Chronic pelvic pain and botulinum toxin

The 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. Two 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. The 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. Falahatkar 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. In 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. The 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. Franco 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. The 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.

Prospective, 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. Additional 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. Pain 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. High 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.

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 Chronic 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. Chronic 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. Botulinum 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. There 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.