Botulinum toxin (BonTA) exerts its main therapeutic by inhibiting neuro-mediator exocytosis [1]. This was originally seen with acetylcholine hence the first diseases to be treated with BonTA injections where ocular strabismus and other striated muscular conditions [2]. In urologic diseases use of BonTA also started with application to striated muscle. In this case the urethral sphincter was targetd for treatment of sphincter-detrusor dissynergia in spinal cord injury patients [3]. With the rationale of smooth muscle relaxation, intra-vesical injections where approved initially for neurogenic detrusor over activity and later for the idiopathic overactive bladder syndrome. These applications showed great success and presently are mainstays of neurogenic and idiopathic bladder over activity treatment [4–6]. Since both the toxic effects as well as therapeutic effects of BonTA were seen as an efferent neuronal effect it was initially overlooked in the treatment of bladder pain.

From the verification that botulinum toxin also affected sensory nerve function it was a matter of time until its use was attempted in Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC). Indeed, the toxin also hinders exocytosis of sensory nerve neuro-mediators and decreases expression of fundamental receptors in nerve fiber activation such as transient receptor potential receptor vanilloid type 1 (TRPV1) and purinergic receptor type 2X3 (P2X3) [7, 8]. The fact that treatment of spastic muscle ameliorated pain by more than simple muscle relaxation turned attention to these basic science findings. Previous experience with BonTA intravesical injection in bladder overactivity showed the technique’s safety and efficacy thus paving the way for trials in BPS/IC.

In 2004 Smith et al., published the first results with bladder wall and trigonal injection in 13 patients with bladder pain syndrome (BPS/IC). The authors reported improvement of pain in 69% of patients [9]. Other groups soon published their results. In a pilot study, Giannantoni et al. injected 200 units (UI), sub-urothelial BonTA, to trigone and bladder floor of 14 patients. Of these, 12 patients (85.7%) showed improvement in frequency, nocturia, pain (VAS) score and increased cystometric capacity [10]. The same group reported on a prospective follow-up of 13 patients with repeat injections for 2 years. All patients received multiple site bladder wall injections totaling 200 U. A total of 58 injections were administered with a mean of 4.8 ± 0.8 injections per patient. The mean interval between two consecutive injections was 5.25 ± 0.75 months. At 1 and 4 months follow up ten patients reported a subjective improvement. Treatment efficacy was maintained in all patients during the observation period [11].

Injection technique varies among groups. Based on a previous study showing a predominance of sensory afferent distribution at the trigone [12], Pinto et al. performed injection at ten trigonal sites only with a total of 100 UI of BoNT-A, in 26 patients with refractory BPS/IC. Pain, frequency and nocturia, O’Leary-Sant Interstitial Cystitis Symptom Index (ICSI) and quality of life of all patients improved significantly. Maximal cystometric capacity also increased and the efficacy remained in >50% of the patients for 9 months [13].

In a single center, prospective randomized study, Kuo et al. injected 100 or 200 UI in 40 sites in the posterior and lateral bladder wall, combined with hydrodistension in 29 patients while 13 control patients also with BPS/IC, underwent hydrodistension only. Seventy one percent of patients in the treatment arm still showed improvement at 6 months, 55% at 12 months, and 30% at 24 months [14].

In a multicenter, randomized, double-blind, placebo controlled trial in patients with IC/BPS refractory to conventional treatment, by Kuo et al., patients were randomized to hydrodistention plus suburothelial injections of BoNT-A 100 U (BonTA group) or normal saline (control group). A total of 60 patients (8 males, 52 females) including 40 in the BonTA and 20 in the control group were enrolled. At week 8, a significantly greater reduction of pain was observed in the BonTA group. Cystometric bladder capacity also increased significantly. Success rate was 63% in the BonTA group versus 15% in the control group. Adverse events (AE) did not differ between groups [15].

A single-center, prospective, open labeled, randomized comparative study by Akiyama et al. studied BonTA application in BPS/IC patients refractory to previous hidrodistension and Hunner lesion ressection when present, performed on average for 2.7 times per patient. Patients were randomly divided into two groups: immediate injection (group A) or 1-month delayed injection (group B) of BonTA. A total of 34 patients (group A n = 18, group B n = 16) were allocated. The response rate was significantly higher in group A than group B (72.2% vs. 25.0%). When both groups were combined as a single cohort, the response rate was 73.5% at 1 month, 58.8% at 3 months, 38.2% at 6 months and 20.6% at 12 months. The mean duration of response was 5.4 months [16].

Studies generally report a limited time of the therapeutic effect spanning from circa 5 to 9 months, implying the need for repeat injections. However, these have been proven as effective as the initial treatment by several groups [11, 14, 17].

Adverse events (AE) were mild and infrequent in all studies and most frequently consisted of dysuria and urinary infection [11, 14, 17]. Acute urinary retention was not found in trigone-only injection studies [17, 18] and was rare in other studies [19, 20]. However no randomized head to head trials comparing bladder wall versus trigonal-only injection for BPS/IC treatment been reported either assessing efficacy or AE. In a comparative study of 72 BPS/IC patients with 89 OAB patients, both groups were treated with 100 UI of botulinum toxin applied to the bladder wall and AE were compared. Fifty eight percent of OAB patients reported at least one adverse event, including gross hematuria (9.7%), urinary tract infection (UTI) (27.8%), straining to void (8.3%), large post void residual (PVR) (31.9%) and acute urinary retention (AUR) (1.4%). On the other hand, 42.7% of BPS/IC patients found at least one AE, including UTI (6.7%), straining to void (30.3%) and large PVR (6.7%). There was neither gross hematuria nor acute urinary retention experienced in the BPS/IC patient group. Overall incidence of AEs was significantly lower in the BPS/ IC than in the OAB group. Different pathophysiological mechanisms at play in BPS/IC and OAB might explain different AE rates for an identical treatment [21].

In the work by Akiyama et al., a total of 10 of 34 (29.4%) patients complained of voiding difficulty after treatment. Three patients (0.9%) had elevated post void residual (PVR) for the first 2 months, which resolved spontaneously. Other adverse events included transient gross hematuria (n = 1–0.3%), which also resolved spontaneously and afebrile urinary tract infection (UTI) (n = 2–0.6%).