Use of Botulinum Toxin for Chronic Pelvic Pain

“it has been suggested that up to 85% of women with chronic pelvic pain have dysfunction of the musculoskeletal system…”

Chronic pelvic pain (CPP) is a significant healthcare problem with estimated prevalence of 2.1–24% of the female population worldwide, depending on the definition [1]. It is defined as continuous or recurrent pain in the lower abdomen or the pelvis lasting at least 6 months, not related to pregnancy, and sufficiently severe to interfere with the habitual activities of the patient.

The etiology of pelvic pain is poorly understood and it is often the result of a complex interaction between the gastrointestinal, urinary, gynecologic, musculoskeletal, and neurologic and endocrine systems and is also influenced by psychological and sociocultural factors [2]. The social, psychological and economic impact of CPP is high. Compared with women who have no pelvic pain, women with any type of pelvic pain were more likely to report having some form of sexual difficulty for at least a month during the previous 12 months [3]. Estimated direct medical costs for outpatient visits for chronic pelvic pain for the US population of women aged 18–50 years are US$881.5 million per year. This medical cost is compounded by the economic cost to the women as reported in a study of 548 employed respondents, 15% reported time lost from paid work and 45% reported reduced work productivity [4].

It has been suggested that up to 85% of women with CPP have dysfunction of the musculoskeletal system, including postural changes, as well as changes in the pelvic muscles, such as spasm of the levator ani or obturator internus muscle [5]. This has recently become easier to classify with the development of the FIGO prolapse assessment scoring system [6].

Botulinum toxin has been successfully used to treat chronic pelvic pain – painful bladder syndrome, detrusor overactivity, vulvodynia, pelvic floor muscle spasm, anismus and chronic constipation.

In this commentary we will limit our discussion for the use of botulinum toxin in the treatment of chronic pelvic pain due to pelvic floor muscle spasm (short pelvic floor syndrome) [7]. Trigger points are described as discrete, nodular, focal, hyperirritable areas, usually less than 1 cm in circumference, located in a taut band of skeletal muscle from which impulses travel to the central nervous system, giving rise to pain at the same location or referred to another area [8]. The muscles commonly involved with chronic pelvic pain are the pubococcygeus, iliococcygeus, ischiococcygeus, piriformis, obturator internus and deep and superficial transverse perinei mucles.

Botulinum toxin is a potent neurotoxin produced by bacteria Clostridium Botulinum. There are seven different serotypes of Botulinum toxin. Botulinum toxin type A and type B have been injected in various spastic disorders, dystonia, extraocular muscles and for reducing facial wrinkles. In 2013, US FDA approved use of onabotulinumtoxin A for overactive bladder refractory to treatment with anticholinergics. The toxin has been researched widely for its safety and efficacy in other areas but the use of botox for gynecological indications is limited and still off-licence.

To understand the use of botox in pain syndromes it is important to understand the mechanism of pain with muscle spasm/myofascial trigger points and mode of action of botox.

The main factor in generating pain appears to be ischemia due to compression of the muscle's blood vessels in cases of muscle spasm. Ischemia leads to the release of bradykinin and sensitization or excitation of nociceptors. Similarly, in a hyperactive muscle nerve compression can occur which leads to pain. Botulinum toxin can relax hyperactive muscle and the pain due to compressions of muscles and nerves. Myofascial trigger points start with a muscle lesion (e.g., overload) that leads to an excessive release of acetylcholine (ACh) into the cleft of the neuro-muscular junction. Botulinum toxin (BoNT) exerts its action by inhibiting the exocytosis of ACh in cholinergic nerve endings. BoNT cleaves proteins (e.g., SNAP-25 or VAMP) that are necessary for the docking of the ACh vesicle to the presynaptic membrane. Without docking, no ACh can be released into the synaptic cleft and the innervated structure is paralyzed [9].

“Vaginal examination is key to the diagnosis…”

Release of muscle tightness (paralysis) due to taut band will improve blood circulation and break the vicious cycle of spasm and pain. Other suggested mechanism is direct analgesic effect of BoNT as few patients report alleviation of pain before muscle relaxing effects of BoNT has set in [9].

When BoNT is injected into a striated muscle, paresis occurs after 2–5 days and lasts for 2–3 months before it gradually starts to wear off. When antibodies against BoNT are formed, the duration of action and the extent of the maximal therapeutic effect are usually reduced after few BoNT applications (partial therapy failure) before complete therapy failure occurs. There does seem to dose effect for BoNT as well [10].

Use of botulinum toxin for different musculoskeletal conditions has been described since 1990s but Brin and Vapnek first described the use of BoNT for vaginismus in 1997 [11]. Since then botox has increasingly been used for pelvic floor muscle spasm but there is still paucity of robust data for its use.

Vaginal examination is key to the diagnosis and taut muscles are easily palpable and usually sufficient to make the diagnosis of pelvic floor spasm on vaginal examination. Electromyography (EMG) and perineometry may be used to aid diagnosis. Similarly ultrasound and EMG have been used for better recognition of trigger points for injections but there is limited use of diagnostic tools in current studies.

Jarvis et al. carried out a prospective cohort study using forty units of BoNT at three different dilutions: 10; 20; and 100 IU/ml in 12 women and median visual analog scale scores were significantly improved for dyspareunia and dysmenorrhea, with nonsignificant reductions in nonmenstrual pelvic pain and dyschezia. Quality of life scores (EQ-5D and SF-12) were improved from baseline at week 12, but did not reach statistical significance. Sexual activity scores were markedly improved, with a significant reduction in discomfort (4.8 vs 2.2; p = 0.02) and improvement in habit (0.2 vs 1.9; p = 0.03). These results were not influenced by dilution [12].

Abbott et al. recruited women who presented with chronic pelvic pain of more than 2 years duration and evidence of pelvic floor muscle spasm in a double-blinded, randomized, placebo-controlled trial [13]. In total, 30 women had 80 units of botulinum toxin type A injected into the pelvic floor muscles, and 30 women received saline. Vaginal manometry was performed preoperatively. There was significant change from baseline in the botulinum toxin type A group for dyspareunia (visual analog scale [VAS] score 66 vs 12; p < 0.001) and nonmenstrual pelvic pain (VAS score 51 vs 22; p + 0.009). In the placebo group only dyspareunia was significantly reduced from baseline (64 vs 27; p + 0.043). The authors concluded that the outcomes show improvement in both groups throughout the 6 months of study, with women in the botulinum toxin group generally reporting better quality of life, although this did not reach statistical significance. In this trial, patients in BoNT group did not suffer an increase in adverse events compared with those receiving saline injections, although there does appear to be a transient and mild effect on pelvic sphincters [13]. This study has well defined criteria and robust methodology but it is notable that there was no statistically significant difference in both the groups.

Adelowo et al. did a retrospective cohort study on 29 patients. Patients had intralevator injection of botox (100–300 units in saline) on the patient reported tender points. In total, 15 patients had repeat injections. The authors used varying doses of botox at different sites. They reported that after one injection most of the women found significant decrease in pelvic pain and repeat injections were used for those women who had improvement in pain after first injection. The side effects reported in this study were urinary retention, fecal incontinence, constipation and rectal pain; all of which resolved spontaneously. The follow-up was up to 7 months [14].

In a most recent prospective study by Morrissey et al. in 2015 the administration of botox (300 IU in 10 ml saline) was performed under EMG guidance. Vaginal manometry demonstrated significant decrease in resting pressures and in maximum contraction pressures at follow-up visits at 8, 12 and 24 weeks (p < 0.05). Digital assessment of pelvic floor muscle (on a scale from 0 to 4) showed decreased tenderness on all visits (mean of 1.9, 1.7, 1.8, 1.9; p < 0.001) compared with baseline (2.8). Reported post-injection adverse effects included worsening of the following preexisting conditions: constipation (28.6%), stress urinary incontinence (4.8%), fecal incontinence (4.8%) and new onset stress urinary incontinence (4.8%) [15].

In a prospective cohort study by Nesbitt-Hawes 100 IU of botox in 4 ml normal saline was given into puborectalis and pubococcygeus. In total, 26 women had single injection while 11 had two or more injections. The follow-up was up to 123 weeks. Single and repeated injections both demonstrated a statistically significant reduction in dyspareunia by VAS scores from 54 to 30 in the single injection group and from 51 to 23 in the multiple injection group (p = 0.001), nonmenstrual pelvic pain VAS from 37 to 25 (p = 0.04), as well as vaginal pressures. The second injection was performed at the earliest at 26 weeks after the first, with subsequent injections having a median time to reinjection of 33.4 weeks [16]. However, with repeat injections muscle atrophy remains a concern as described by Dressler. When botox is injected into a hyperactive muscle, the induced paresis produces a reduction of the diameter of the target muscle. When the target muscle is hypertrophic due to long-lasting hyperactivity, botox-induced paresis can normalize its size. When botox is given over a prolonged period of time then muscle atrophy can occur [10].

Botulinum toxin has temporary effect so repeat injections may be needed. Few studies [14,16] have used repeat injections if the patient has some benefit following first injection. The timing of repeat injection and doses also varied in the studies. The side effects reported from these studies were self-limiting which is encouraging.

Overall, the results from the studies have to be considered with caution. Only one randomized controlled trial (RCT) has been done so far while other studies are either case report, retrospective or prospective cohort studies.

There are generally small numbers in studies with very few studies having robust methodology.

Future perspective

Despite being widely used for musculoskeletal disorders in other areas, the use of botox for pelvic pain is still limited. There is under-recognition of pelvic floor spasm as a cause of chronic pelvic pain. It has negative impact on quality of life of women that even after investigation majority of women will have no cause found for their pain. Usually laparoscopy is performed for pelvic pain and if no cause is found, further exploration of chronic pelvic pain and the diagnosis of pelvic muscle spasm is not considered. With our current knowledge, use of botox for pelvic floor spasm is beneficial in cases where conservative management has failed.

There is paucity of data and only one RCT performed till now has shown nonsuperiority of botox over placebo. Botox should only be used after detailed counseling and presenting available data to the patients. There are adverse effects reported mainly with concerns regarding urinary and fecal incontinence but the effects were self-limiting which is promising and can be helpful in counseling women. The doses of botox, diluents and amount of dilution varied in different studies. There is no consensus about the single and repeat injections, maximum number of repeat injections, which can be given safely, minimum interval between injections and dose response co-relation of botox.

“Despite being widely used for musculoskeletal disorders in other areas, the use of botox for pelvic pain is still limited.”

Further clinical trials with robust methodology may provide considerable evidence for the use of the FIGO prolapse assessment scoring system, EMG and ultrasound in Botox injections. These will also provide evidence for the use of clinically safe and effective dosage of botox with standard diluent and the amount of diluent, sites and number of injections of botox alongside evaluating long-term outcomes, treatment adverse effects, and potential long-term risks.

Longer follow-up may give more evidence for efficacy and safety of repeat injections.

Conclusion

Overall pelvic floor muscle spasm is an important cause of chronic pelvic pain and should be considered in diagnosis. Vaginal examination alone seems sufficient to make the diagnosis of pelvic floor muscle spasm. The use of botox in pelvic floor muscle spasm is encouraging but data from robust trials need to support its continued use in future.