Applications of botulinum toxin to the female pelvic floor: Botulinum toxin for genito-pelvic pain penetration disorder and chronic pelvic pain in women

Chronic pelvic pain (CPP) is defined as pain perceived in structures related to the pelvis and “is often associated with negative cognitive, behavioral, sexual, bowel, pelvic floor or gynecological dysfunction.” 13 Pelvic pain is usually considered chronic if it has been continuous or recurrent for at least 6 months; some professional societies utilize a shorter 3 month duration. There are multiple possible anatomic sources of pain within the female pelvis ( Table 1 ) and pain conditions specific to it ( Table 2 ). Management of CPP in women begins with evaluation for an identifiable cause followed by condition-specific treatment, if available, and analgesics as needed. However, even if an initial and triggering cause is diagnosed, pelvic pain can persist despite condition-specific or pain-focused treatment. CPP can also arise in the absence of an identifiable etiology. Such pain can be termed “nociplastic” pain, defined by the International Association for the Study of Pain as “pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing pain.” 14 Nociplastic pain is associated with both peripheral and central sensory sensitization. A particularly common cause of female CPP is endometriosis, estimated to affect about 10% of reproductive age women and up to 87% of those with CPP. In endometriosis, retrograde menstruation leads to estrogen-dependent, progesterone-resistant lesion growth outside of the uterus. The primary symptoms of endometriosis are pain and infertility. Pain is not solely due to the lesions as there is no correlation between pain and the location, number of lesions or severity of disease. Pain persists in about 30% of women despite endometriosis treatment including surgery to remove lesions and hormones to suppress lesion development and growth. The pathophysiology of endometriosis and of endometriosis-associated pain are complex involving endocrine, immunologic, pro-inflammatory, and pro-angiogenic processes. 15 Endometriosis lesions develop their own blood supply and innervation, including by sensory and autonomic nerve fibers that provide direct connection to nervous system pain pathways. 16 Peripheral and central pain sensitization have been demonstrated in women with endometriosis and endometriosis-associated chronic pelvic pain as evidenced by hyperalgesia and allodynia within the pelvis and beyond. 17 Women with CPP often manifest myofascial trigger points and spasm in muscles of the pelvic floor as well, which may contribute to the initiation and maintenance of pain as well as sensitization. Such sensitization is the likely mechanism sustaining pain following endometriosis treatment. The initial treatment of endometriosis is usually empiric hormonal therapy, often with menses suppression. Surgery to detect and resect endometriosis lesions is generally reserved for those who fail to respond to hormonal therapy. When surgery and hormone treatment fail to resolve pain, standard pain management approaches are added. Similar to GPPD, CPP and endometriosis are complex disorders with multiple overlapping biopsychosocial comorbidities. Evaluation and treatment of these overlapping comorbidities also warrant consideration as part of the overall treatment strategy.

GPPD and CPP are common chronic pain conditions in women that remain underdiagnosed and undertreated. BoNT presents an opportunity for treatment utilizing a medication that can safely be combined with other pain and hormonal therapeutics and with the potential to lessen both pain and spasm. Although the literature is expanding, randomized controlled trials are lacking. Almost 40% of recent publications on the subject are review articles, each concluding that there is currently insufficient evidence to recommend the use of BoNT for GPPD or CPP. The time has come to stop reviewing the literature and to start conducting high qualify clinical trials of efficacy and safety and to explore optimal approaches to injection for these chronic, debilitating conditions.

The treatment of female pelvic pain disorders with BoNT dates back to 1997 with a case report of the successful injection of onabotulinumtoxinA into the anterior vaginal wall to treat vaginismus. 20 The literature has expanded, with 35 publications in PUBMED in the past 10 years alone, the vast majority of which have been prospective open trials, case reports, case series, retrospective studies, and literature reviews. [ Figure 1 ] The cumulative literature on BoNT for GPPD indicates that 71–100% of women achieve intercourse or experience a significant decrease in pain during intercourse. 21 The results from the few double-masked, randomized, placebo-controlled clinical trials for GPPD, however, are more mixed. Diomande et al. failed to show benefit from 50 Units (U) or 100U onabotulinumtoxinA compared to saline placebo injected subcutaneously into the dorsal vestibulum in women with provoked vulvodynia. 22 A decrease in pain was achieved, however, in 58% of their study patients who subsequently received 2 open 100U injections 3 months apart after the masked injection. The authors postulated that the study injections may have been ineffective because the study was underpowered or because the injections were too localized and placed posteriorly whereas the pain was anterior. Petersen et al. similarly failed to show decreased pain or improved sexual function or quality of life in a randomized, double-masked clinical trial of 20U onabotulinumtoxinA into bulbocavernosus for women with provoked vestibulodynia. 23 Haraldson et al. compared injection of 50U onabotulinumtoxinA into the bulbocavernosus muscles twice 3 months apart to placebo, finding no significant pain reduction on VAS scores between cohorts, but in their secondary outcome measures, they did find a reduction in pain on tampon use, lowered pelvic hypertonicity, and increased sexual activity. 24 The literature on BoNT for CPP, without consideration of specific etiology, similarly finds benefit in 58–100% of women. In our prior analysis of 38 unique reports with information on injection technique published as of 2017, pain score on VAS decreased 19–100%. 21 The first randomized controlled study of BoNT for CPP was reported in 2006 by Abbott et al., who compared 80U onabotulinumtoxinA to placebo, injected into prescribed locations in the puborectalis and pubococcygeus muscles of women with CPP and elevated pelvic floor pressure. While there was no significant difference in overall pain reduction between the 2 cohorts, only the BoNT group had a decrease in non-menstrual pelvic pain compared to baseline and a decrease in resting pelvic floor pressure. 25 In a more recent clinical trial, Dessie et al. evaluated the effects of 200U onabotulinumtoxinA compared to placebo injected into foci of participant-reported pain in muscles of the pelvic floor in women with myofascial pelvic pain. 26 Their study incorporated pelvic floor physical therapy beginning 4 weeks after injection in all participants. There was a higher percentage of participants in the BoNT cohort reporting improved pelvic pain 4 weeks after injection, but no significant differences on other pain outcome measures. Their BoNT cohort also had more worsening on the pelvic floor distress index, Colorectal-Anal Distress Inventory and Urinary Distress Inventory than the placebo group 2 weeks after injection; however, adverse effects of constipation, urinary incontinence, fecal incontinence and urinary retention were not more frequent. Their results are confounded by differences between study cohorts at baseline; the BoNT group had more participants with severe or moderate pain and dyspareunia than the placebo group. Differences between groups beyond 4 weeks were further confounded by the addition of pelvic floor physical therapy for all study participants. The authors noted that their study may have been underpowered as they assumed a low placebo effect when determining their sample size and they did not account for the potential effect of physical therapy. A novel use of BoNT for dysmenorrhea is proposed by Bautrant, who piloted intrauterine myometrial BoNT injections and found improvement in dysmenorrhea and dyspareunia, lasting up to 6 months in some patients. 27 In our prior analysis of the literature on methodology for BoNT injection for CPP, we found that studies did not focus on a single initiating cause of pain but included women with CPP regardless of etiology. Some studies used fixed BoNT doses and fixed muscles or sites of injection, others adjusted the dose and muscle location based on the location and/or severity of pain. Many injectors relied on palpation or anatomic landmarks for injection, some using a transperineal approach and others a transvaginal approach to reach the pelvic floor. A guidance technique, like ultrasound or EMG, may be important to assure needle placement into, and not beyond, the muscles of the pelvic floor. 28 BoNT doses reported to be effective had an extremely wide range- from 10–300U onabotulinumtoxinA and 20–500U abotulinumtoxinA. The dose is important not only to assure an adequate dose for efficacy, but also to minimize adverse effects. Our review of the literature showed that urinary and fecal adverse effects were more likely with doses above 100U onabotulinumtoxinA. Despite expanding practitioner utilization of BoNT for GPPD and CPP, the literature remains insufficient due to the paucity of high quality, randomized, controlled clinical trials. Interpretation of the literature is further compromised by the lack of a standard approach to virtually all aspects of BoNT use for these indications. There is high variability in the reports regarding patient selection, muscle selection, injection technique, toxin brand, dose, dilution, use of a guidance technique for injection and outcome measures. 21 To address this gap in knowledge, we are conducting a randomized controlled study of BoNT for endometriosis-associated chronic pelvic pain (endo-CPP) ( NCT01553201 ). Women were required to have surgically documented endometriosis, no indication for further endometriosis surgery, and pain persisting despite hormonal and pain treatment optimized by their own care providers. For this proof-of-concept trial, we chose a fixed dose of 100U onabotulinumtoxinA to maximize efficacy while minimizing potential adverse events, especially bowel and bladder events. In our procedure ( Table 3 ), we injected transvaginally with EMG guidance to assure needle placement within the selected muscle and used a “follow the pain” approach to individualize the site of injection within levator ani and/or obturator internus muscles. Our study design included a first injection for which participants were randomized to BoNT or saline. At the time of the primary outcome assessment at 1 month after the randomized injection or later over the next year, participants could request an open 100U onabotulinumtoxinA injection. Our 2019 analysis of response to the open injection in the first 13 women to complete at least 4 months of follow up after the open injection showed a reduction in pain and pelvic muscle spasm. Results from the masked, randomized phase of the study are under analysis.

Chronic pelvic pain is a major source of morbidity in women worldwide, leading to lowered quality of life, diminished ability to work and significant utilization of healthcare resources. 1 – 3 Epidemiological surveys estimate a prevalence of 6–27% of reproductive age women with a yearly cost in the US of $2.8B in 1996. 4 , 5 Botulinum toxin (BoNT) use for pain conditions is rapidly expanding. BoNT for female pelvic floor dysfunction has most often been studied in the context of genito-pelvic pain penetration disorders (GPPD) such as vaginismus and vulvodynia and chronic pelvic pain (CPP), including that due to endometriosis. In this article, we discuss the indications and evidence for BoNT injection into the female pelvic floor for GPPD and CPP.

The term “vaginismus” was first used 1862 to describe recurrent and persistent involuntary contractions of perineal muscles during attempted vaginal penetration, resulting in pain, anxiety, and fear. Vaginismus (involuntary spasm of the outer third of the vagina or surrounding muscles that make penetration during intercourse impossible or painful) together with dyspareunia (pain with sexual intercourse), vestibulitis and vulvar pain (provoked or spontaneous) are now encompassed within “genito-pelvic pain penetration disorder (GPPD)” as the individual conditions can be difficult to differentiate clinically and may be part of a continuum leading to female sexual dysfunction. 6 To be considered GPPD, symptoms must have persisted for at least 6 months, cause significant distress and not be better explained by another disorder or condition. 7 The muscles involved in GPPD most commonly include bulbospongiosis, bulbocavernosus, and levator ani, comprised of the paired puborectalis, pubococcygeus, and iliococcygeus muscles. GPPD has an estimated prevalence of 10–16% of women. 7 – 9 Altered vulvar innervation and changes in sensory and pain thresholds as well as signs of sensitization have been found in women with GPPD. 7 , 10 GPPD can be associated with comorbid conditions including depression, chronic fatigue syndrome, migraine, fibromyalgia, interstitial cystitis/painful bladder syndrome, and irritable bowel syndrome as well as other biopsychosocial symptoms. 11 , 12 GPPD is, thus, multifaceted and requires a multidisciplinary approach to evaluation and treatment. Non-pharmacological strategies include cognitive behavioral therapy, sex therapy, pelvic floor physical therapy, and progressive vaginal dilation. Neuromodulatory approaches such as TENS (transcutaneous electrical nerve stimulation) and electromyography (EMG)-guided biofeedback may be incorporated. Pharmacologic treatments include hormones, topical anesthetics, and oral medications typically used for pain.