**3. Clinical Evidence of BoNT-A for Pelvic Floor Muscle Pain in CPPS Women**

BoNT-A was first used for therapeutic purposes in the 1960s when Dr. Alan B. Scott, an ophthalmologist, injected BoNT-A into extraocular muscles of rhesus monkies to treat strabismus. His results were successfully replicated in humans [31]. BoNT-A has been widely studied in several therapeutic applications and different diseases. However, previous studies and clinical trials have not confirmed the effect of BoNT-A for relieving myofascial pain in the neck, shoulders, or trunk [17,32].

Although BoNT-A has been widely used for muscular disorders, its role in treating CPPS has yet to be established. Present literature suggests that injecting BoNT-A into the PFMs may improve symptoms in women with CPPS. Joo et al. reported a 50% success rate of BoNT-A injection in anismus for a long-term period [33]. Brin and Vapnek first reported the injection of BoNT-A to treat vaginismus in 1997 [34].

A systematic review including five studies supports that BoNT-A treatment was beneficial for relieving spasms of PFMs due to CPPS [17,35]. BoNT-A administration could relieve symptoms of dyspareunia, dysmenorrhea, non-menstrual pain and dyschezia. After BoNT-A treatment, it also improved the quality of life and sexual activity. The improvement may because of BoNT-A injection causing localized, partial denervation of the PFMs resulting in muscle weakness and reduction of pressure.

CPP can occur at several muscles in the pelvic region such as pubococcygeus, ischiococcygeus, iliococcygeus, piriformis, transverse perinei muscles, and obturator internus. Preliminary studies

have reported that BoNT-A injection could be able to decrease levator ani muscle spasms in women with CPP [14,36,37]. Halder et al. reported 200 U of BoNT-A injections into the trigger points of the perineum in 50 women with CPP [38]. The outcomes showed a significant decrease in pelvic pain scores (3.7 ± 4.0 vs. 6.4±1.8, *p* = 0.005), and fewer trigger points (44% vs. 100%, *p* < 0.001). There was an improvement (20.7%) in patients with the previous placement of incontinence sling versus no improvement (0%) in pain (*p* = 0.003).

The major factor of pelvic pain in women with a spasm of PFMs appears to be ischemia due to vessel compression of the muscles, which leads to the release of bradykinin and sensitization or excitation of nociceptors [5]. BoNT-A injection can improve symptoms of CPP by the antispasticity effect on a spasm of PFMs rather than the result of the antinociceptive activity [17]. Injected BoNT-A into PFMs in women with CPP has been reported to improve the overall quality of life significantly, specifically to improve dyspareunia and female sexual function [30].

Because of the reversible effect and natural metabolism by the body, treatment with repeated BoNT-A injection for CPPS is frequently required. A low dosage of BoNT-A was injected in other muscle groups of the body at three-month intervals, as it was unlikely to produce significant side effects [14].

Injection of 300 U of BoNT-A into PFMs may be safe, especially administered to the regions of hyper-spastic muscles [30]. However, the timing for repeat injection, the optimal dilution, and injected dosage are still challenging to maximize the therapeutic effects of BoNT-A in CPPS of women. It is unclear how significantly the pain will be relieved after BoNT-A injection. The outcome of BoNT-A in relieving CPPS needs more large prospective, randomized, controlled studies.

Table 1 lists important clinical studies of BoNT-A injection for relieving pain symptoms of PFMs.


StudyofBoNT-AforpelvicfloormusclepaininCPPS

#### **4. Clinical Application of BoNT-A in IC**/**BPS Women**

The etiology and pathophysiology of IC/BPS are still unclear. There are many treatments for relieving IC/BPS including analgesic medicine, changing habits of lifestyle, pentosan polysulfate sodium, cystoscopy with hydrodistention, or instillation of dimethyl sulfoxide in the bladder.

Smith et al. first reported that submucosal BoNT-A injection into 20 to 30 sites of the trigone and bladder floor for a total of 100 to 200 U would result in a 69% improvement of IC/BPS patients, including daytime frequency episodes, nocturia, pain, and bladder capacity [39]. In 2009, Kuo et al. reported a prospective, randomized, and controlled study including 67 patients with IC/BPS who failed conventional treatments, comparing intravesical BoNT-A injection in 100 U or 200 U plus hydrodistention with hydrodistention alone. The IC/BPS symptom score significantly improved in all three groups. However, it only showed a significant reduction of pain visual analogue scale (VAS), an increase of functional bladder capacity (FBC) and cystometric bladder capacity in the BoNT-A group [40].

In 2016, a multicenter, randomized, double-blind, placebo-controlled trial compared hydrodistention plus 100 U of BoNT-A injections at 20 sites with injections of normal saline at 20 sites in 60 patients with refractory IC/BPS. A significantly greater reduction of bladder pain symptoms and increased bladder capacity under cystoscopy were observed in the group with BoNT-A injection, with 63% of overall success rates versus 15% in the normal saline group [41].

Compared to single intravesical BoNT-A injection for IC/BPS patients, there were long-term therapeutic effects in repeated injections, such as pain relief, improved bladder capacity, and better success rates for a long-term period. Kuo et al. reported a repeated intravesical injection of 100 U of BoNT-A every six months for up to four times or until symptoms improved in 81 patients with refractory IC/BPS. It showed significant improvement in pain relief, FBC, and daytime frequency after repeated therapy with different BoNT-A injections. Compared to one single injection, it also reported significantly better success rates for four repeated injections (*p* = 0.0242) and three repeated injections (*p* = 0.050) [42]. In a recent prospective study, 104 patients received an intravesical injection of 100 U of BoNT-A and cystoscopic hydrodistention for refractory IC/BPS. Repeated BoNT-A injections were done every six months for two years. The study showed that 56.7% of patients received four injections of BoNT-A and 34% of patients received another fifth injection because of progressive IC symptoms. It showed a better success rate in those patients who completed repeated BoNT-A injections and significant improvements of O'Leary-Sant IC symptom and problem indexes (ICSI, ICPI, OSS), painful VAS, FBC, frequency, and global response assessment (GRA) during 79 months of follow-up [43].

Liu et al. reported the levels of nerve growth factor (NGF) in the bladder tissue were significantly increased in 19 patients with IC/BPS compared with 12 healthy patients. After injections with 100 U or 200 U of BoNT-A followed by cystoscopic hydrodistention two weeks later, they showed a decrease of the NGF mRNA levels and no significant difference compared with the healthy controls [44]. Intravesical BoNT-A injections could improve chronic bladder inflammation, decrease apoptosis, and decrease the level of bladder vascular endothelial growth factor in patients with IC/BPS [45,46].

The injection sites and the numbers of injections are controversial. It has been reported to inject BoNT-A into the trigone and the posterior bladder wall simultaneously, only the trigone, and sites excluding out the trigone. Pinto et al. reported injecting 100 U of BoNT-A into ten trigonal sites compared to saline injections for refractory IC/BPS patients. They showed significant improvements in bladder pain and quality of life [47]. Jiang et al. injected 100 U of BoNT-A into 20 bladder body sites or 10 trigonal sites in 39 IC/BPS patients. After eight weeks from baseline, they showed no significant difference in changes in urinary frequency, voided volume, post-void residual volume, and bladder capacity. No significant difference in decreasing VAS, symptom improvement, and dysuria were also noted [48].

Kuo et al. investigated the therapeutic predictors, such as ICSI, ICPI, FBC, frequency, and first desire to void for successful treatment of BoNT-A injection in the bladder for refractory IC/BPS patients. Successful treatment was defined as GRA ≥ 2 at six months. The success rate was 45.54% at six months. Multivariate logistic regression showed the only therapeutic predictor for successful management was the baseline ICSI. Patients with an ICSI ≥ 12 may indicate a poorer therapeutic outcome of BoNT-A injections [49]. For refractory IC/BPS, the effectiveness and success of BoNT-A injections has been shown.

To summarize, BoNT-A injection has been widely studied for IC/BPS patients and it has become a promising treatment for refractory IC/BPS patients with the combination with hydrodistention (Table 2), although repeated injection may be needed for long-term therapeutic effects.


**Table 2.** Study of BoNT-A for IC/BPS women.
