI medications than PDE5i with a meta-analysis of 11 non-comparative case-series reports showing a random effects pooled estimate of 90% success rate (95% CI from 83-97%) achieving a satisfactory erection with intracavernosal injections (DeForge et al. 2006). Moemen et al. (2008) found a similar success rate of satisfactory erection with ICI but this was also comparable to the success rate of PDE5i found in the same subjects. Subjects also noted however that erections were firmer on ICI than PDE5i. It is clear that there is a dose response to the efficacy of ICI, with combination therapy introduced for synergistic effect as well as for possible economic reasons. Yildiz et al. (2011) reported that the efficacies of ICI of papaverine were similar to orally administered sildenafil citrate at all neurological lesion levels and severity in paraplegic men within the first year after SCI. In general, lower ICI doses were required in neurogenic patients, but the combination of SCI with co-morbidity such as diabetes or hypertension decreased the efficacy of injections (Sidi et al. 1987Zaslau et al. 1999).

Complication rates with ICI have been reported to range from 15-32% (Lloyd & Richards 1989Dietzen & Lloyd 1992Renganathan et al. 1997Moemen et al. 2008), with the caveat that accumulated clinical experience and choice of vasoactive medication/s with judicious adjustment of dosage reduce the risks substantially. The most common side effects of ICI are transient, such as pain and swelling at the injection site. The more serious side effect of priapism (or prolonged erection) has typically been reported with use of papaverine and can be treated with aspiration of blood from corpora with injection of an alpha-adrenergic medication (Sidi et al. 1987Bodner et al. 1992). A reported long-term complication of ICI is fibrosis (scarring of the tunica albuginia), the risk of which can be reduced by lowering frequency of injections and minimising medication dose. Hirsch et al. (1994) noted evidence of sub-clinical corporal fibrosis in 2 out of 27 patients using ICI PGE1 with monitoring by quarterly penile ultrasound scans over 18 months.

Several small case series studies using intracavernosal injection of PGE1 (Hirsch et al. 1994Tang et al. 1995) or PGE1 in combination with papaverine (Zaslau et al. 1999) have confirmed safety and efficacy in over 50 men with SCI without incidence of priapism. Soler et al. (2009) reported controversial results where some patients developed priapism after PGE1 administration, but it was easily treated by orally administered midodrine. Tang reported full functional erections with ICI PGE1 lasting an average duration of 59 minutes (range 30-120 mins) in 14 out of 15 men with 8 of them (7 with incomplete T4-L5 lesions and 1 with a complete L1 lesion) able to ejaculate. Prior to the availability of PDE5i, ICI had a high acceptance rate (70-86%) in the SCI population (Sidi et al. 1987Earle et al. 1992Watanabe et al. 1996), although longer term discontinuation has been reported in approximately 30-40%. Intracavernosal injection is also an option to consider in patients taking nitrate medications, where there are concerns about drug interactions with PDE5i.

Conclusion

There is level 2 evidence (from 1 low quality RCT: Renganathan et al. 1997) that supports the use of ICI as treatment for erectile dysfunction in men with SCI.

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