(1)
Botulinum Toxin Treatment Program, Yale School of Medicine, New Haven, CT, USA
Abstract
High-quality data regarding the efficacy of botulinum neurotoxins (BoNTs) in pelvic and urogenital pain disorders is limited. In female pelvic pain, one double, placebo-controlled study (class II) has shown significant improvement of pelvic pain after injection of onabotulinumtoxinA (onaA) into pelvic floor muscles (level C evidence, possibly effective). In male pelvic pain, related to prostatitis, a small study of 13 patients demonstrated modest improvement compared to placebo (level C evidence, possibly effective). For pain associated with interstitial cystitis (bladder pain syndrome), one small double-blind study showed no difference between 50 units of onaA and placebo (one class II study, possibly ineffective for that dose), whereas a comparator blinded study found 100 and 200 units of onaA injections were statistically more effective than the conventional treatment with hydrodistention alone (one class II, possibly effective for that dose in a comparator study). All four open long-term studies with BoNT-As in bladder pain syndrome also have suggested initial efficacy and better efficacy with repeat injections. In vulvodynia and vestibulodynia, one double-blind study of 60 patients has shown no efficacy with a dose of 20 units, whereas two open studies with comparable numbers suggest efficacy with 100 units of onaA. More controlled and blinded data are needed to discern the effectiveness of BoNT injections in bladder pain syndrome and vulvodynia, preferably with larger doses, comparable to those which suggested efficacy in the open trials.
Keywords
Pelvic painInterstitial cystitisBladder pain syndromeVulvodyniaVestibulodyniaBotulinum toxinBotulinum neurotoxinOnabotulinumtoxinAAbobotulinumtoxinAIncobotulinumtoxinAPelvic Pain
Introduction
Chronic pelvic pain (CPP) is a disabling disorder which is more common among women.
The American College of Gynecology defines chronic pelvic pain as noncyclic pain of more than 6 months duration that localizes to the pelvis, anterior abdominal wall at or below the umbilicus, the lumbosacral region, or the buttocks and is of sufficient severity to cause functional disability or require medical care (ACOG practice bulletin 2004).
In a prospective study of 5,253 women between ages 18 and 50, 14.7 % met the criteria of chronic (>6 months) pelvic pain and 45 % reported reduced work productivity. The cost to US economy for this age group is estimated as $881.5 million per year (Mathias et al. 1996). Among men, chronic pelvic pain is the cause of two million clinic visits per year and an annual economic burden of $86 million in the USA (Duloy et al. 2007). In many affected patients (female or male), CPP is manifested in the form of myofascial pain with trigger points in the muscles of the pelvic floor causing local and referred pain. In some patients, pain is a reflection of a serious pathology involving adjacent genitourinary structures. A careful examination of pelvic floor muscles and investigation (including advanced imaging, if necessary) of genitourinary pathology are necessary in order to avoid misdiagnosis.
Anatomy of the Pelvic Floor
The pelvic floor encompasses three layers of muscles. The most superficial layer consists of the bulbocavernosus, ischiocavernosus, and superficial transverse perineal muscles and external anal sphincter. The puborectalis muscle is between the superficial and deep muscles. The deepest layer or pelvic diaphragm consists of the pubococcygeus and iliococcygeus (together they form the levator ani), coccygeus, and ischiococcygeus muscles (Raizada and Mittal 2008) (Fig. 9.1). The piriformis and obturator internus are also deep muscles. The superficial layers are innervated by the pudendal nerve, while the deepest layer is innervated by S3, S4, and S5 sacral nerve roots.
Fig. 9.1
Anatomy of the female pelvic floor (From Frank Netter collection. Netter illustration used with permission of Elsevier, Inc. All rights reserved www.netterimages.com)
The referred pain from these muscles’ trigger points can be felt in the distribution and territory of the pudendal nerve. The pain emanating from the superficial muscle layer (bulbocavernosus and ischiocavernosus) is referred to the perineum and adjacent urogenital structures. Pain of the external anal sphincter may be referred to the posterior pelvic floor. The pain in the levator ani and coccygeus muscles would radiate to the vagina or sacrococcygeal area. The obturator internus generates referred pain to the anococcygeal region.
Pathophysiology and Treatment
A number of therapeutic strategies are employed in the management of pelvic pain. Pelvic floor physical therapy can be helpful and provides some pain relief to 63 % of the patients (Bedaiwy et al. 2013). Pharmacological therapy often encompasses a multimodal approach tailored to the needs of the individual patient: antispasmodic/anticholinergic drugs and analgesic agents (including nonsteroidal anti-inflammatory drugs) and, in some cases, antibiotics. Neuromodulation techniques (transperineal electromagnetic stimulation, pudendal nerve stimulation, sacral nerve root stimulation) have been tried with some success in small open-label studies. Surgical approach is a last resort and is reserved for selective patients.
Carinci et al. (2013) recently reviewed the use of alternative and complementary therapies (acupuncture, pollen extract, mind and body practices) in chronic pelvic pain. The potential contribution of these modalities is discussed below.
Acupuncture
Two blinded studies have reported on the efficacy of acupuncture in pelvic pain. Both studies were conducted in male patients with pelvic pain related to chronic prostatitis. In one study (Lee et al. 2008), patients who underwent 20 sessions of acupuncture over 10 weeks demonstrated significant reduction in pelvic pain compared to the group who had sham acupuncture (six-point decrease in NIH-CPSI score at week 10, p = 0.02, week 24, p = 0.04). In another study (Lee and Lee 2009), the effect of electrical acupuncture (EA) with advice and exercise was compared to sham EA with exercise or with exercise only (three arms), in 63 subjects. After 12 biweekly sessions, symptoms, mostly pain related, improved (six points in NIH-CPSI) in the group with electrical acupuncture (p = 0.001). No blinded data in a female population with pelvic pain is available.
Pollen Extract
Pollen extracts containing amino acids, carbohydrates, lipids, vitamins, and minerals have been shown to relax sphincters of the bladder and urethra and have anti-inflammatory effect. A double-blind, placebo-controlled study of 60 patients with CPP (Elist 2006) revealed lower pain scores and less voiding symptoms in subjects who took pollen extract (p = 0.05) at 6 months. In another controlled and blinded study (Wegenlehner et al. 2009) of 139 patients, subjects who took pollen extract demonstrated significantly (p = 0.008) lower pain score (subset of NIH-PSI) and showed improved quality of life at 12 weeks (p = 0.002).
Minimal data are available on mind and body practice which includes massage, spinal manipulation, deep-breathing exercises, guided imagery, hypnotherapy, progressive relaxation, qigong, and tai chi. These practices are based on using the mind to improve physical function. Although some small positive observations are reported in respect to improvement of pelvic pain, to date, no blinded observations are available.
Botulinum Toxin Treatment of Chronic Pelvic Pain
Botulinum neurotoxins (BoNTs) can improve pain via a number of different mechanisms. In addition to blocking the release of acetylcholine that could lead to relaxation of pelvic floor muscles, selective inhibition of pain mediators can decrease peripheral and central sensitization and alleviate pain (Chap. 2). Two prospective, placebo-controlled, double-blind studies have investigated the efficacy of BoNTs in chronic pelvic pain.
Abbott et al. (2006) studied 60 patients (30 toxin, 30 placebo) with CPP, 55 % of whom had endometriosis and a majority had had surgery to remove foci of endometriosis. Patients’ major symptoms were non-menstrual pelvic pain, menstruation-related pelvic pain, dyspareunia, and dysmenorrhea. Patients were injected under conscious sedation either with 1 cc of study drug (80 units of onabotulinumtoxinA) or comparable volume of saline into two sites bilaterally within each of the puborectalis and pubococcygeus muscles (Fig. 9.1). Participants completed the VAS questionnaires for pain, bowel, and bladder and had examinations to assess pelvic floor tenderness and vaginal manometry measurements at 2, 4, 8, 12, 16, 20, and 26 weeks after injection. There was significant change from baseline in the botulinum toxin type A group for non-menstrual pelvic pain (VAS score 51 versus 22; chi2 = 16.98, p = .009) but not in the placebo group. Both onaA and placebo subjects showed marked improvement of dyspareunia compared to baseline; this improvement was more prominent for the onaA (p = 0.009 versus 0.04) group. Both onaA and saline injections decreased the pelvic floor manometric pressure significantly.
The same group of investigators (Nesbitt-Hawes et al. 2013) studied the effect of a single injection of 100 units of onabotulinumtoxinA into the pelvic floor with multiple injections over time (2 or more) in 26 and 11 female patients with pelvic pain. The technique of injection was similar to that of their previous report (Abbott et al. 2006). Second injections were done no sooner than 26 weeks. Both single and repeat injections reduced non-menstrual pelvic pain (VAS value of 51 down to 23, p = 0.04) and vaginal pressure (40 versus 34 cmH2O p = 0.2) and dyspareunia (VAS value of 54 down to 30 for single versus 51 down to 23 for multiple injections, p = 0.001).
In another double-blind, placebo-controlled study, Gottsch et al. (2011a) compared the effect of onabotulinumtoxinA (100 units) with saline in 13 male subjects with moderate to severe pelvic pain with chronic prostatitis. Injections were made into proximal and mid-bulbospongiosus muscle posterior to the perineal body. The response rate for onaA subjects was 30 % compared to 13 % in the saline group (p = 0.002). The pain component of the chronic prostatic symptom index (PCSI) improved significantly in the onaA subjects compared to the placebo group (0.05).
Comment
The placebo-controlled literature on use of BoNTs in chronic pelvic pain (CPP) is limited. The study of Abbott et al. (2006), a class II study, provides level C evidence (one class II, possibly effective) for the efficacy of onaA in female pelvic pain (AAN guidelines—Appendices 3.1 and 3.2). For male CPP, reports are encouraging, but the evidence is still limited to retrospective and one small prospective, double-blind study with modest results (Gottsch et al. 2011a). The optimal technique and dosage remain an evolving issue. For female pelvic pain, the technique and dose of Abbott et al. (2006) is the only one supported by a controlled study. It is crucial that only individuals with significant knowledge of pelvic anatomy perform the injections since improper injections can result in significant and unacceptable impairment of bladder and anal functions. Other techniques to improve pelvic pain with BoNT are being explored. One such technique involves BoNT block of ganglion impar that marks the termination of paravertebral sympathetic chain at the sacrococcygeal junction. Blockage of this ganglion with 100 units of onaA (mixed with 5 % anesthetic) is reported to ease pelvic pain for 6 months (Lim et al. 2010). Further confirmation of this approach is needed via blinded studies. The current data suggest that in recalcitrant chronic pelvic pain, BoNT treatment can be a useful addition to physical therapy and pharmacological treatment.
Painful Bladder Disorders
A number of bladder disorders have pain as a part of their symptomatology. These include bladder pain syndrome (BPS)/interstitial cystitis and to a much lesser extent detrusor muscle overactivity and detrusor sphincter dyssynergia. Since pain is the major symptom of BPS/interstitial cystitis, recent literature has focused on a potential role for BoNTs in relief of pain associated with this syndrome.
Bladder pain syndrome, caused by interstitial cystitis, is defined as a clinical condition characterized by suprapubic pain (due to bladder filling), diurnal and nocturnal frequency, and urgency in the absence of urinary tract infection or organic urological disease (Van de Merweet et al. 2008). Cystoscopic evaluation may show presence of glomerulations, petechiae, and sometimes mucosal ulceration.
The treatment is often difficult and generally unrewarding. In a recent communication, Cardella et al. (2014) reviewed pharmacological treatments currently used for interstitial cystitis. Amitriptyline, gabapentin, duloxetine, and venlafaxine were described as the most commonly used analgesic drugs for this condition with nonsteroidal anti-inflammatory agents (NSAIDs) and opioids as second line of treatment. The authors emphasized that, currently, there is no evidence from controlled studies that any of these drugs work. Hydroxyzine is used in cases where allergy seems to be a major contributing factor as it inhibits connective tissue mast cell infiltration.
Intravesical drug delivery approach for treatment of IC has gained popularity in recent years. These include introduction of locally active anesthetics (which have both anti-inflammatory and anti-mast cell effect), hydraulic acid and chondroitin sulfate (to promote regeneration of damaged GAC layer in BPS), and pentosan polysulfate (currently approved for oral use by FDA in interstitial cystitis). Pentosan polysulfate is believed to repair the GAG layer and has an anti-inflammatory effect and degranulates mast cells. These drugs, however, have not shown long-term positive effects. As another approach, bladder hydrodistention is currently used with limited success.
Botulinum Treatment of BPS/Interstitial Cystitis
A growing body of information has developed over the past 10 years (particularly past five) regarding the role of BoNT treatment in BPS (Smith et al. 2004; Kuo 2005; Giannantoni et al. 2006, 2010a, b; Ramsay et al. 2007; Kuo and Chancellor 2009; Pinto et al. 2013; Chung et al. 2012; Gottsch et al. 2011b; Shie et al. 2013; Lee and Kuo 2013). Russell et al. (2013) recently published a review on this subject and detailed the data in a comprehensive table. A total of 16 manuscripts had been published on this subject. Two were double blind and placebo controlled, four had long-term (beyond 2 years) follow-up with repeat injections, and ten were shorter retrospective studies. With the exception of one double-blind study that used only 50 units of onaA, all other studies used 100 units or more (100–300 units). In most studies, injections were into the posterolateral wall of the bladder. The two blinded trials will be discussed first in some detail, followed by a brief account of the other studies.
In a double-blind, parallel design study, Kuo (2013) compared the efficacy of onabotulinumtoxinA in two groups receiving 100 and 200 units plus cystoscopic hydrodistention (HD) 2 weeks later and a third group treated with HD only. All 67 patients of the study had failed to respond to the conventional treatment for BPS. Injections were made into the urothelium of the posterior and lateral bladder walls at 40 points. In the 200 units group, each injection was 5 units, whereas the subjects of the 100 units group received 2.5 units per injection site.
The primary treatment outcome was change on global response assessment (GRA), a 7-point response from markedly worse to markedly better acknowledged by the patient and assessed at 3 months postinjection. A number of other scales including VAS for pain were also employed. At 3 months, 80 and 72 % of the patients in the 200 unit and 100 unit onaA groups, respectively, had significant improvement expressed in GRA compared to 48 % in the placebo group (0.032). The VAS pain scores decreased to 39, 55, and 18 % for 100 and 200 unit onaA and HD groups, respectively (p = 0.007). The bladder capacity also increased significantly in the onaA groups: 26 % in the 100 unit group and 63 % in the 200 unit group compared to 4 % in the HD group. In the succeeding open arm of the study, GRA score was 71, 55, and 30 % at 6, 12, and 24 months but still significantly better than HD only (p = 0.002).
Gottsch et al. (2011a) compared the effects of onabotulinumtoxinA in 20 women with placebo (saline) in a prospective and double-blind study. In the onaA group (nine patients), 50 units of toxin was diluted in 2 cc saline and injected periurethrally. Assessments included female modification of prostatitis symptom index (PSI). Symptom improvement by visual analog scale (VAS), AUA symptom index, and graded pain scale performed at baseline, 1, 2 (by mail), and 3 months during visit and examination. Although both the onaA and saline groups showed modest improvement of CPSI scores (more for saline 3.9 versus 1.9 for onaA), no statistically significant difference was found between the onaA and saline group as to CPSI score at 3 months (p = 0 .97). All other indices also showed no difference between groups. The authors concluded that periurethral injection of BoNT in female patients with BPS does not improve pain and other symptoms.
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