Erectile dysfunction: a global review of intracavernosal injectables

Abstract

Purpose
Data assessing the effectiveness of intracavernosal injections (ICIs) for the treatment of erectile dysfunction (ED) are limited. This study evaluates intracavernosal injectable therapies for ED and reviews available guidelines that inform clinical practice.

Methods
A systematic search using electronic databases (Medline, Pubmed) was performed for studies investigating injectable management strategies for ED published after 1990. Primary outcome measures were to comparatively evaluate clinical efficacy, continuation rates and adverse event profiles of each injectable agent as monotherapy or in combination. The secondary outcome measurement was to discuss available guidelines that inform clinical practice for injectable agents.

Results
ICIs demonstrate clinical efficacy in 54–100% of patients, early discontinuation rates of ≤ 38% and adverse events in ≤ 26%. Discontinuation rates are typically greatest within 3–6 months of commencement. Anxiety related to the initial injection occurs in approximately 65% and anxiety levels can remain high for 4 months. Approval of intracavernosal injection agents is mainly limited to alprostadil with the recent addition of aviptadil/phentolamine combination therapy in a select few geographical regions. Although combination therapies are attractive alternative options, their formulations are variable and should be standardised before widespread acceptance is achieved.

Conclusions
ICIs are associated with good clinical efficacy rates, high discontinuation rates and a moderate side-effect profile. They represent an important tool in the urological armamentarium for treating ED in patients that cannot tolerate or are refractory to oral therapies.

Full text

Vol.:(0123456789)
1 3
World Journal of Urology
https://doi.org/10.1007/s00345-019-02727-5
TOPIC PAPER
Erectile dysfunction: aglobal review ofintracavernosal injectables
CatrionaDuncan1,2,3· GhadirJ.Omran1,3· JiasianTeh1,3,4· NiallF.Davis1· DamienM.Bolton1·
NathanLawrentschuk1,4,5
Received: 27 August 2018 / Accepted: 9 March 2019
© Springer-Verlag GmbH Germany, part of Springer Nature 2019
Abstract
Purpose Data assessing the effectiveness of intracavernosal injections (ICIs) for the treatment of erectile dysfunction (ED)
are limited. This study evaluates intracavernosal injectable therapies for ED and reviews available guidelines that inform
clinical practice.
Methods A systematic search using electronic databases (Medline, Pubmed) was performed for studies investigating inject-
able management strategies for ED published after 1990. Primary outcome measures were to comparatively evaluate clini-
cal efficacy, continuation rates and adverse event profiles of each injectable agent as monotherapy or in combination. The
secondary outcome measurement was to discuss available guidelines that inform clinical practice for injectable agents.
Results ICIs demonstrate clinical efficacy in 54–100% of patients, early discontinuation rates of ≤ 38% and adverse events
in ≤ 26%. Discontinuation rates are typically greatest within 3–6months of commencement. Anxiety related to the initial
injection occurs in approximately 65% and anxiety levels can remain high for 4months. Approval of intracavernosal injection
agents is mainly limited to alprostadil with the recent addition of aviptadil/phentolamine combination therapy in a select few
geographical regions. Although combination therapies are attractive alternative options, their formulations are variable and
should be standardised before widespread acceptance is achieved.
Conclusions ICIs are associated with good clinical efficacy rates, high discontinuation rates and a moderate side-effect
profile. They represent an important tool in the urological armamentarium for treating ED in patients that cannot tolerate or
are refractory to oral therapies.
Keywords Erectile dysfunction (ED)· Intracavernosal injections· Treatment of erectile dysfunction· Treatment of ED
Abbreviations
AUA American Urology Association
BSSM British Society of Sexual Medicine
cAMP Cyclic adenosine monophosphate
cGMP Cyclic guanosine monophosphate
EAU European Association of Urology
ED Erectile dysfunction
FDA Food and Drug Authority, USA
ICI Intracavernosal injection
JSSM Japanese Society of Sexual Medicine
KSSM Korean Society of Sexual Medicine
PDE5 Phosphodiesterase type 5
PGE1 Prostaglandin 1
TGA Therapeutic Goods Administration, Australia
VIP Vasoactive intestinal polypeptide
Introduction
Erectile dysfunction (ED) is defined as inadequate erectile
function to allow penetrative intercourse on a persistent or
recurrent basis [1]. The estimated prevalence of ED in men
> 40 years of age is almost 50% [2]. Risk factors for ED
Electronic supplementary material The online version of this
article (https ://doi.org/10.1007/s0034 5-019-02727 -5) contains
supplementary material, which is available to authorized users.
* Nathan Lawrentschuk
lawrentschuk@gmail.com
1 Department ofUrology, Austin Health, Heidelberg, VIC,
Australia
2 North Eastern Urology, Heidelberg, VIC, Australia
3 Young Urologists Research Organization (YURO),
Melbourne, Australia
4 Department ofSurgical Oncology, Peter MacCallum Cancer
Centre, Parkville, VIC, Australia
5 Department ofSurgery, Austin Hospital, University
ofMelbourne, Melbourne, VIC, Australia

World Journal of Urology
1 3
become more prevalent and include increasing age, smok-
ing, obesity and systemic cardiovascular medical conditions
such as hypertension, dyslipidaemia and diabetes mellitus
(DM). In addition, with increasing numbers of male patients
undergoing pelvic surgery and pelvic radiation, the burden
of ED has risen [3].
A variety of therapeutic agents have been developed
for the treatment of ED and their mechanism of action is
primarily based on an understanding of the physiology of
erections (Fig.1). Combining pharmacotherapeutic agents
can have a synergist effect for improving erectile function
as these agents target different points in the erection physi-
ological pathway. Phosphodiesterase inhibitors (PDE-5
inhibitors), such as sildenafil, were introduced in the 1990s
and represent the first-line treatment option for men with
ED refractory to lifestyle modification. PDE-5 inhibitors are
non-invasive, generally well tolerated and efficacious in a
large proportion of men. However, in the 25–50% of patients
who do not respond and for those whom PDE5 inhibitors are
contraindicated, alternative therapies such as intracavern-
osal injections (ICIs), intraurethral and topical preparations
of alprostadil, vacuum devices and penile prosthesis may
be considered. The aim of this review is to comparatively
evaluate intracavernosal injectable therapies for ED and to
appraise guidelines that inform clinical practice.
Methods
Overview ofliterature search
A systematic literature search of electronic databases (Med-
line, Pubmed) was performed to identify original peer-
reviewed articles that investigated injectable management
strategies for ED. The search was conducted using the fol-
lowing search algorithm: “erectile dysfunction” and “intra-
cavernosal “or “intracorporal injections” or “injectables”
limited to articles published after 1990. Two authors (CD
and GO) independently examined the title and abstract of
citations and the full texts of potentially eligible trials were
obtained; disagreements were resolved by discussion. The
reference lists of retrieved papers were further screened
Fig. 1 Intracavernosal injection
therapy in erectile dysfunction
search strategy Records idenfied through
database searching
(n = 415)
Screening
Included
Eligibility Identiication
Addional records
idenfied through
guidelines
(n = 87)
Records aer duplicates removed
(n = 463)
Records screened
(n = 208)
Records excluded (case reports,
review arcles, diagnosc
studies)
(n = 126)
Full-text arcles assessed
for eligibility
(n = 82 )
Full-text arcles excluded as did
not assess outcome data of
injectable therapy
(n = 49)
Studies included in
qualitave synthesis
(n = 33)
Records excluded due to
eligibility (since 1998,
English language)
(n = 255 )

World Journal of Urology
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for additional eligible publications. If a patient group was
reported twice, the most recent paper was chosen. If data
were unclear or incomplete, the corresponding author was
contacted to clarify data extraction. Institutional review
board was not sought as this study was a narrative review.
Case reports were excluded, and the latest literature search
was performed on the 1st of August 2018.
Eligibility criteria
Studies with human data on injectable agents were included.
Inclusion criteria were studies in English with outcome data
on injectable agents for ED. Primary outcome measures
were to comparatively evaluate clinical efficacy, continua-
tion rates and adverse event profiles of each injectable agent
as monotherapy or in combination. The secondary outcome
measurement was to discuss available guidelines that inform
clinical practice for injectable agents.
Eligible studies
The initial search identified 415 articles and 82 full-text stud-
ies were assessed for eligibility; 33 of which were included.
Studies were excluded as they did not contain outcome data
assessing intracavernosal treatment. This search strategy is
summarised in Fig.1. All included studies were reflective
of modern clinical practice and included data on clinical
efficacy, continuation rates and adverse event profiles.
Results
Intracavernosal injectable therapy is not reliant on an intact
nerve supply. Consequently, if there is adequate blood supply
to the penis an improvement erectile function should occur.
Outcome measures to assess the response to intracavernosal
therapy include subjective patient satisfaction measurements
and objective validated scoring systems [e.g. International
Index of Erectile Function (IIEF) Questionnaire]. Overall,
intracavernosal injections demonstrate clinical efficacy in
54–100% of patients [1]. Published data on outcomes are
heterogenous and limited by small sample sizes and a dearth
of recent comparative randomised controlled trials. Figure2
demonstrates the mechanism of action of commonly used
agents in intracavernosal therapy is demonstrated by iden-
tification of their major physiological target in the erection
pathway.
Alprostadil
Alprostadil is a synthetic form of prostaglandin-E1
(PGE1). Its mechanism of action is by binding to intra-
cavernosal PGE1 receptors resulting in smooth muscle
relaxation and blood flow through cavernosal sinusoids
to fill the penile corpora. Side effects are related to the
injection site and include penile pain, priapism and penile
fibrosis with long-term use.
In 1996, Linet etal. performed a landmark double-
blinded randomised controlled trial by comparing the
efficacy of alprostadil with a placebo at doses ranging
from 2.5 to 20μg. A dose–response relationship was
demonstrated with a minimal effective dose of < 2μg
advised for neurogenic, vasculogenic, psychogenic and
multifactorial causes of ED. In a subsequent open label
6-month self-injection trial, clinical efficacy was reported
in 94% of patients and defined as ‘patient-reported ability
to have sexual activity’. ‘Satisfaction’ with sexual activity
occurred in 87% of men and in 86% of partners [4]. More
recently, Rabbani etal. demonstrated 76% efficacy with
flexible dosing techniques for alprostadil (range 2.5–30μg,
mean 14μg) with only 50% of patients continuing therapy
at 3months [5]. Furthermore, Khan etal. compared office
administration of the agent with ‘self-administration’ at
home and noted improved efficacy when the agent was
administered under office supervision (50% versus 44.4%,
respectively) [6].
Papaverine
Papaverine is a non-selective PDE-5 inhibitor that results
in increased intracellular cAMP, decreased intracellular
calcium concentrations and subsequent smooth muscle
relaxation. Notable adverse effects are penile fibrosis and
priapism. Papaverine is frequently described as the origi-
nal intracavernosal injectable agent as it was first reported
by Virag etal. in 1984 and initial efficacy rates of 66%
after 12months were described [7]. Due to increased rates
of adverse events such as priapism (6–7%) and penile
fibrosis (5.7–11%), papaverine is not approved for mono-
therapy and is typically injected in combination formula-
tions with phentolamine (i.e. Bimix©) or with phentola-
mine and alprostadil (i.e. Trimix©) or with atropine (i.e.
Quadmix©) [3].
Phentolamine
Phentolamine is a non-selective alpha-adrenergic antagonist
that inhibits smooth muscle contraction with a direct dila-
tory effect on corpus cavernosum smooth muscle and blood
vessels. Phentolamine has weak efficacy as single agent
and is no longer used as monotherapy; however, it can be
used in combination therapy. Chlorpromazine represents an
alternative option to phentolamine Trimix© and Bimix©
formulations.

World Journal of Urology
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Vasoactive intestinal peptide
Aviptadil is a synthetic vasoactive intestinal polypeptide
(VIP) that increases the activity of adenosine cyclase, lead-
ing to cavernosal smooth muscle relaxation with subsequent
filling of cavernosal sinuses and erection. Adverse effects
include flushing and headaches. Aviptadil has been com-
bined with phentolamine when monotherapy is ineffective.
Aviptadil (25μg) in combination with 1–2mg of phentola-
mine has demonstrated clinical efficacy in 74% compared
to 13% with a placebo control [3]. A favourable side-effect
profile with this combination was reported, as the incidence
of priapism, pain and fibrosis was low at 0.06, 0.5 and 0%,
respectively, after 12-month follow-up. Aviptadil/phentola-
mine combination therapy is also effective in patients that
do not respond to other single monotherapy injections with
efficacy rates of 67–73% described [8]. Aviptadil/phentola-
mine combination (Invicorp©) has been clinically approved
in Denmark, the United Kingdom and in New Zealand.
Combination therapy
Combination therapies represent an attractive alternative
when monotherapy has failed. The common therapeutic
Fig. 2 Targets for erectile
dysfunction therapies in the
penile erection pathway. Modi-
fied from Porst H, Burnett A,
Brock G, Ghanem H, Giuliano
F, Glina S, Hellstrom W,
Martin-Morales A, Salonia A,
Sharlip I (2013) SOP Conserva-
tive (Medical and Mechanical)
Treatment of Erectile Dysfunc-
tion. Journal of Sexual Medi-
cine 10(1):130–171

World Journal of Urology
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combinations are Trimix© which contains alprostadil papa-
verine and phentolamine or Bimix© which contains the
latter two agents. In addition, atropine may be added to a
combination of phentolamine, papaverine and alprostadil to
form Quadmix© [9].
At present, there is no combination therapy that is glob-
ally approved. Therefore, these agents are formulated by
compounding pharmacies with sterile laboratory facilities
which can lead to variations in constituents and consisten-
cies among such therapies. Inevitably, significant variabil-
ity results in difficulties in interpreting evidence and may
produce inconsistent and unreliable data for patients and
prescribers [1]. One large series by Coombs etal. of 1412
patients treated with Trimix© reported a clinical efficacy
rate of 89%, defined as erection adequate for penetration up
to 24-month follow-up. Efficacy was reduced in patients with
diabetes mellitus and with a prior history of pelvic radiation.
In this prospective observational study, the discontinuation
rate was higher among patients post-radical prostatectomy,
as a significant proportion of this cohort recovered erectile
function with PDE-5 inhibitors [10]. A smaller series by
Aulitzky etal. (n = 67, of whom n = 36 had undergone radi-
cal prostatectomy) conducted a retrospective chart review to
evaluate combinations of ICI in conjunction with tadalafil,
measuring efficacy as achieving adequate erection for pen-
etration. The authors reported efficacy rates of 90% overall
and of 95% in the post-radical prostatectomy group [11].
Guidelines oninjectable therapy forED
Many urological bodies have produced guidelines on the
management of ED and their salient features are summarised
in Table1. Intracavernosal injections are recommended as
a second-line treatment option for patients who have not
responded to PDE5 inhibitors in the BSSM, Canadian and
EAU guidelines. However, the AUA recommend a less linear
approach to treatment and advocate that male patients should
be offered information on the administration method, effi-
cacy and adverse effects of all ED therapies prior to select-
ing a pharmacological agent.
AUA and EAU guidelines advise combination intracav-
ernosal therapy as an alternative to monotherapy due to its
more favourable side-effect profile and comparable effi-
cacy rates (92%) [1, 12]. EAU, BSSM and Korean guide-
lines emphasise important patient issues such as significant
discontinuation rates, and the importance of education on
administration techniques and on patient follow-up when
considering ICIs. Discontinuation rates are typically great-
est within 3–6months of commencement and are usually
due to factors such as pain, fibrosis, lack of sexual partner,
loss of spontaneity and anxiety [12–14]. One comparative
study by Wespes etal. demonstrated discontinuation rates
of 27.5% with alprostadil compared to 37.6% with combina-
tion therapy. When patients continue with ICIs, the attrition
rate is approximately 10% despite efficacy rates of 70–85%
[12]. Other limiting factors associated with ICI are limited
shelf-life availability and the lack of standardisation when
preparing combination formulas. Alprostadil loses efficacy
within 3 months of cold storage and within 1 week when
stored at room temperature.
ICIs are a moderately invasive therapeutic option and
require a degree of manual dexterity, from the patient or
partner, with education to learn the mechanics of self-injec-
tion. All guidelines recommend counselling and education
at the outset with a supervised administration consultation to
facilitate patient queries, observe administration techniques
and to assess response for dose titration if required [1–3, 12,
14, 15, 16, 17, 19]. Adverse effects of ICIs are summarised
in Table2. ICIs are also associated with significant anxiety
related to the initial injection which occurs in approximately
65% and anxiety levels can remain high for 4months [15].
It has been well established that ICIs are contraindicated
in patients with a known hypersensitivity to the constituents
and in patients with a predisposition to priapism (e.g. sickle
cell anaemia, multiple myeloma and leukaemia). Anticoagu-
lation medication is not an absolute contraindication; how-
ever, patients should be counselled on their increased risk of
bleeding and bruising. There are also reports of broken and
retained needles with ICIs and evolution into “needle-less”
or auto-injection devices may eliminate this complication
[18].
Beyond the delivery systems, evolution and change within
the treatment of erectile dysfunction are ongoing with new
agents and new combinations being tested. Stem cell therapy
is being investigated as an alternative to conventional agents
though this is still in the early stages [16].
Conclusion
ICIs are associated with good clinical efficacy rates, high
discontinuation rates and a significant side-effect profile.
They represent an important tool in the urological arma-
mentarium for treating ED in patients that cannot tolerate or
are refractory to oral therapies. Their primary role appears to
be as a second-line therapy in motivated and well-counselled
male patients and for penile rehabilitation in male patients
after pelvic surgery. Approval of intracavernosal injec-
tion agents is mainly limited to alprostadil with the recent
addition of aviptadil/phentolamine combination therapy in
a select few geographical regions. Although combination
therapies are attractive alternative options in patients with
an adverse response to alprostadil alone, their formulations
are variable and should be standardised before widespread
acceptance can be achieved.

World Journal of Urology
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Table 1 Global overview of injectable agents for erectile dysfunction
Guideline Role in treatment algorithm Approved agents Combination profile Efficacy
AUA 2018 [1] Second-line, however, all men
should be informed of all treatment
options
Alprostadil is the only agent
approved as monotherapy
Combinations used:
Bimix: papaverine + phentolamine
Trimix: alprostadil + papaver-
ine + phentolamine
Quadmix: alprostadil + papaver-
ine + phentolamine + atropine).
Concentrations vary widely but
ratios of 12–30mg papaverine:
10–20μg alprostadil: 1mg phen-
tolamine are common. A standard
dose regimen includes a mixture
of 30mg papaverine + 10μg
alprostadil + 1mg phentolamine
per 1mL with a starting dose of
0.1–0.5mL
Erection sufficient for intercourse in
53.7–100%
EAU 2016 [12] Second line after failed response to
oral agents
Alprostadil is the only agent
approved as monotherapy
Combination therapy:
Papaverine (7.5–45mg) + phentola-
mine (0.25–1.5mg)
Papaverine (8–16mg) + phentola-
mine (0.2–0.4mg) + alprostadil
(10–20μg): efficacy up to 92%
VIP (25μg) + phentolamine
mesylate (1–2mg) (InvicorpTM,
currently licensed in Scandinavia)
ICI + PDE5i: adding sildenafil to
trimix may salvage 31% of patients
who do not response to trimix
alone, with increased adverse
effects in 33%
Discontinuation rates of 41–68%
within 2–3months
In one comparative study, alprostadil
monotherapy had the lowest discon-
tinuation rate (27.5%) compared to
overall drug combinations (37.6%),
with an attrition rate after the first
few months of therapy of 10% per
year.
5–10% of patients do not respond to
combination intracavernous injec-
tions
Canadian Practice Guidelines 2015
[2]
Stepwise approach by initiating least
invasive option that will satisfy
goals of treatment
NR NR To choose approaches which are
reversible when possible
ICUD 2010 [3] Effective as rescue therapy following
non-response to PDE51
Alprostadil 2.5–40μg Invicorp: 25μg Aviptadil
(VIP) + 1.0 or 2.0mg phentola-
mine
TRIMIX: ratios of 12–30mg
papaverine: 10–20μg alprostadil:
1mg phentolamine described as
standard.
NR

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Table 1 (continued)
Guideline Role in treatment algorithm Approved agents Combination profile Efficacy
BSSM 2017 [14] Second line after failed response to
oral agents
Alprostadil 5–40μg Not approved but can be effective,
either alprostadil with oral PDE5i
or combination with papaverine
20–80mg and phentolamine
0.25–2mg
Aviptadil (VIP) + phentola-
mine = Invicorp, similar efficacy
in crossover study, fewer injection
pain, needs sexual stimulation
Alprostadil adverse effects: priapism
1%, fibrosis 2%.
Compliance is low: 50% discontinue
treatment in first 2–3months
Andrology Australia 2010 [16] Second line after failed response to
lifestyle modifications and oral
agents
Alprostadil 10 and 20mcg is first
choice due to high efficacy rate
and low risk of priapism and
fibrosis
Used in combination with vasoactive
drugs (bimix/trimix) to increase
efficacy or reduce side effects
Korean 2013 [15] Second line after failed response to
oral agents and vacuum devices
Alprostadil Alprostadil alone or in combination
of papaverine, phentolamine, and
PGE1 (bimix = papaverine + phen-
tolamine, trimix = bimix + PGE1)
is recommended
Bimix is effective and inexpensive,
while prolonged erection and
cavernous fibrosis were more
common, and the success rate was
lower than that of trimix
Trimix: better efficacy rate (92%)
and less pain, higher risk of
prolonged erection and cavernous
fibrosis compared to PGE1
Standro (lyophilised trimix, Shin
Poong Pharm, Korea) success rate
per trial 74.1%, per patient 91.2%,
complication rate < 1%
Add PDE5i which may achieve
erection in trimix non-responders,
complications 33% dizziness
Success rates of ICI 70–85%. High
discontinuation rates (41–68%),
majority in the initial 2–3months.
Follow-up required at 3–6months
to evaluate efficacy, adverse events
and dose
Japan 2008 [19] Second line after failed response to
oral agents
NR PGE1 5–20μg dissolved in 1ml
saline (on trial; not approved for
clinical use in Japan)
Guidelines do not include combina-
tion therapy
High efficacy, moderate tolerability
A comparison of their role, clinical efficacy and approval status among global guidelines
NR not recorded, PDE5i phosphodiesterase type 5 inhibitors, PGE1 prostaglandin, E1: Alprostadil, VIP vasoactive intestinal peptide, Aviptidil, ICI intracavernosal injection

World Journal of Urology
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Author contributions CD: Project development, data collection, data
analysis, manuscript writing & revision. JGO: Project development,
data collection, data analysis. JT: data analysis, manuscript writing &
revision. NFD: manuscript writing and editing. DMB: Project develop-
ment, manuscript editing. NL: Project development, data collection,
manuscript editing
Funding No funding was provided for this review.
Compliance with ethical standards
Conflict of interest None of the authors have conflicts of interest to
disclose.
Ethical approval Ethics approval for this project was not required as no
human or animal participants were involved in this review.
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Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
Table 2 Side-effect profile for
vasoactive injectable agents
in the management of erectile
dysfunction. Data modified
from [1, 3, 12]
NR not recorded
a Bimix: papaverine + phentolamine
b Trimix: papaverine + phentolamine + alprostadil
c Quadmix: apaverine + phentolamine + alprostadil + atropine
d Aviptadil: vasoactive intestinal polypeptide
Agent Dose Priapism (%) Fibrosis (%) Penile pain (%) Pain with
injection
(%)
Haematoma (%)
Alprostadil 5–40μg 1.78 4.92 12.77 25.39 10.17
Papaverine 20–80mg 7.14 9.88 NR 40.22 23.87
BimixaVariable 5.5 13.02 14.06 14.43 14.46
TrimixbVariable 3.15 4.53 NR 14.83 14.83
QuadmixcVariable 4.8 6.26 NR 0.0 26.03
Aviptadild25μg 0.06 0.0 0.5 NR NR