Int Urogynecol J
DOI 10.1007/s00192-012-2035-1
REVIEW ARTICLE
Botulinum toxin for conditions of the female pelvis
Dominique El-Khawand & Salim Wehbe & Kristene Whitmore
Received: 31 July 2012 / Accepted: 20 December 2012
# The International Urogynecological Association 2013
Abstract
Introduction and hypothesis Botulinum toxin has recently
been approved by the Food and Drug Administration (FDA)
for the treatment of urinary incontinence associated with
neurogenic detrusor overactivity. However, it has also been
used off-label for a multitude of other conditions in the
female pelvis, including urological, gynecological, and co-
lorectal. This article reviews the most recent data regarding
its efficacy and safety, and administration techniques for those
conditions.
Methods A literature review of the most relevant reports
published between 1985 and 2012.
Results Urinary incontinence related to neurogenic detrusor
overactivity is currently the only approved indication in the
female pelvis. Other supported off-label uses include: idio-
pathic detrusor overactivity, interstitial cystitis/bladder pain
syndrome, detrusor sphincter dyssynergia, high-tone pelvic
floor dysfunction, anal fissure, anismus, and functional anal
pain.
Conclusions Botulinum toxin may effectively and safely be
used in many conditions of the female pelvis. More high
quality research is needed to better clarify its role in the
therapeutic algorithm for those indications.
Keywords Botulinum toxin . Neurogenic detrusor
overactivity . Interstitial cystitis . High tone pelvic floor
dysfunction . Anismus . Anal fissure
D. El-Khawand : S. Wehbe : K. Whitmore
Division of Female Pelvic Medicine and Reconstructive Surgery,
Drexel University College of Medicine, Philadelphia, PA, USA
D. El-Khawand (*)
Pelvic and Sexual Health Institute, 207 N. Broad Street, 4th floor,
Philadelphia, PA 19107, USA
e-mail: dominique.el-khawand@drexelmed.edu
Introduction
Botulinum toxin (BT) has been used for medical therapeutic
purposes for the last three decades. Justinus Kerner (1786–
1862), a German medical writer referred to as the “godfather
of BT research,” was the first to describe the clinical effects of
BT. The first human clinical application was described by Dr.
Alan B. Scott in 1980 to treat strabismus. Since then, thera-
peutic applications have widened to include neurological and
non-neurological disorders [1]. BT is currently approved by
the Food and Drug administration (FDA) for chronic migraine
headaches, strabismus, blepharospasm, cervical dystonia, gla-
bellar lines, axillary hyperhidrosis, and most recently (August
2011) for urge urinary incontinence (UI) secondary to a neu-
rological condition (Table 1).
Over the last few years, there has been growing evidence to
support the off-label use of BT for multiple conditions of the
female pelvis, which are the focus of this article (Table 2).
Pharmacology and mechanism of action
Botulinum toxin is a protein secreted by the anaerobic gram-
positive bacterium Clostridium botulinum. It works on both
smooth and striated muscles by inducing a temporary chemo-
denervation through presynaptic inhibition of the release of
acetylcholine. In the bladder, it is also thought to cause afferent
desensitization by blocking other transmitters (neuropeptide
substance P, ATP) and through downregulation of the axonal
expression of purinergic P2X3 and capsaicin-TPRV1 receptors
of the nerve endings in the (sub)urothelium [2]. There are seven
known subtypes [3], with BT type A (BT-A) being the most
commonly used in the female pelvis. BT-A is widely available
under the trade names Botox (Allergan Inc, Irvine, CA, USA),
Dysport (Ipsen Ltd, Slough, Berks, UK), and Xeomin (Merz
Pharmaceuticals GmbH, Frankfurt, Germany; Table 1). The
 Int Urogynecol J

cervical dystonia, axillary hyperhidrosis, hemifacial

Table 2 Clinical applications and side effects of botulinum toxin in

spasm, focal spasticity, urge urinary incontinence

Cervical dystonia, blepharospasm, focal spasticity,

the female pelvis

Blepharospasm, spasticity due to cerebral palsy,

Blepharospasm, hemifacial spasm, strabismus

Chronic migraine headaches, blepharospasm,

Cervical dystonia, blepharospam, post-stroke

Indication Side effects/complications

secondary to a neurological condition

Urological
Neurogenic detrusor overactivity Urinary retention, autonomic
Idiopathic detrusor overactivity dysreflexia, urinary tract

spasticity of the upper limb

Interstitial cystitis/bladder pain infections, need for self-
syndrome catheterization
Detrusor sphincter dyssynergia Urinary incontinence
hemifacial spasm
Europe/worldwide

Gynecological

glabellar lines
High tone pelvic floor
dysfunction (levator ani spasm)
Provoked vestibulodynia
Colorectal
Anal fissure
Anismus (puborectalis syndrome)
blepharospasm, cervical dystonia, glabellar lines,
axillary hyperhidrosis, urge urinary incontinence
Pain during injection, urinary
incontinence, fecal/flatal
incontinence
Pain/swelling at injection site
Temporary fecal/flatal
incontinence, perianal pain,

perineal hematoma, perianal

Cervical dystonia, blepharospasm, glabellar lines

Functional anal pain

thrombosis
Chronic migraine headaches, strabismus,

secondary to a neurological condition

Cervical dystonia, glabellar lines

three products use BT-A proteins of different sizes and different

biological activities and therefore direct comparison of dosage
should be avoided. However, in general, 1 mouse unit (U) of
Botox is equivalent to approximately 3 U of Dysport and 1 U of
Xeomin [4]. Most studies on conditions of the female pelvis use
United States

Botox; therefore, in this article, this formulation is the one

referred to unless otherwise specified.
N/A

N/A

Contraindications for BT-A use include known hypersen-

sitivity to BT, infection at the injection site, urinary tract
infection or acute urinary retention. Caution should be used
Table 1 Botulinum toxin-A worldwide formulations and approved indications

in patients with pre-existing neuromuscular disorders (pe-

BTXAa (Lanzhou Institute of Biological Products, Lanzhou, Gansu, PRC)

ripheral motor neuropathic diseases, amyotrophic lateral

sclerosis or neuromuscular junction disorders such as myas-
Xeomin (Merz Pharmaceuticals GmbH, Frankfurt/Main, Germany)

thenia gravis or Lambert–Eaton syndrome). Side effects in-

clude pain at the injection site, spread of the toxin effect
Neuronox and BTXA are not approved in the USA or EU

(asthenia, generalized muscle weakness, diplopia, ptosis, dys-

phagia, dysphonia, dysarthria, urinary incontinence, and breath-
ing difficulties), and hypersensitivity reactions (Table 3). Site-
specific adverse reactions are reviewed in the corresponding
sections (Table 2).
Dysport (Ipsen Ltd, Slough, Berks, UK)
Botox (Allergan Inc, Irvine, CA, USA)

Neuronoxa (Medytox, Seoul, Korea)

Clinical applications in the female pelvis

As previously mentioned, the only FDA-approved indica-

tion for BT-A in urogynecology is UI due to neurogenic
detrusor overactivity. All other clinical applications are con-
sidered off-label use, and patients should be counseled ac-
Formulation

cordingly. As a general rule, treatment with BT-A should be

reserved for severe refractory cases after failure of conser-
vative therapies.
a
Int Urogynecol J
Table 3 Contraindications for and general side effects of botulinum
toxin
Contraindications/cautions General side effects
Known hypersensitivity Hypersensitivity reactions
to botulinum toxin
Infection at the injection site Pain at the injection site
For intradetrusor injection Spread of the toxin effect
Acute urinary tract infection (asthenia, generalized muscle
Urinary retention weakness, diplopia, ptosis,
dysphagia, dysphonia,
Pre-existing neuromuscular
dysarthria, urinary incontinence,
disorders (e.g., myasthenia
and breathing difficulties)
gravis, Lambert–Eaton
syndrome)
Pregnancy Worsening of an already
compromised respiratory
function
Urological conditions
Neurogenic detrusor overactivity
This indication for UI was approved by the FDA on 25 August
2011 and was the culmination of more than 10 years of research.
The most recent relevant clinical trial (phase 3) was a multicen-
ter randomized double-blind placebo-controlled study of
patients with UI and neurogenic detrusor overactivity associated
with multiple sclerosis or spinal cord injury published by Cruz
et al. [5]. A total of 275 patients were randomized to receive
either 200 U of BT-A (n=92), 300 U (n=91), or placebo (n=92)
injected into the detrusor muscle at 30 different locations (spar-
ing the trigone) via cystoscope. At 6 weeks both doses equally
and significantly reduced the number of UI episodes per week
and significantly improved maximum cystometric capacity
(MCC), maximum detrusor pressure, and quality of life (QoL)
compared with placebo. The median time to patient request for
retreatment was 42.1 weeks in the two treatment groups and
13.1 in the placebo group (p<0.001). However, a dose-related
increase in post-void residual (PVR) and urinary retention
(31.5 %, 19.8 %, and 3.3 % in the 300 U, 200 U, and placebo
groups respectively) was observed in patients not self-
catheterizing prior to treatment. Based on this data, the manu-
facturer’s currently recommended dose for this indication is 200
U. The most commonly reported adverse event was urinary tract
infection (UTI), whose rate was significantly higher in the
treatment groups (64 % and 56 % of patients in the 300-U and
200-U groups respectively) compared with placebo (40 %). The
difference was only seen in the multiple sclerosis patients and
was attributed to the increased use of clean intermittent cathe-
terization (CIC) after treatment in that group.
Technique The following technique is recommended by the
manufacturer based on the previously mentioned study [5].
Patients should not have an active urinary tract infection at the
time of injection. Owing to the reported increased risk of UTI,
the use of peri-procedural prophylactic antibiotics is advised
(avoiding aminoglycosides, which may potentiate the neuro-
muscular effect of the toxin). After appropriate informed
consent, 200 U of BT-A are diluted in 30 ml of 0.9 % non-
preserved saline. An intravesical instillation of diluted local
anesthetic with or without sedation or general anesthesia may
be used prior to injection. Using a flexible or a rigid cysto-
scope, 30 injections (1 ml each) are administered into the
detrusor muscle at a depth of 2 mm and 1 cm apart, avoiding
the trigone [5]. Afterward, the bladder is drained and the
patient is observed for 30 min. Retreatment can be performed
after a minimum of 12 weeks.
Whether better outcomes are achieved with intradetrusor or
suburothelial injections is not well known. Only one random-
ized pilot study compared the two techniques in 32 patients
(300 U of BT-A) with neurogenic detrusor overactivity sec-
ondary to spinal injury and found similar post-treatment im-
provement in both groups regarding subjective satisfaction,
the number of daily catheterizations and incontinence epi-
sodes, catheterized volume, cystometric capacity, volume at
first involuntary detrusor contraction, and maximal detrusor
pressure during filling. The only significant difference was
improvement in detrusor compliance, which was better in the
intradetrusor group. However, the authors favored the subur-
othelial injection because, in their opinion, it allowed more
precise toxin localization [6].
The combination of trigonal and intradetrusor injections
led to better outcomes in one study compared with intra-
detrusor injections alone. Thirty-six patients with refractory
neurogenic detrusor overactivity secondary to spinal cord
injury were randomized to receive either 300 U of BT-A in
the detrusor or 200 U of intradetrusor plus 100 U in the
trigone. At 8 weeks follow-up, the combination group had
fewer incontinence episodes (81 % vs 52 % decrease), and
higher complete dryness rates (67 % vs 33 %). There were
no de novo or upgraded vesico-ureteral reflux (VUR) cases
post-treatment [7].
Idiopathic detrusor overactivity
The FDA approval process for idiopathic detrusor overac-
tivity is underway and is expected to be completed in the
next few years. In 2007, a Cochrane review found that
intravesical injection of BT-A was more effective than pla-
cebo in improving incontinence episodes, maximum bladder
capacity, maximum detrusor pressure, and QoL, at doses
ranging from 100 to 300 U (300 U being more effective
than 100–150) [8]. However, this report included a mixed
population of patients with neurogenic and idiopathic detru-
sor overactivity. Later, a review by Leong et al. [2] conclud-
ed that about 80 % of treated patients with idiopathic
detrusor overactivity experienced improvement; the number

of daily voids decreased by 12 % to 53 %, urgency episodes
by 28 % to 70 %, and incontinence episodes, 35 % to 87 %.
The mean duration of clinical improvement was 6–
14 months, and the mean interinjection interval was 14–
23 months. Recent dose range trials showed that the optimal
dose may be 100–150 U, with the main complication being
greater PVR at higher doses [9, 10]. Because the currently
commercialized BT-A comes in 100- and 200-U vials, a
dose of 100 U would be more practical to avoid unnecessary
waste of the expensive drug. Repeated injections have been
shown to be safe [11]. In one of the largest randomized
trials, the most common side effects were urinary tract
infections (31 %) and the need for self-catheterization
(16 %) [10]. Increased PVR after treatment with BT-A has
been shown to peak at week 2 and then gradually decrease
thereafter [9, 10]. Patients with increased PVR may be
required to use CIC and therefore have to be counseled
accordingly prior to the procedure.
Technique A technique similar to that described above for
neurogenic detrusor overactivity may be used. However, the
dilution can be made in a total solution of 10 to 20 ml, and
20 total injections of 0.5–1 ml each are administered [9–12].
Injections traditionally spared the trigone; however, a re-
cent report showed equal effectiveness and similar incidence
of adverse events when comparing injections at the bladder
body, the bladder body and trigone, and the trigone alone in a
randomized controlled trial (RCT) [13]. There was no VUR
reported after treatment in either group. In contrast, another
study showed that combined detrusor and trigone injections
(500 U Dysport) lead to better overactive bladder symptom
scores at 6, 12, and 26 weeks compared with intradetrusor
injections alone in 22 patients (19 women) with refractory
idiopathic detrusor overactivity [14]. Mean PVR and CIC
rates of the two groups were similar, and none of the patients
developed VUR.
Kuo [15] compared intradetrusor, suburothelial, and
bladder base injections of BT-A (100 U) in a randomized
trial of 45 patients (7 women) with refractory idiopathic
detrusor overactivity. The effective therapeutic duration
was significantly longer in patients who received intradetru-
sor or suburothelial injection compared with bladder base
injections. However, bladder base injections had the advan-
tage of a lower incidence of difficult urination and lower
rates of increased PVR (>150 ml). No cases of de novo
VUR were reported. Nevertheless, this study is not as rele-
vant to this article owing to the small number of female
participants (7 out of 45) and the lack of power analysis.
Interstitial cystitis/bladder pain syndrome
The use of BT-A for interstitial cystitis/bladder pain syndrome
(IC/BPS) is supported by some studies, although strong
Int Urogynecol J
evidence is still lacking. A recent systematic review found
significant heterogeneity among the available studies [16].
Eight out of 10 studies (including 2 RCTs) reported improve-
ment in some or all of the following areas: frequency, pain,
voided volume, and QoL. One randomized prospective study
comparing suburothelial injection of 200 U (n=15) or 100 U
BT-A (n=29), followed by hydrodistention 2 weeks later, with
hydrodistention alone (n=23), found moderate to marked sub-
jective improvement in 72 % of the patients receiving com-
bined BT-A compared with 48 % in the control group at
3 months (p=0.032). The statistical difference remained at
24 months follow-up. The incidence of urinary retention was
higher in the group receiving 200 U than in the group receiving
100 U without added clinical benefit [17].
Technique The high variability among the available studies
makes it difficult to recommend a single technique. In
summary, the injections were done suburothelially, sparing
or including the trigone, using a volume of 10–30 ml, over
10–40 injection sites, with a dose of 100–300 U [16].
Detrusor sphincter dyssynergia
Some evidence suggests a benefit of BT-A in patients with
detrusor sphincter dyssynergia (DSD). However, because all
of the available studies were carried out on either an all-male
or a combined male/female population, it is hard to draw
conclusions as to the efficacy in women. The literature sug-
gests a decrease in PVR, maximum urethral closure pressure,
and maximum voiding detrusor pressure and the potential
benefit of protecting the upper urinary tract [18]. One of the
largest trials evaluated the effectiveness and safety of BT-A in
86 patients (58 women) with DSD secondary to multiple
sclerosis, randomized to either 100 U BT-A (n=45) or placebo
(n=41) in the sphincter [19]. No significant decrease in PVR
between the two groups was found. However, compared with
placebo, BT-A significantly increased voiding volume (+54 %,
p=0.02) and reduced pre-micturition (–29 %, p=0.02) and
maximal (–21 %, p=0.02) detrusor pressures.
Technique Injections could be performed through a tran-
surethral approach or a transperineal technique using elec-
tromyography or ultrasound to localize the striated urethral
sphincter. Common dosage is 50–100 U BT-A in 4 ml,
injected via 1–8 sites [18].
Gynecological conditions
High-tone pelvic floor dysfunction (levator ani spasm)
High-tone pelvic floor dysfunction (levator ani spasm) is a
potentially debilitating condition of the pelvic floor muscles
Int Urogynecol J
causing painful spasm leading to dyspareunia and/or chronic
pelvic pain. The etiology is uncertain, but it appears to be
associated with IC/BPS, vulvodynia, and skeletal or psycho-
sexual trauma. Diagnosis is made by history and physical
examination whereby digital palpation of the muscles sur-
rounding the vagina reveals spastic contraction and elicits
pain. The goal of therapy is to induce muscle relaxation
using physical therapy, muscle relaxants, and trigger-point
injections with local anesthetics. Recent data suggest that
BT-A injections to the pelvic floor muscles may be benefi-
cial for refractory cases. A few small noncontrolled studies
reported reduction in pain scores, decreased pelvic floor
pressures, increased tolerability of pelvic examination and
intercourse, and significant improvement of symptoms and
QoL [20]. In the only published RCT, 60 women with
chronic pelvic pain and high-tone pelvic floor dysfunction
were randomized to receive 80 U BTA injected into their
pelvic floor muscles (n=30) versus saline (n=30) and were
followed for 26 weeks. The BTA group showed a significant
decrease in both nonmenstrual pelvic pain and dyspareunia
compared with baseline. In the placebo group, only dyspar-
eunia was reduced. There was no difference when the pain
scores of the two groups were compared. Resting vaginal
pressures were significantly lower in the BT-A group for up to
16 weeks after injection. QoL scores were equally improved
in both groups compared with baseline. The authors suggested
that there may be a therapeutic effect from repeated manom-
etry testing (acting like physical therapy) and needling of the
muscles contributing to the improvement in the placebo
group. Reported side effects included temporary urinary and
anal incontinence [21].
Technique Pelvic floor muscle injections can be performed
via a transvaginal or a transperineal approach. The transvagi-
nal technique has been described in detail by Goldstein and
colleagues [22]. In the transperineal route, a pudendal nerve
block using local anesthetic is given first. A dose of 100–300
U of BT-A is diluted in 10 ml of saline and injected into the
hypertonic muscles, which may include the pubococcygeus,
iliococcygeus, coccygeus, or obturator internus muscle. The
number of treated muscles and the amount injected can be
adjusted according to severity and location of the spasm.
Electromyographic guidance may be used [23]. After the
injections, the muscles are digitally massaged to further dis-
perse the BT-A.
Provoked vestibulodynia
Provoked vestibulodynia, a subclass of the general term vul-
vodynia, is a chronic pain disorder of the vulva not explained
by other conditions, characterized by localized discomfort
(most often described as burning pain) of the vestibule, which
is provoked by physical contact, whether sexual, nonsexual,
or both [24]. Treatment modalities may include vulvar care
measures; dietary modifications; physical therapy; topical,
injectable or oral medications; and surgery [25]. Small non-
controlled studies have suggested a benefit of BT-A in
the treatment of provoked vestibulodynia [20]. However,
the recent and only RCT of 64 women with this condition
randomized to receive either 20 U BT-A or saline in the
bulbospongiosus muscle found no significant difference be-
tween the two groups at 6 months follow-up. Both groups had
equally reduced pain and improved sexual function compared
with baseline [26].
Colorectal conditions
Anal fissure
Anal fissure is a linear split in the long axis of the distal
anoderm. It most often occurs in the posterior midline. It is
typically defined as a circumscribed ulcer with a large
sentinel tag of skin, induration at the edges, and exposure
of the horizontal fibers of the internal anal sphincter causing
post-defecation pain or nocturnal pain and bleeding for over
2 months [27]. Anal fissure can be acute or chronic.
Generally, acute anal fissures are treated with dietary mod-
ifications and tend to heal within 1 to 2 weeks. Chronic
fissures (longer than 6 weeks) usually require further thera-
pies ranging from conservative medical treatments to inva-
sive surgical options.
Conservative treatment modalities include topical nitrates,
calcium antagonists, and BT [27]. In contrast, surgery, in
particular lateral internal sphincterotomy (LIS), is considered
the therapeutic gold standard. However, it is associated with a
high rate of long-term fecal/flatal incontinence, which may
decrease its appeal to patients.
In 1993, “chemical sphincterotomy” using BT emerged as
a minimally invasive therapeutic option for chronic anal fis-
sure [28]. Since then, multiple reports have emerged to sup-
port its use. A recent review [27] systematically examined the
currently available data and concluded that BT-A is an effec-
tive treatment modality for chronic anal fissure. Although not
as effective as LIS, it is less invasive, can be repeated, and
carries a lower risk of long-term fecal or flatal incontinence.
Success rates ranged from 41 % to 73.8 % and recurrence rates
from 0 % to 52.5 %; reported side effects included temporary
flatal (10 %) and fecal (5 %) incontinence (compared with as
high as 30 % with LIS) [29], perianal pain, and hematoma or
thrombosis. A more recent RCT by Valizadeh [30] random-
ized 50 patients to either 50 U BT-A or LIS and followed them
for 1 year. Healing rates at 2, 3, 6, and 12 months were 44 % vs
88 % (p=0.001), 80 % vs 92 % (p>0.05), 52 % vs 88 % (p=
0.005), and 48 % vs 92 % (p=0.001), whereas anal inconti-
nence rates were 12 % vs 48 % (p=0.005), 0 % vs 20 % (p<
0.05), 0 % vs 16 % (p<0.05), and 0 vs 4 % (p >0.05)

respectively. The authors concluded that treatment should be
individualized because treatment with BT-A has a higher
recurrence rate, whereas LIS carries a higher rate of anal
incontinence.
An analysis [31] of one of the published RCTs [32],
taking into account both the benefits (healing of fissure)
and the risks (anal incontinence) of both surgery and BT-
A, concluded that patients should first begin with BT-A
injections and should only consider LIS if botulinum treat-
ment failed many times.
Technique Botulinum toxin type A is injected into the in-
ternal anal sphincter on each side of the anterior midline for
posterior anal fissures (the most common location of a
fissure) [33] and on each side of the posterior midline for
anterior fissures [30]. Common dosage is 20–50 U of Botox
[27], or 90–150 U of Dysport [34, 35].
Anismus (puborectalis syndrome, outlet constipation)
Anismus, also known as puborectalis syndrome or dyssyner-
gic defecation, is a functional disorder of evacuation caused
by failed relaxation and/or paradoxical contraction of the
puborectalis muscle and the external anal sphincter during
defecation [36, 37]. It manifests as chronic constipation from
outlet obstruction. Symptoms may include severe, prolonged
straining, inability to initiate defection, feeling of incomplete
evacuation, need for manual disimpaction, laxative or enema
abuse, and rectal pain [38]. It is more common in
women [39, 40]. Initial treatment options typically include
dietary modifications, laxatives, stool softeners, and enemas
[41]. Biofeedback (BFB) has been used as the next line of
treatment with varying rates of success [38, 42, 43]. Surgical
division of the puborectalis muscle has been considered a last
resort because of the previously described conflicting results
and the high rate of anal incontinence, although a recent paper
showed a 70 % success rate with only a 10 % risk of flatal
incontinence 1 year after partial division of the puborectalis
muscle [38].
Botulinum toxin type A was first used for anismus in 1988
[37]. In that study, 4 out of 7 patients reported symptomatic
improvement at 4 weeks post-injection. Since then there have
been multiple case series, but only 3 RCTs with varying
success rates between 29 % and 95 % [37, 38, 43–48].
Shafik and El-Sibai [45] showed disappearance of straining
at defecation and normalization of stool frequency in 13 out
of 15 patients (87 %; 13 women and 2 men) for a mean
duration of 4.8 months after injection of 25 U of BT-A. In
2006, Maria et al. reported symptomatic improvement (not
defined) after a 2-month follow-up in 19 out of 24 (80 %)
patients (14 women) following injection of 60 U of BT-A into
the puborectalis muscle under ultrasound guidance [48]. Ron
et al. [47] randomized 25 patients (15 women) to receive 20 U
Int Urogynecol J
BT-A either posteriorly or divided on each side of the pubor-
ectalis muscle. He found manometric improvement in 75 %,
but symptomatic improvement of the straining index in only
29 %. The main outcome, which was successful rectal balloon
expulsion, occurred in 37.5 % after the first injection. The
results were similar in the two groups. The only two other
RCTs comparing BT-A with other treatment modalities were
carried out by the same group, Farid et al. The first study [43]
randomized 48 patients (33 women) to receive either biofeed-
back (n=24) or 100 U Dysport (n=24) in the puborectalis and
external anal sphincter. They reported initial clinical improve-
ment of 50 % in the BFB vs 71 % in the BT-A group (p=
0.008), but only 25 % vs 33 % at 1 year (p=0.23). However,
the outcome of “clinical improvement” was not clearly de-
fined as it was described as a return to normal with regard to
bowel habits using an unnamed questionnaire. In the second
study [38], 60 patients (43 women) were randomized to either
BFB, 100 U Dysport, or partial division of the puborectalis
(PDPR). The primary outcome was clinical improvement,
defined as normalization of bowel habits using the Agachan
constipation score. At 1 month, the groups differed signifi-
cantly regarding clinical improvement (50 % for BFB, 75 %
for BT-A injection, and 95 % for PDPR, p=0.006) and differ-
ences persisted at 1 year (30 % for BFB, 35 % BT-A
injection, and 70 % for PDPR, p=0.02). They concluded that
BT-A was successful in the short term, but surgery was better
in the long term.
Finally, Hompes et al. [37] demonstrated that therapeutic
response to BT-A injection could be diagnostic of true
anismus (compared with rectal prolapse misdiagnosed as
anismus) and that in such cases, success rates are high; their
initial response rate was 96 %, with 95 % long-term success
when misdiagnoses were excluded.
Technique The reported dose range is 12–100 U of Botox or
100–500 U of Dysport diluted in a solution of 0.5 to 1 ml.
The most common technique is to inject BT-A at 3 and 9
o’clock on each side of the puborectalis muscle and the
external anal sphincter. This process can be carried out using
digital or ultrasound guidance.
Functional anal pain
This term describes a condition in a group of patients whose
symptoms occur in the absence of demonstrable pathologi-
cal anal conditions. Spasm of the sphincter muscles has been
suggested as the etiology [49]. Only two studies directly
examined the efficacy of BT-A for functional anal pain.
Christiansen et al. [50] reported long-term improvement in
4 out of 8 patients after injections of BT-A. More recently,
Hollingshead et al. [49] showed improvement in 7 out of 14
patients (50 %; 6 women) at 3 months after 20–200 U of BT-
Int Urogynecol J
A injected into the internal anal sphincter at 3 and 9 o’clock.
At 59 months mean follow-up, 4 out of the 7 remained
improved; the other 3 were lost to follow-up.
Injection guidance techniques
Intravesical injections are usually easily performed with cys-
toscopic guidance. However, injections into the pelvic floor or
anal sphincter can be more challenging because of the depth or
the small size of the injected muscle. Multiple guidance mo-
dalities have been used to better pinpoint the injected site to
ensure actual intramuscular injection of BT-A rather than in
the surrounding tissue. Those modalities include electromy-
ography (EMG) and ultrasound. For intralevator injections,
Bertolasi et al. [23] used EMG to localize spastic pelvic floor
muscles before injections of BT-A. She reported a 63 % cure
rate for vaginismus; however, there was no control group. For
injecting the PDPR muscles in patients with anismus, Maria et
al. [48] used transrectal ultrasound. For the same indication,
Hallan et al. [51] used EMG to localize the puborectalis,
which subsequently proved unnecessary because they could
localize the muscle by digital rectal examination. There are no
comparative trials to prove the efficacy of guidance techni-
ques over digital localization.
Summary of the therapeutic value of botulinum toxin
in the female pelvis
When deciding to use BT-A as a treatment, potential benefits
over other available therapeutic options and possible risks
should be carefully balanced. In view of the available data,
the suggestions listed below can be made with regard to the
therapeutic value of BT-A in the female pelvis (Table 4).
Neurogenic detrusor overactivity (level A) There is ample
strong evidence to support the use of BT-A as a second-line
treatment after medical therapy. Patients should be counseled
about the increased risk of UTI and urinary retention (espe-
cially those who are not using CIC before treatment).
Idiopathic detrusor overactivity (level A) Strong evidence
supports the use of BT-A after failure of medical therapy.
Patients should be capable of and willing to initiate CIC if
Table 4 Levels of recommendation
Level Description
A Based on good and consistent scientific evidence
B Based on limited and inconsistent scientific evidence
C Based primarily on consensus and expert opinion
needed after treatment in the case of increased PVR.
Whether BT-A or sacral neuromodulation (SNM) comes
first in the therapeutic line is still unclear. A decision anal-
ysis comparing outcomes (efficacy and complications) of
both modalities found a consistently higher overall utility of
BT-A over SNM over a 54-month period. However, the differ-
ences were not significant [52]. Another analysis found that
BT-A is cost-effective during a 2-year period compared with
SNM for the treatment of refractory UI [53]. In contrast, a
third model found that when starting with SNM, treatment is
cost-effective after 5 years compared with BT-A in patients
with idiopathic overactive bladder. However, in some scenar-
ios, such as the use of local anesthesia for BT-A treatment and
SNM peripheral nerve evaluation or bilateral test, SNM was
not cost-effective [54].
Interstitial cystitis/bladder pain syndrome (level B) The lev-
el of evidence is variable. The American Urologic Association
suggests using BT-A as a fifth-line treatment of refractory
IC/BPS after failure of dietary and behavioral modifications,
medical therapy, cystoscopy with hydrodistention, and
SNM [55].
Detrusor sphincter dyssynergia (level C) Strong evidence is
lacking in the female population. Therefore, we suggest that
the use of BT-A is reserved for patients in whom conven-
tional therapy fails, but may be attempted before more
invasive surgical interventions are considered.
High tone pelvic floor dysfunction (level B) Strong evidence
is still lacking, and current evidence is controversial. Owing
to the debilitating nature of this condition, and the low risk
of complications from the medicine, we suggest that BT-A
may be used in patients who exhaust other treatment
modalities.
Provoked vestibulodynia (level B) The available evidence
suggests no benefit from BT-A for this condition, and therefore
we do not currently recommend using it for this indication.
Anal fissure (level B) Weighing the risks and benefits, the
current evidence is in favor of using BT-A before sur-
gery (LIS).
Anismus (level B) The available evidence suggests that BT-
A is a reasonable therapeutic option after failure of conser-
vative management and before more invasive surgery is
attempted (PDPR). Furthermore, BT-A may have diagnostic
value in this condition.
Functional anal pain (level B) The available evidence is of
low quality and therefore we suggest that BT-A is reserved
for patients in whom other available therapies fail.

Conclusion
Botulinum toxin type A may be used safely for treating
multiple conditions of the female pelvis and can offer relief
of symptoms to many patients who have exhausted other
treatment modalities. It is minimally invasive and should be
considered before more invasive surgical options. Further
research is needed to elucidate the best indications, techni-
ques, and optimal dosing.
Conflicts of interest Kristene Whitmore has accepted a research
grant from Allergan.
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