{"paper_id":"caf3a32c-b759-44e7-9ea7-6147760b6e4d","body_text":"In 2022, chronic pain received its own category in the International Classification of Diseases, 11 th  Revision (ICD-11), underscoring its high prevalence and profound impact on health irrespective of any underlying condition. As noted by Barke et al., chronic pain is a “major contributor to individual suffering with substantial direct and indirect societal costs.” 1  Chronic pain, defined by the International Association for the Study of Pain (IASP) as pain that lasts or recurs for at least 3 months, encompasses primary and secondary syndromes, depending on the presence or absence of an identifiable underlying cause. 2\nChronic pelvic pain (CPP) is pain perceived in the pelvic region. The many potential anatomical sources of pelvic pain include the gastrointestinal tract (bowel, anus), urological system (bladder, urethra, kidneys, ureters, sphincters), the nervous system (nerves, nerve roots), and musculoskeletal elements (pelvic floor and abdominal musculature and spinal and pelvic bones). Sex specific sources of pain in women include the vulva which includes the vestibule and clitoris, vagina, uterus, fallopian tubes, and ovaries and, in men, the prostate gland and scrotum which contains the testes and epididymis. CPP in both sexes is commonly associated with negative cognitive, behavioral, sexual, and emotional symptoms.\nChronic pelvic pain may arise in the context of or appear to be initiated by an infection, disease, condition or trauma, but often occurs in the absence of an identifiable etiology or persists despite resolution of the initial trigger. The breadth of causes and scope of CPP makes it difficult and costly to diagnose and treat. Hutton et al. reported an average cost of nearly $30K per individual for diagnostic evaluation and treatment for CPP in men and women prior to presentation at their specialized pelvic rehabilitation practice. They further observed that many of the prescribed diagnostic procedures and treatments appeared to be unnecessary and redundant. 3  CPP significantly diminishes overall quality of life 3 , 4  and imposes additional indirect economic impact through loss of workplace productivity. Consequently, the effective management of CPP in both men and women merits careful, thoughtful evaluation and individualized therapeutic strategies.\nBotulinum toxin (BoNT) is an emerging treatment for pain including chronic migraine, piriformis syndrome, musculoskeletal pain, and neuropathic pain, as well as painful bladder syndrome. 5 – 8  Botulinum toxin may mitigate pain through multiple possible mechanisms. Botulinum toxin disrupts acetylcholine exocytosis at the cholinergic neuromuscular junction resulting in focal muscle denervation. Decreased muscle contraction likely contributes to relief in those with pain from muscle spasm. BoNT also inhibits the release of pain-related neurotransmitters including substance P, calcitonin-gene related peptide (CGRP) and glutamate, directly modulating pain neurotransmission pathways. Through retrograde transport, BoNT may have direct central effects contributing to its analgesic potential.\nThere have been numerous publications on the use of BoNT for CPP, but few rigorously designed well-controlled clinical trials. In this paper, we review the treatment of chronic pelvic pain, other than painful bladder syndrome, with botulinum toxin in men and women.\n\nThe American College of Obstetrics and Gynecology defines CPP in women similarly to the IASP but requires a pain duration of at least six months. 9  Definitions of CPP in women vary as some exclude pain due solely to menses, intercourse, or pregnancy. 10  The prevalence of female CPP ranges between 6–27% of reproductive age women. 11 – 13\nA common initiating trigger of CPP in women is endometriosis, a condition in which hormone-sensitive endometrial tissue grows outside of the uterus. 14  Endometriosis affects approximately 10% of reproductive age women. The most prominent symptoms are pain and infertility. Standard treatment includes surgery to remove lesions and hormones to suppress the menstrual cycle events and prevent lesion growth. Despite treatment, pain persists or returns by one year in about 30% of women with endometriosis.\nAdditional types of pelvic pain in women are the genito-pelvic penetration disorders (GPPDs) that include vaginismus (involuntary spasm of the lower 1/3 of the vagina and surrounding muscles that rendering intercourse impossible or unbearably painful), dyspareunia (pain with sexual intercourse), vestibulitis and vulvar pain. These disorders are considered together as they are difficult to differentiate clinically and are on a continuum leading to female sexual dysfunction.\nThe earliest report of BoNT for CPP or GPPD was a 1997 case report of successful treatment of vaginismus. Since then, publications on BoNT treatment of CPP and/or GPPD have been primarily uncontrolled trials and retrospective analyses with the majority showing benefit. 15  The reports varied widely in the muscles injected with BoNT, including various combinations of obturator internus, levator ani (pubococcygeus, iliococcygeus, puborectalis) and coccygeus for CPP and/or bulbospongioussus and ischiocavernosus for GPPD. Pelvic floor muscles were sometimes injected via a transvaginal approach and sometimes transperineally. For superficial muscles, subcutaneous injection was sometimes used. Toxin doses ranged from 10–300U (Units) of onabotulinumtoxinA (Botox ® ), 20–500U abobotulinumtoxinA (Dysport ® ), and 100–400U incobotulinumtoxinA (Xeomin ® ). A single study used 2500 U rimabotulinumtoxinB (Myobloc ® ). These differences in the toxin used, study populations, treatment methodology and drug preparation, dose, and dilution hampered interpretation of the literature. 15\nAdverse events likely related to toxin included new or worsening urinary and/or fecal incontinence, urinary retention, constipation, flu-like symptoms, vaginal dryness and worsened vaginal prolapse. Common procedure-related adverse events included pain and hematoma with injection. Sufficient data were available in the published reports to evaluate a relationship between dose and adverse events for onabotulinumtoxinA only, showing that bowel and bladder adverse events were more likely with doses over 100U onabotulinumtoxinA. 15\nOnly six randomized clinical trials (RCTs) on BoNT for female CPP/GPPD have been reported to date. In 2006, Abbott et al. published a RCT of 60 women randomized to 80U onabotulinumtoxinA or saline injected restricted to paired puborectalis and pubococcygeus muscles. 16  Pain scores decreased in both groups with no significant difference between cohorts. On exploratory subanalysis, however, only the BoNT cohort had a significant decrease in non-menstrual pain and in resting pelvic floor pressure on vaginal manometry. The authors noted several limitations to this trial, including a wide variability in pain rating scores at baseline and a higher-than-expected placebo response that may have affected their ability to detect between group differences.\nDessie et al. randomized 59 women with CPP to 200U onaBoNTA or saline into pelvic floor muscles areas most tender on palpation. 17  Both cohorts began pelvic floor physical therapy 4 weeks after study injection. They found that BoNT was similar to placebo in decreasing pain in the most painful muscle group at 2 weeks after injection, their primary outcome measure. However, a higher percent of the BoNT group rated their overall CPP as improved at 4 weeks after injection.\nPetersen et al. studied GPPD/vestibulodynia, randomizing 64 participants to injection of the bulbocavernosus muscles with either 20U onaBoNTA or placebo. 18  At 6 months following injection, both study cohorts experienced less dyspareunia, but there were no significant differences between the groups. Notable limitations of this investigation included the use of a low toxin dose into a single paired superficial muscle. Furthermore, the primary outcome assessment occurred at 6 months post-injection, after the pharmacological effects of the toxin (generally lasting about 3 months) were likely to have worn off.\nDiamonde et al. also assessed the efficacy of BoNT among a cohort of 33 women in the management of GPPD/vestibulodynia. Participants were randomized to receive either a 50U or 100U dose of onabotulinumtoxinA or placebo, with injections administered subcutaneously into the dorsal aspect of the vestibule. At 3 months post-injection, no significant improvement was observed in any of the treatment groups. The authors highlighted a crucial study limitation, noting that while pain localization in many patients was predominantly ventral, all injections targeted the dorsal vestibule.\nHaraldson et al. reported their RCT of BoNT for GPPD/vestibulodynia in 2020, with a follow-up report in 2022. Eighty-eight women were randomized to 50U onabotulinumtoxinA or placebo injected into the bulbocavernosus muscles, with a second masked injection 3 months later. The primary outcome, self-reported dyspareunia or pain on tampon insertion, was assessed 3 months after each injection. Neither group had a significant decrease in pain by visual analog score nor was there a difference between groups. A significant reduction in pain on tampon insertion, lower intravaginal pressure, and an increased ability to engage in intercourse was detected in the BoNT cohort. At 12 months, sexual function was improved in the BoNT cohort only. Results from this study may have been confounded by combining results from 2 injections for analysis. Other limitations included only injecting superficial muscles and assessment of the primary outcome at 3 months after each injection, when toxin may have worn off.\nSpruijt et. al. conducted an RCT with 94 women with CPP, combining a randomized BoNT or placebo injection with pelvic floor physical therapy (PT); all subjects had failed prior pelvic floor PT. At 8 weeks after injection, they found a significant improvement in the patient global impression of improvement in the BoNT cohort compared to the placebo cohort. While no difference in pain relief between the 2 cohorts was reported at 26 weeks after injection, electromyography showed decreased pelvic floor muscle activity in the BoNT cohort.\nBoNT for female CPP and GPPD has been the subject of several systematic reviews, each with a different focus and criteria for article selection. Luo et al. included 17 studies (5 RCTs and 12 observational studies) published in English and including more than 10 adult women in their review. 19  All of the cited observational studies had at least 1 positive outcome while all the RCTs were negative for superiority over placebo on pain and function outcomes. However, there were concerns for bias identified in most of the included RCTs.\nMeister et al. reviewed 9 studies on CPP that used onabotulinumtoxinA, employed a transvaginal approach to injection, and reported quantitative pain scores, including 2 RCTs, 4 prospective trials, 1 retrospective report and 2 case series each with more than 10 participants. 20  The data from these studies indicated that onaBoNT was superior to placebo and that BoNT treatment led to an improvement in quality of life, and a decrease in pressure on pelvic floor manometry.\nIn 2022, Spruijt et al. focused on CPP limiting the review to studies of onabotulinumtoxinA injection into levator ani muscles that utilized a visual analog score for the primary outcome. 21  The eight reports included 2 RCTs, 4 prospective trials and 2 retrospective studies. Their analysis showed a significant decrease in pain visual analog score at 12 weeks with BoNT compared to control injection, along with improvements in dyspareunia, the physical component of quality-of-life assessment and pelvic floor resting pressure.\nThe review of Parsons et al. included 4 studies of BoNT for gynecological pelvic pain syndrome with an at least 3-month follow-up period. 22  Their analysis found no effect of BoNT on pain scores at 6-month follow-up.\nPanunzio et al. performed a pooled meta-analysis of RCTs and prospective comparative studies of botulinum toxin for male and female CPP with at least 20 participants and 3 months follow-up. 23  Four studies were of BoNT for gynecologic pelvic pain and indicated benefit.\nKnapman et al. reviewed RCTs and prospective studies with at least 5 participants and retrospective studies of more than 10 participants published up to 2022. 24  Their analysis of 24 studies found a high placebo response rate and no benefit of BoNT compared to placebo in RCTs, while prospective and retrospective studies showed improvement with BoNT.\nSerious adverse events were not common with BoNT injections for CPP or GPPD. Adverse events, usually transient, include those related to toxin and those related to the injection procedure. The most common adverse events attributable to the toxin itself included urinary incontinence or retention, fecal incontinence or constipation, and flu-like syndrome. The injection procedure was associated with procedural pain and bleeding or hematoma.\nThe prospective reports, retrospective reviews and open studies of BoNT for CPP and GPPD in women are largely positive. Yet randomized controlled clinical trials have shown mixed results, with some reporting benefit from BoNT and others finding no advantage of BoNT over placebo. Differences in RCT design, including in participant eligibility criteria, study population, dose, dilution, muscles targeted, primary outcome measures, and timing of outcome assessment may account for the inconsistencies in results. Of particular note is outcome assessment timing. When used for motor disorders and chronic migraine, botulinum toxin typically has an onset of effect 1–2 weeks after injection with peak effect at about 4 weeks. The effects then gradually wane, wearing off by about 12 weeks. The duration of benefit may be longer for some indications, such as overactive bladder. 25  The period of benefit in CPP/GPPD has not yet been determined; however, trials with the primary outcome assessment later than 12 weeks do not consider the typical dosing time frame for this treatment and may have missed the period of efficacy.\n\nThe definition of chronic pelvic pain in men is similar to that in women: persistent or recurrent pain (for at least 3 or 6 months) perceived in structures related to the pelvis. As in women, it often encompasses symptoms of lower urinary tract and sexual dysfunction and is commonly associated with anxiety and depression. 26 , 27  The prevalence of CPP in men is estimated at 2–10% and increases with age. 28  The potential key role of the prostate in male CPP led to its incorporation in the terminology for the condition: chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Diagnostic examination and testing often focus on identification of prostate infection or inflammation and initial treatment often includes alpha-blockers, antibiotics, 5 alpha-reductase inhibitors, as well as analgesics. In men as well as women, pain often persists in the absence or after treatment of an identifiable underlying etiology.\nTwo instruments commonly used in the evaluation of CP/CPPS include the NIH-Chronic Prostatitis Symptom Index (NIH-CPSI) and the UPOINT. 29 – 31  The CP/CPPS parses symptoms into three domains: pain, urination, and quality of life. The UPOINT phenotyping system categorizes symptomatology into six clinically relevant domains:  U rinary,  P sychosocial,  O rgan specific,  I nfection,  N eurologic/Systemic, and  T enderness of musculoskeletal structures.\nThe literature on the clinical utilization of BoNT in the management of CP/CPPS includes 3 RCTs and 3 systematic reviews. Gottsch et al. randomized 29 men with at least moderate CPPS symptoms to receive injection of 100 U onabotulinumtoxinA or saline into the perineal body and bulbospongiosis. 32  At 1-month post-injection, the response rate on their primary outcome measure, the Global Response Assessment (GRA), was significantly higher in the BoNT group. The effects wore off by 3 months after injection. Changes the total NIH-CPSI did not reach significance but improvement on the pain and quality of life subscales of the NIH-CPSI were significant in the BoNT cohort only. Ten of the participants originally assigned to placebo opted to receive an open BoNT injection one month after the initial randomized injection. These participants also had significant improvement on the GRA at 1 and 2 months after active injection. No complications were identified in this trial.\nFalahatkar et al. studied 60 men with CPPS who were randomized to transurethral intraprostatic injection of 100 U or 200 U onabotulinumtoxinA or a similar volume of saline. 33  At 3 months after injection, the BoNT cohort had improved pain on the NIH-CPSI, pain VAS, and quality of life compared to the participants who received placebo.\nIn contrast, Dockray et al., focusing on chronic scrotal pain, randomized sixty-four men to local anesthetic and 200U onabotulinumtoxinA or saline spermatic cord injection targeting the ilioinguinal and genital branches of the genitofemoral nerve. 34  Injections were unilateral or bilateral, depending on the pain location. Patients with no response at 1 month had the study treatment unmasked; those in the control group were offered up to 3 open injections, 3 months apart. Following masked injection, there was no significant difference on the pain VAS at 1 month after injection in either group and no difference between the cohorts. In the second phase of the study, however, two-thirds of those requesting open injection, all of whom initially had saline injections, had improvement in the pain VAS at 1 month after injection.\nThe pooled meta-analysis of Panunzio et al. included two RCTs and one prospective comparative study of BoNT for CP/CPPS including a total of 180 men refractory to antibiotics, alpha blockers or anti-inflammatory drugs and that utilized intraprostatic injection. 23  The authors concluded that BoNT may be an effective and safe treatment for CP/CPPS.\nFranco et al. conducted a systematic review of pharmacologic treatments for CP/CPPS. 35  The only 2 studies on BoNT meeting their inclusion criteria, those of Gottsch  32  and Falahatkar 33  described above, incorporated different approaches to treatment so that the reviewers could not provide recommendations on the use of BoNT for CP/CPPS. The review of Parsons et al. included 2 RCTs and one comparative study of transurethral v. transrectal approach of BoNT for CPPS. 22  They were similarly unable to reach conclusions or generate recommendations on the use of BoNT due to missing data and methodological variability.\nThe limited available data on BoNT for CP/CPPS are suggestive of benefit and safety but remains insufficient to guide clinical practice. The inability to synthesize the published reports is hampered by the use of different injection targets in each of the RCTs with perineal body and bulbospongiosis, prostate, and spermatic cord being injected in one study each.\n\nProspective, retrospective, and uncontrolled studies largely support BoNT efficacy and safety for chronic pelvic pain conditions. The failure of RCTs to consistently demonstrate benefit does not necessarily mean that BoNT is ineffective for pelvic pain. The methodological problems and differences noted above in the clinical trials conducted to date and the many variations in almost every aspect of use of BoNT for CPP and GPPD in women and CP/CPPS in men make the literature difficult to synthesize and interpret. The clinical trials differed in their target populations, control for concomitant treatments, muscles or other targets of injection, BoNT drug, dose, dilution, and injection technique, as well as outcome measures utilized and timing of outcome assessments.\nAdditional confounding features in the reported clinical trials may have made it difficult to detect a difference between active and placebo cohorts. First is the choice of control for the study intervention, the most common of which is placebo saline injection. The placebo injection itself may have had an acupuncture-like effect or acted as a myofascial trigger point release, leading to improvement in the placebo cohort that was not accurately estimated when determining study sample size, leading to under-powered studies.\nPain clinical trials are, in fact, increasingly confounded by a high placebo response rate. Smith et al. explored possible explanations for the failure of RCTs to demonstrate efficacy of truly efficacious treatments and the role of unforeseen placebo group improvement. 36  Among the identified reasons for such trial failures were unanticipated improvement in the placebo group, failure to choose the optimal patient population or patient phenotype, use of outcome measures with limited sensitivity to treatment effects, and inadequate sample size. To understand the difficulties encountered in pain clinical trials, Finnerup et al. performed meta-analyses of assay sensitivity and placebo group changes in RCTs of FDA-approved drugs for the treatment of chronic neuropathic pain. 37  They found that treatment effects decreased while placebo group changes have increased over the past several decades, especially in the U.S. They attributed these findings to changes in research methods, sites and patients. Larger placebo group response was associated with longer and larger studies, greater frequency of study visits, a lower probability of receiving placebo, and higher patient expectation of improvement. They also found that high variation in individual baseline pain ratings was associated with higher placebo response.\nHigh quality RCTs that mitigate confounding factors are critically needed, as well as those that explore the optimal targets, dose and approach to BoNT treatment of CPP/GPPD in women and CP/CPPS in men. Such studies should standardize variables to the extent possible, consider ways to minimize placebo response, assess outcome at a time consistent with the known time course of BoNT action, and utilize validated outcome measures that can reliably detect clinically relevant changes in response to treatment.","source_license":"CC0","license_restricted":false}