Few therapies have so galvanized management of a urologic condition as that witnessed over the past decade regarding use of onabotulinumtoxinA (BoNT-A) for bladder dysfunction. The range of clinical applications in the urologic realm, coupled with relative ease of administration, has revolutionized therapeutic options for several prevalent conditions. Although injection of BoNT-A is generally considered low risk, there remain a number of critical considerations with regard to contraindications and adverse events which must be carefully weighed prior to including BoNT-A in a patient’s treatment algorithm. Herein, we discuss common urologic applications and the associated potential sequela of utilization of BoNT-A in the urinary tract.

Botulinum neurotoxin (BoNT) is produced by the Gram-positive obligate anaerobe Clostridium botulinum , initially isolated in 1897 by van Ermengem [1]. Despite the weighty role of BoNT in the manifestations of food-borne botulism, decades of innovative research have exploited the toxin’s properties revealing a multitude of clinical applications which impact a variety of debilitating conditions. In addition to the urologic indications outlined below, BoNT is routinely employed for treatment of chronic migraines, pain, head and neck dystonia, hyperhidrosis, and anal fissures in addition to the commonly recognized cosmetic applications [2].

BoNT induces flaccid muscle paralysis by inhibiting release of the neurotransmitter acetylcholine from the presynaptic nerve terminal at the neuromuscular junction. In the lower urinary tract, effects are principally mediated at the parasympathetic presynaptic nerve terminal [3]. Generally considered the most potent neurotoxin recognized, and classified by the Centers for Disease Control and Prevention as a Category A bioweapons threat, it has been postulated that a mere 1 g of appropriately dispersed purified BoNT could be lethal to a million people [4, 5].

C. botulinum produces seven antigenically distinct serotypes of BoNT, each with multiple subtypes; however, only types A and B are currently employed clinically [6]. Expansive discussion of the molecular mechanism of action and pharmacology of BoNT is outside the scope of this review and extensively detailed in other publications [7]. However, several salient aspects are critical to understand applications, limitations, and complications for urologic utilization. The most commonly utilized serotype, type A, is a 150 kDa polypeptide with several domains imparting distinct function. As mentioned above, end-organ lower urinary tract manifestations are mediated by BoNT-A at the parasympathetic presynaptic nerve terminal. BoNT-A directly cleaves synaptosomal-associated protein (SNAP-25), required for fusion of synaptic vesicles at the cellular membrane, thus specifically preventing release of neurotransmitters into the synaptic cleft [8]. However, despite our classic concepts of BoNTs impact on the neuromuscular junction, emerging robust data implicate a diversity of alternative mechanisms of action to account for the clinical effects demonstrated in the lower urinary tract [9]. BoNT-A inhibits release of an assortment of neurotransmitters (acetylcholine, ATP, substance P), in addition to downregulating purinergic and capsaicin receptors on afferent neurons with potential culmination in a central desensitization [10]. Indeed, many of the alternative targets of BoNT-A have been previously implicated to contribute to the pathophysiology of detrusor overactivity and the overactive bladder (OAB) symptom complex. BoNT-A binds with high affinity to synaptic vesicle protein 2 (SV2), expressed predominantly in the parasympathetic fibers of the human bladder and additionally present in approximately half of the sensory fibers [11]. Clinical effect of BoNT-A likely integrates both efferent, parasympathetic pathways and afferent, nociceptive pathways. Also critical for understanding clinical utility, and potential complications, is that BoNT produces a reversible chemical denervation with recovery due to axonal sprouting and formation of novel synaptic connections [12]. Clinical results are not typically completely manifested for several weeks following injection and duration of response is variable depending on indication, dosage, and patient symptomatology.

Use of BoNT in lower urinary tract disorders was pioneered by Dykstra and colleagues in 1988 for treatment of detrusor-external sphincter dyssynergia (DSD) [13]. Currently, BoNT-A is utilized predominantly for the Federal Drug Administration (FDA)-approved indications of neurogenic detrusor overactivity (NDO) and refractory overactive bladder (OAB) [14, 15]. Additional applications have been extensively investigated for benign prostatic hyperplasia (BPH), interstitial cystitis/bladder pain syndrome (IC/BPS), radiation cystitis, urethral stricture disease, detrusor underactivity, and myofascial pelvic pain with variable clinical results. Full synopsis of the current data regarding each of the urologic applications is outside the scope of this chapter and expertly detailed in several meta-analyses and reviews [16–18]. Potential complications associated with the commonly employed on-label usage are generally applicable to investigational applications. For the purposes of this discussion, adverse event (AE) is defined by the FDA as an “untoward medical occurrence associated with the use of a drug in human, whether or not considered drug related” [19].

Remarkably, there are few definitive contraindications to administration of BoNT-A for lower urinary tract applications. Several relative contraindications should be carefully weighed but remain at the clinician’s discretion. The primary absolute contraindication to BoNT-A administration is a known hypersensitivity to the toxin. Immediate hypersensitivity reactions have been reported including anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea. A solitary fatal case of anaphylaxis was reported with lidocaine as the diluent, and thus the causal agent for the reaction remains unidentified [20]. Systematic review of efficacy and safety for NDO revealed no reported anaphylactic reactions for detrusor injection in the neurogenic population in the published literature [21].

For bladder indications, a more consequential absolute contraindication includes the presence of active urinary infection at the time of injection. Clinical trials for both NDO and OAB indications excluded patients reporting more than two urinary tract infections (UTI) in the past 6 months or those taking chronic antibiotics for UTI treatment [14, 15]. Careful vigilance in assessing active infection must be undertaken by the treating physician as, particularly for the neurogenic population, atypical UTI symptoms may manifest. As will be discussed in a following section, UTI was the primary AE documented in multiple clinical trials. Therefore, embarking on detrusor injection in the setting of active infection significantly increases the global risk to the patient for adverse outcomes , including potential progression to urosepsis.

Although not an absolute contraindication , exceptional caution must be employed for patients with diagnoses of preexisting peripheral motor neuron diseases, amyotrophic lateral sclerosis, or neuromuscular junction disorders such as myasthenia gravis or Lambert–Eaton syndrome. Such patients may demonstrate increased risk of generalized effects following BoNT injection such as weakness, diplopia, ptosis, dysphonia, dysarthria, dysphagia, and respiratory compromise. Careful deliberation in collaboration with the treating neurologist should be undertaken prior to embarking on detrusor injections for this patient population as the risks often outweigh the potential benefits. Likewise, in spinal cord injury and MS patients with restrictive lung disease treated for NDO, at least 15% reduction in Forced Vital Capacity (FVC) was noted in BoNT-A treatment arms compared to placebo [20]. Therefore, exceptional caution and monitoring is mandated in patients with concomitant pulmonary pathology and neurologic disease in the periprocedural period.

Spinal cord injury patients additionally display elevated risk for autonomic dysreflexia (AD) with intradetrusor injection of BoNT-A as compared to placebo (1.5% versus 0.4%) [14]. This data suggest it may be prudent to forgo clinic injection and consider monitored anesthesia care for patients with known or potential issues with AD desiring BoNT-A injection.

BoNT-A is considered by the FDA as Pregnancy Category C, indicating there are no adequate and well-controlled studies conducted in pregnant women to determine safety [20]. In animal models, intramuscular injection resulted in reductions in fetal body weight and skeletal ossification. During the critical phases of organogenesis in rats and rabbits at doses which extrapolate to the maximum recommended human dose of 400 Units, daily injections revealed significant maternal toxicity, abortions, early deliveries, and even maternal death was observed. However, a single dose at three different periods resulted in no AEs on fetal development. Overall, it is recommended to only employ BoNT-A during pregnancy if the benefit significantly outweighs the risk. Likewise, it remains unknown if BoNT-A is secreted in breast milk, so caution should be exercised when administering to nursing mothers.

Note that the FDA-approved indications include only dosage regimens and applications for adults >18 years of age. Utilization of BoNT-A for bladder applications in the pediatric population, although widely investigated for decades and generally reported safe and effective, remains off-label.

For geriatric patients undergoing 100 Unit BoNT-A injections for OAB indications, AEs such as UTI and urinary retention were demonstrated to be markedly more common in patients 75 years or age or older compared to younger patients. Rates of UTI for patients ≥75 years receiving BoNT-A was 38% (placebo 19%) compared to 30% for patients 65–74 years old and 21% for patients ≤65 years of age [15]. In general, caution is recommended for dose selection in the geriatric population with preferential initiation at low dose ranges to accommodate for the amplified frequency of decreased hepatic, renal, or cardiac function in addition to concomitant diseases and pharmaceuticals .

Significant possible drug interactions critical to consider include avoidance of co-administration of BoNT-A with aminoglycosides or curare-like compounds which may interfere with neuromuscular transmission and potentiate toxin effects [22]. Therefore, broadly employed periprocedural urologic antimicrobial medications such as gentamicin must be carefully eliminated from the treatment pathway for patients surrounding BoNT-A injections. For patients treated for NDO or OAB, concurrent usage of anticholinergics may potentiate systemic antimuscarinic effects and risk of urinary retention. Additionally, patients concurrently utilizing muscle relaxants may experience exaggeration of weakness following administration of BoNT-A.

Commercially available BoNT-A preparations in the United States include Botox^® (onabotulinumtoxinA, Allergan Pharmaceuticals, Dublin, Ireland), Dysport^® (abobotulinumtoxinA, Ipson Biopharm, Basking Ridge, NJ, USA), and Xeomin^® (incobotulinumtoxinA, Merz Pharmaceuticals, Frankfurt, Germany). A single type B BoNT preparation is additionally available, Myobloc^® (rimabotulinumtoxinB, Solstice Neurosciences, Inc., Louisville, KY, USA). Presently, only onabotulinumtoxin A possesses FDA approval for urinary tract indications. With substantial differences in dosing, efficacy, and safety profiles, these BoNT preparations should not be considered interchangeable. Indeed, significant inconsistencies were revealed between studies determining dose equivalency and therefore no standardized data exist to provide robust clinical guidance for interchange of toxin preparations for intradetrusor applications [23].

BoNT-A is administered via intradetrusor injection under local, regional, or general anesthesia using a rigid or flexible cystoscope, frequently in a clinic setting. While no protocol regarding the location and number of injections is universally accepted, general best practices for injection have been previously described [24]. Prior to injection, 30 mL of 2% lidocaine are instilled into the bladder and allowed to dwell for 30–60 min to provide local anesthesia. For FDA-approved indications, 100 Units of BoNT-A is diluted in 10 mL preservative-free saline (OAB) or 200 Units is diluted in 30 mL preservative-free saline (NDO) and commonly injected in a grid pattern on the posterior bladder wall in 0.5 mL increments for OAB and 1 mL increments for NDO separated by a distance of 1–1.5 cm. Dilution modification is commonly employed in clinical practice to provide 10 Units per mL allowing reproducible 1 mL injection volumes for both indications. Injection depth is optimized at 2 mm which, in most instances, allows spread of BoNT-A deep to the mucosal layers and directly into the detrusor. Injections to the bladder dome are generally avoided to prevent perforation and extravesical injection. The trigone has additionally been circumvented as an injection site due to a theoretical risk of vesicoureteral reflux, detailed in a following section.

Transient adverse events associated with the act of injection, rather than BoNT-A itself, include dysuria, pain, hematuria, bacteriuria, and elevation of post-void residual (PVR). Of note, most mild AEs occurred within the first week following injection. Occasionally, needle or anxiety-related events, such as vasovagal responses, may occur at the time of injection and should be treated per the clinician’s standard of care. Additional AEs reported at low frequencies included nausea, depression, muscle spasm, constipation, de novo incontinence, generalized or localized muscle weakness, insomnia, dizziness, diarrhea, influenza, hypertension, headache, back pain, mycotic infection, multiple sclerosis (MS) relapse, pain, fever, and de novo autonomic dysreflexia.

As mentioned previously, BoNT is often considered the most potent biological toxin recognized, thus potential AEs from administration are theoretically profound [25]. Although generally considered a focal therapy on local peripheral nerves, a black box warning accompanies the prescribing information for BoNT-A highlighting the prospect for systemic spread. Doses of BoNT-A are represented by mouse units (U), with one unit of toxin representing the dose necessary for mortality following intraperitoneal injection in 50% of a group of female mice. In humans, an extrapolated lethal dose of BoNT-A would range from 2000 to 3000 Units [26]. Although incidence of such systemic events remains exceedingly rare, the clinician must employ a high index of suspicion for such sequela [27]. New onset symptoms such as focal or generalized muscle weakness, hoarseness or dysphonia, dysarthria, de novo or worsening urinary incontinence, difficulty with breathing or swallowing, and impaired vision are potential indications of regional or systemic toxin spread [28–30]. Reports of progression to respiratory depression and death have thus far been limited to children receiving elevated doses for skeletal muscle spasticity [31]. Meta-analysis of long-term efficacy and safety of 2309 patients encompassing 36 studies reported overall risk of mild or moderate AEs in patients receiving BoNT-A to be 25% compared to 15% in controls [31]. The only AE occurring more significantly in the BoNT-A group was focal weakness, again highlighting the potential for infrequent, yet significant, AEs. Similar literature reviews for both OAB and NDO demonstrated the exceptional rarity of systemic events [21, 32, 33].