Abstract
Keywords
Pelvic pain in women is a complex and challenging problem that is a major cause of morbidity and disability for the sufferer and results in significant costs to health services. In women with acute pain the majority of cases with definite causes of pain are effectively treated by existing medical and surgical interventions. Still, a group of women remains where it is difficult to diagnose a cause for pain, as investigation by laparoscopy reveals no obvious cause and the pathogenesis is poorly understood, which results in ineffective treatment and dissatisfaction. In the majority of women a cause can be identified, such as endometriosis, adhesions, interstitial cystitis (IC) or history highly suggestive of underlying functional abnormality such as irritable bowel syndrome. Chronic pelvic pain (CPP) is not a disease, but a syndrome that results from a complex interaction between neurologic, musculoskeletal and endocrine systems and is further influenced by behavioral and psychological factors.
Botulinum toxin (BTX)-A is used for the treatment of pain resulting from muscle spasm in the body. There is evidence from different studies suggesting that women with CPP and pelvic floor muscle hypertonicity may respond to BTX injection into the pelvic and perineal muscles.
This article reviews the overall causes of pelvic pain, the clinical data on the application of BTX-A, gynecological causes of CPP and the future role of BTX-A in managing pain. An electronic search of the Medline (1966–2007) and EMBASE (1980–2007) databases was conducted using a combination of keywords ‘Botulinum toxin’, ‘Botulinum toxin-A’, ‘rectal dysfunction’, ‘anal fissure’, ‘genital pain, ‘musculoskeletal’, ‘interstitial cystitis’ and ‘pelvic pain’ to obtain references.
Prevalence
Chronic pelvic pain can be defined as intermittent or constant pain in the lower abdomen or pelvis of at least 6 months' duration, not occurring exclusively with menstruation or intercourse and not associated with pregnancy [1]. In the USA and UK the estimated prevalence of CPP is 14.7 and 24.0%, respectively, among women in the reproductive age group [1,2].
Reliable epidemiologic data are rare. Over 40% of all diagnostic laparoscopies and 12% of all hysterectomies are performed because of chronic lower abdominal pain [3]. The overall direct costs of healthcare for CPP in the USA are estimated to be more than US$ 2.8 billion and indirect costs greater than US$ 555 million per year [2]. Serious psychiatric morbidity (depression) has been reported in 30–45% of women with CPP [4]. Therefore, it is a problem where there can be significant benefit from greater clinical attention and public education.
Causes of pelvic pain
Every structure in the abdomen and/or pelvis could have a role in the etiology of CPP. Therefore, it is very important to consider both reproductive and nonreproductive organs and also consider contributions from the peripheral and CNS, blood vessels, muscles and fascia of the abdominal wall and pelvic floor. The pain can result from a variety of gynecologic, urologic, gastrointestinal, musculoskeletal and psychoneurologic causes [5]. Conditions that have strong and consistent scientific evidence of a causal relationship with CPP are listed in Box 1.
There is also a possibility of some patients having an exaggerated pain response, resulting from changes induced in the CNS from painful stimuli known as visceral hyperalgesia. The pathophysiology of CPP involves two neuro-physiological mechanisms: nociceptive pain, which results from injury to a pain-sensitive structure and is somatic or visceral in origin, and non-nociceptive pain, which is neuropathic or psychogenic in origin [6].
Disorders commonly associated with chronic pelvic pain
Gynecological
– Endometriosis
– Adenomyosis
– Pelvic adhesion disease
– Pelvic congestion syndrome
– Chronic pelvic infection
– Ovarian remnant syndrome
– Myomas
– Endosalpingiosis
– Vulvodynia
– Vestibulitis
– Vaginismus
Urological
– Interstitial cystitis
– Chronic urinary tract infection
– Chronic urethral syndrome
– Renal and bladder stones
Gastrointestinal
– Irritable bowel syndrome
– Inflammatory bowel disease
– Chronic constipation
– Anafl fissure
– Colitis
– Diverticulitis
Musculoskeletal
– Myofascial pain (trigger point)
– Pelvic floor myalgia (levator ani spasm)
– Piriformis syndrome
– Fibromyositis
– Chronic coccygeal pain
– Neuralgia
Others
– Psychogenic
It is important to remember that psychological factors such as premorbid personality, depression and behavioral disturbances have a definite effect on the pain experience. Muscular spasm is reported to cause chronic pain in a variety of locations around the body. The mechanism by which muscular spasm causes pain is unclear, although there is a hypothesis that it is caused by primary impairment of nerve and muscle membranes, producing abnormal myogenic and neurogenic impulses and leading to myotonic contraction with constant excitation of nociceptive afferents [7].
Botulinum toxin
Botulinum toxin is a potent neurotoxin produced by the Gram-positive, anerobic, spore-forming organism Clostridium botulinum. It was first isolated by Van Ermengem in 1897 [8]. There are seven immunologically distinct antigenic subtypes of BTX, of which type A is the most widely used. BTX-A is a purified neurotoxin complex that blocks the release of acetylcholine and other transmitters from presynaptic endings. This results in decreased muscle contractility and muscle relaxation. Surprisingly, side effects of BTX in local injections are mild and uncommon considering its toxicity. It does not cross the blood–brain barrier and hence has no CNS side effects. In 1980, the first therapeutic application of BTX toxin was reported in patients with strabismus [9]. BTX-A is distributed as Botox®, Dysport®, Xeomin® and Hengli/CBTX-A®, and Neuronox and BTX-B as NeuroBloc/Myobloc®. These are produced from different strains of C. botulinum and, therefore, differ in their potency. Differences in potency labeling of therapeutic BTX preparations can be corrected by introduction of a conversion factor of 1:3 between Botox and Dysport, of 1:1 between Botox and Xeomin, and of 1:40 between Botox and NeuroBloc/Myobloc. The adverse effect profiles of the available BTX preparations are similar [10].
Pharmacology
Botulinum toxins are synthesized within the bacterial cytosol as single-chain peptides with a molecular weight of approximately 150 kDa [11]. Proteolytic cleavage of the parent chain results in a dichain polypeptide, consisting of a 100 kDa heavy chain and a 50 kDa light chain that remains linked by a noncovalent protein interaction and a disulphide bond, essential for neurotoxicity [12]. Although the use of BTX was approved by the US FDA for the treatment of strabismus and blepharospasm in 1989, and for the treatment of cervical dystonia in 2000, it is yet not licensed for use in bladder symptoms and pelvic pain. The discovery that BTX blocks neuromuscular transmission and thereby causes weakness laid the foundation for its development as a therapeutic tool.
The beneficial effects last for 3–4 months when injected in skeletal muscles and tend to persist even longer (6–9 months) when injected into smooth muscles (bladder). Based on histological evidence, recovery of the chemodenervation after 3–6 months is thought to be caused by a turnover of presynaptic molecules and nerve sprouting from the nerve terminal, forming a new functional synapse [13]. Recovery of function after toxin paralysis depends on toxin type, and type of nerve terminal. Therefore, BTX-A provides a durable yet reversible treatment option and repeat injections may be needed for persistent therapeutic benefit.
Mechanism of action
Normally at the neuromuscular junction, presynaptic motor nerve endings contain acetylcholine-filled synaptic vesicles, which fuse with the neuronal cell membrane through a ‘docking’ process. It is facilitated by a complex of proteins known as soluble N-ethylmaleimide sensitive factor attachment receptor (SNARE) proteins. These proteins anchor the synaptic vesicle membrane to the neuronal cell membrane by forming a complex known as a synaptic fusion complex. It releases acetylcholine into the synaptic space, which binds to the receptors on the muscle cells to cause contractions.
Botulinum toxin induces paralysis by preventing the release of acetylcholine through four steps: binding to a receptor, internalization, cleavage and inhibition. BTX binds to the neuronal cell membrane at the nerve terminus and enters the neuron by endocytosis. The C-terminal of the heavy chain is responsible for binding to the receptor and subsequently helps in the internalization process. The disulphide bond between the light and heavy chains is then cleaved and the light chain translocates into the cytosol. The light chain of BTX cleaves specific sites on the SNARE proteins, preventing complete assembly of the synaptic fusion complex and thereby blocking acetylcholine release (exocytosis), thus muscle contraction is inhibited [14].
Originally, the success of BTX in pain management was attributed to its ability to prevent acetylcholine being released at the synapse. One important feature of BTX in pain treatment is that the effects of the neurotoxin are thought to act only upon motor nerve endings, while sensory nerve fibers are spared from such effects. More recently, however, effects of BTX on nociceptive neurons were demonstrated in preclinical studies. Thus, analgesic effects are likely to occur, not as a result of blocking afferent sensory fibers at the site of injection, but rather from secondary effects that may be attributed to muscle paralysis, improved blood flow and release of nerve fibers under compression by abnormally contracting muscle, and perhaps more importantly by effects on nociceptive neurons [15].
Adverse effects
Safety of BTX-A across the wide range of therapeutic uses was analysed in a systematic review article by Naumann et al. and they concluded that it is generally well tolerated with no serious or severe adverse events [16].
Possible side effects are rash, transient flu-like symptoms, dysphagia, diplopia and blurred vision. Uncommon cases of generalized muscle weakness have been reported with different doses of Botox (140–300 units) and Dysport (1000 units) [17]. The causes of generalized adverse events are not clear, but spread outside the target organ and into the systemic circulation may contribute. Its effect diminishes with increasing distance from the injection site, but spread to nearby muscles is possible, particularly when high volumes are injected. Therefore, patients hould be informed of the potential for either too much weakness in the area injected or weakness in nearby muscles. The dose used, the injection volume, the injection technique and the specific biological activity of the BTX preparation may all play a role. Recently Grosse et al. reported transient muscular weakness in the extremities of four out of 66 patients with neurogenic detrusor overactivity treated with repeat doses of Dysport (750–1000 units) [18].
When to consider botulinum toxin
It is beyond the scope of this article to deal with the evaluation and different treatment modalities for CPP, but an accurate, detailed and chronological history, thorough physical examination and appropriate investigations are of importance in the management of patients with CPP.
Indications for BTX treatment are not entirely clear for patients with CPP. Pelvic pain conditions that have been effectively treated with BTX include chronic pelvic floor muscle spasm (either primary or secondary as a response to other pelvic pain causes) and IC. These patients may be considered candidates for BTX-A if they have not responded to traditional forms of treatment, have had a chronic refractory problem for 6 months or longer and have had proper counseling.
The clinician should proceed with caution before considering using BTX in the treatment of a patient as it is only approved in the USA for pain related to cervical dystonia. Use of BTX for these indications should still be audited closely or carried out within the boundaries of prospective studies.
Botulinum toxin & gynecological causes for pain
Use of BTX in gynecological causes of pelvic pain has mainly been studied in cases of vulvodynia, vestibulitis, vaginismus and pelvic floor spasm.
Vulvodynia means pain in the vulva, and vulvar vestibulitis is a syndrome in which there is pain at specific points in the vulvar vestibule. Whatever the initial cause, it seems possible that for some people pain pathways are activated that do not deactivate when the source of irritation has been removed. Tonic contraction of the pelvic floor muscles is also triggered as a defense reaction, leading to increased pain perception. Vaginismus is the recurrent or persistent involuntary contraction of the perineal muscles surrounding the outer third of the vagina when penile, finger, tampon or speculum penetration is attempted. It is relatively rare, affecting approximately 1% of women [19]. Few patients suffering from these problems are refractory to standard therapies and often pose a therapeutic dilemma.
Effect of BTX was evaluated initially in a pilot study involving 11 women with CPP and pelvic floor hypertonicity [20]. In the study, 40 units of BTX were injected bilaterally into the puborectalis and pubococcygeus muscles under conscious sedation. At 3 months follow-up, mean dyspareunia and dysmenorrhea visual analog scale (VAS) scores significantly decreased from baseline. Improvements were also seen in dyschezia and nonmenstrual pelvic pain VAS and quality of life as measured by the short form (SF)-12 and EuroQoL (EQ)-5D, but these results were not statistically significant.
A subsequent randomized, controlled trial was designed to assess the effect of BTX in reducing pelvic pain and muscle spasm [21]. In 30 women suffering from CPP for more than 2 years, who were refractory to other treatments, 80 units of BTX were injected into the pelvic floor muscles, and 30 women received saline. Vaginal manometery was used to measure pelvic floor pressure and VAS at baseline and monthly for 6 months to assess dysmenorrhoea, dyspareunia, dyschezia and nonmenstrual pain. There was a significant change from baseline in the BTX group for dyspareunia (VAS score 66 vs 12; p < 0.001) and nonmenstrual pain (VAS score 51 vs 22; p = 0.009). In the placebo group only dyspareunia was reduced. Significant reduction in pelvic floor pressure was observed from baseline in the BTX group (49 vs 32; p < 0.001) and in the placebo group (44 vs 39; p = 0.003). They concluded that BTX reduces pelvic floor muscles pressure and associated pain symptoms more than placebo and may be useful in the treatment of women with pelvic floor spasm who are unresponsive to conservative physical therapy. There were no serious adverse events noted in the BTX group compared with controls, although two women suffered from transient, mild effects on their pelvic sphincters: one had urinary stress incontinence on several occasions, and another had both urinary and fecal incontinence intermittently for 4 months. This information is useful in counselling patients for this procedure.
Yoon et al. injected 20–40 units of BTX into the vestibule, levator ani muscle or the perineal body in seven women with pain that was refractory to conventional pain management [22]. Five patients needed to be injected twice. The subjective pain score improved from 8.3 to 1.4 and none of the women experienced a recurrence during a mean follow-up period of 11.6 months. However, this was a small, nonrandomized study with no control group. There are several case reports or case series showing the beneficial effect of BTX injection under electromyographic guidance into pelvic floor muscles, particularly in the levator ani in women suffering from pelvic pain who were resistant to conventional treatment [23–26]. Vestibular pain was associated with levator ani tenderness in a case report by Brian and Romato. They used different doses (20, 40 and 80 units). All of these women reported benefit in pain within 2–7 days after injection and this benefit lasted several months (5–6 months). Coital pain completely resolved in three case reports [24–26]. None of them reported any adverse reactions. Dykstra et al. found significant benefit when using 35 units of BTX in seven patients suffering from vestibulodynia [27]. Although these studies provide encouraging evidence regarding the beneficial effect of BTX in relieving vulva pain, many methodological weaknesses were present. The overall summary of main results of different studies is given in Table 1.
Studies assessing therapeutic effects of botulinum toxin injections in the treatment of chronic pelvic pain caused by pelvic floor spasm.
n: Number of subjects.
However, in a study by Brown et al., subjective and objective outcomes of BTX-A treatment in vestibulodynia were assessed in two patients using 20 units and 40 units of BTX-A at 12-week intervals [28]. They used VAS, weekly coital pain diaries, surface electromyography (sEMG) and a vulvar algesiometer to assess the outcome. They found that BTX modestly reduced coital pain in one patient and was ineffective in the other. Pelvic floor hypertonicity and variability were markedly reduced in both patients, but negligible changes occurred in vestibular hyperalgesia.
Properly designed and executed randomized, controlled trials with larger numbers of subjects are needed to determine the true effectiveness of BTX treatment for these conditions.
Botulinum toxin & musculoskeletal causes for pain
Since its introduction in the late 1970s for the treatment of strabismus and blepharospasm, BTX has been increasingly used in the interventional treatment of several other disorders characterized by excessive or inappropriate muscle contractions, such as focal dystonia, spasticity, spasmodic dysphonia, esophageal achalasia, chronic anal fissure, vaginismus, eye movement disorders, hyperkinetic disorders, tremors, over-active and neurogenic bladder, nonbacterial prostatitis and benign prostatic hyperplasia.
Dysfunction of the pelvic musculoskeletal structures is an important cause for pain in a subset of patients with CPP and may be amenable to treatment using physical therapy, massage, biofeedback or medication [29,30]. Management of this myofascial component of CPP involves a multidisciplinary approach including physicians, physical therapists, neurologists and psychiatrists [31]. ‘Pelvic floor myalgia’, ‘piriformis syndrome’, ‘levator ani spasm syndrome’, ‘diaphragma pelvis spastica’ and ‘coccydynia’ are terms used for syndromes that appear to be similar to pelvic floor pain [32].
Pelvic floor pain may be a primary problem or it may be secondary to other diseases such as IC or endometriosis. Although the mechanisms that trigger the pain in these syndromes vary, recent data suggest that a central neuroplastic mechanism may contribute to many complex pain syndromes. Several studies have demonstrated the efficacy of BTX in treating several neuropathic pain disorders refractory to traditional treatment with physical therapy, electrical muscle stimulation and other approaches.
Porta compared BTX-A plus bupivacaine with methylprednisolone plus bupivacaine for treatment of chronic muscle spasm of the piriformis, psoas and scalenus anterior muscles (abdominal wall trigger point injection), and found larger improvement in self-reported VAS scores for the BTX group compared with the methylprednisolone group at 60 days post-treatment [33]. Unfortunately, he did not report the randomization method.
Local anesthetic agents, such as bupivacaine, have been used for injection into the local areas of muscle spasm identified in the abdomen, vagina and sacrum of women with CPP, which may be palpable on physical examination and are labeled as trigger points by some investigators. Improvement in pain symptoms was noticed in over 50% of subjects [34]. Although dry needling and saline injections were also effective, the addition of a local anesthetic agent reduced postoperative pain [35,36]. However, there was a lack of quantitative data.
The existing literature largely consists of retrospective, uncontrolled observational studies. The systematic review of BTX-A for myofascial trigger point injection by Ho et al. does not support the use of BTX-A injection in trigger points for myofascial pain based on the current evidence [37]. Of the five clinical trials discussed, only one concluded that BTX was effective in reducing pain arising from trigger points. The data were limited and clinically heterogeneous. Further studies are needed to better characterize its use for the treatment of CPP.
Botulinum toxin & interstitial cystitis
Painful bladder syndrome/IC is a chronic sterile inflammatory disease of the bladder of unknown cause and persists as a challenging syndrome in urology. Recent research suggests that an increasing number of women with CPP have bladder-origin pelvic pain specifically caused by IC. There is, as yet, no one definitive diagnostic criteria for IC, but most commonly it is defined clinically by the following triad [38]:
Irritative voiding symptoms
Absence of objective evidence of another disease that could cause the symptoms
Characteristic cystoscopic appearance of the bladder (diffuse glomerulations) with cystoscopic distention and redistention of the bladder
A number of treatments have been suggested, but very few have been subjected to proper controlled trials. Bladder irrigation with different agents has been used in an attempt to treat painful bladder syndrome/IC. Approximately 50% of patients will have persistent symptoms subsequent to this and in this group BTX injections into the detrusor muscle may be used. However, the evidence regarding the beneficial effects of BTX in treatment of pain as a result of IC is sparse.
A decrease in the release of neuropeptides from nociceptive primary afferent nerve fibres after BTX-A injection has been suggested as a mechanism. Smith et al. reported symptomatic improvement in nine (69%) out of 13 patients with IC after intravesical BTX (100–200 units of Dysport) treatment and beneficial effects lasted for a mean of 4 months [39]. A pilot study by Giannantoni et al. looked at the efficacy and tolerability of 200 units of BTX intravesical injections in patients affected by painful bladder syndrome with increased urinary frequency and refractory to conventional treatment modalities [40]. The results indicated that BTX intravesical injections were effective in the short-term management of painful bladder syndrome as overall, 12 out of 14 patients (85.7%) reported subjective improvement at 1- and 3-month follow-up. The mean VAS score was significantly reduced at 1 and 3 months after treatment (p < 0.05) and bladder cystometric capacity significantly increased (p < 0.01). By modulating afferent C-fiber activity within the bladder walls, BTX significantly improves urodynamic parameters and reduces bladder pain and urinary frequency. There were no systemic side effects noted during or after treatment. However, two subjects reported incomplete bladder emptying. A recent study has also supported the beneficial effect of intravesical BTX-A injections plus hydrodistension in reducing bladder pain in patients with IC [41]. In an article by Sinha et al., the use of BTX in different urogynecological conditions has been discussed in detail [42].
However, results of 200 units of BTX treatment in patients with IC at the Cleveland Clinic Foundation (n = 10) did not show any statistically significant change in objective or subjective outcome measures [43]. Clearly, more experimental work and well designed placebo-controlled clinical trials are necessary to explore the antinociceptive properties of BTX.
Experimental data strongly support the use of both neurotoxins in the treatment of pain and frequency in patients with IC/painful bladder syndrome, although the results from available clinical trials for this use are still inconclusive. In spite of promising results overall, it should be made clear that the administration of these neurotoxins is still considered an experimental procedure and that more clinical studies are necessary before a license for their use will be issued by health authorities.
Botulinum toxin & gastrointestinal/rectal dysfunction/ anal fissure
Symptoms suggestive of irritable bowel syndrome are present in 50–80% of women with CPP [29]. Dietary treatment is the mainstay of therapy. The management of disorders of the lower gastrointestinal tract that are responsible for CPP, such as chronic anal fissures and pelvic floor dysfunction, have undergone re-evaluation recently. To a large extent this is caused by the advent of neurochemical treatments, such as BTX injections and topical glyceryl trinitrate ointment. BTX inhibits contraction of gastrointestinal smooth muscles and sphincters; it has also been shown that the neurotoxin blocks cholinergic nerve endings in the autonomic nervous system. This aspect has further promoted the interest in using BTX as a treatment for outlet-type constipation, or the lower esophageal sphincter to treat esophageal achalasia. BTX has also been used selectively to weaken the external anal sphincter and puborectalis muscle in Parkinson's disease.
In a recent randomized clinical trial Brisinda et al. compared BTX injections with 0.2% nitroglycerin ointment for the treatment of chronic anal fissure and found that the BTX was the more effective option [44]. A total of 100 adults were assigned randomly to receive treatment with either type of BTX (30 units Botox or 90 units Dysport) injected into the internal anal sphincter or 0.2% glyceryl trinitrate ointment applied three-times daily for 8 weeks. The fissures were healed in 46 (92%) of 50 subjects in the BTX group and in 35 (70%) of 50 in the nitroglycerin group (p = 0.009) after 2 months. Three subjects in the BTX group and 17 in the nitroglycerin group reported adverse effects (p < 0.001). Those treated with BTX had mild incontinence to flatus that lasted 3 weeks after treatment but disappeared spontaneously, whereas nitroglycerin treatment was associated with transient, moderate-to-severe headaches. However, in the review article by Sajid et al., who analysed systematically the prospective, randomized, controlled trials on the effectiveness of BTX and glyceryltrinitrate for the pharmacological management of chronic anal fissure [45], no difference was found in effectiveness among these two drugs for the management of chronic anal fissure but BTX was found to be associated with a lower complication rate. They suggested BTX can be recommended as a first-line therapy for chemical sphincterotomy in patients with chronic anal fissure.
Combined fissurectomy and BTX injection for chronic anal fissure has also been found to be an excellent and safe procedure with low morbidity and a 79% healing rate [46].
The role of BTX has been compared with myectomy of the internal anal sphincter for the treatment for chronic idiopathic constipation in children in a randomized trial [47], and the result was suggestive that BTX is equally effective and less invasive than myectomy of the internal anal sphincter.
A total of 24 consecutive subjects with chronic outlet obstruction constipation resulting from puborectalis syndrome were included in a study by Maria et al. to evaluate the effect of BTX [48]. These subjects were treated with 60 units of BTX-A, injected into two sites on either side of the puborectalis muscle under ultrasonographic guidance. At 2 months, evaluation inspection revealed a symptomatic improvement in 19 subjects with decreased tone during straining as demonstrated by anorectal manometry.
The use of BTX seems to be a promising and safe approach for the treatment of chronic anal fissure, particularly in patients at high risk for incontinence and chronic outlet obstruction constipation. However, large randomized studies comparing the effects of this treatment against the placebo are necessary.
Practical aspects of botulinum toxin injection treatment
Botulinum toxin has to be injected into affected muscles after proper palpation of the affected muscle. It needs to be tailored according to the mode of use and individual patients. Generally, the effective dose depends on the mass of muscle being injected: the larger the muscle the higher the dose required. However, susceptibility to the toxin varies and lower doses may be required in patients with pre-existing weakness, women and lighter patients.
Conclusion & future perspective
Women who suffer from CPP are a heterogeneous group. The pathophysiology behind CPP is very complex and associated with multiple factors. Diagnosis and treatment can be complex, and the goals of treatment must be realistic. BTX may be appropriate therapy for patients with CPP who have failed to respond to conventional therapies. However, its treatment should be considered experimental and ideally administered as part of clinical trials. Further research would be needed before definitive treatment recommendations are made.
Large, randomized, prospective trials are necessary to confirm the beneficial efficacy, optimal dose and need for repeating the treatment of BTX in the treatment of CPP.
Executive summary
Chronic pelvic pain is a common and distressing symptom.
It can affect a woman's ability to work, her self image, her relationships and her sexuality.
In the USA and UK the estimated prevalence of chronic pelvic pain is 14.7 and 24.0%, respectively, among women in the reproductive age group.
It accounts for 10% of all referrals to gynecologists, over 40% of all diagnostic laparoscopies, 12% of all hysterectomies and more than US$ 2.8 billion direct costs of healthcare in the USA.
Many women will have more than one potential etiology for their pain.
Botulinum toxin (BTX) is a potent neurotoxin that blocks the release of acetylcholine and other transmitters from presynaptic endings, resulting in decreased muscle contractility and muscle relaxation.
Muscular spasm is reported to cause chronic pain, which could be due to primary impairment of nerve and muscle membranes, producing abnormal myogenic and neurogenic impulses and leading to myotonic contraction with constant excitation of nociceptive afferents.
Use of BTX for gynecological causes of pain has mainly been studied in conditions such as vulvodynia, vestibulitis, vaginismus and pelvic floor spasm.
Randomized, controlled trials comparing BTX with placebo showed a greater improvement in pelvic floor muscle pressure and associated pain symptoms compared with placebo and may be useful in the treatment of women with pelvic floor spasm who are unresponsive to conservative physical therapy.
Evidence regarding the beneficial effects of BTX in treatment of pain due to interstitial cystitis is sparse.
A decrease in the release of neuropeptides from nociceptive primary afferent nerve fibres after BTX-A injection has been suggested as a mechanism for pain relief.
Symptoms suggestive of irritable bowel syndrome are present in 50–80% of women with chronic pelvic pain.
BTX inhibits contraction of gastrointestinal smooth muscles and sphincters, which has promoted the use of BTX as a treatment for outlet-type constipation, or the lower esophageal sphincter to treat esophageal achalasia.
A recent randomized clinical trial compared BTX injections with 0.2% nitroglycerin ointment for the treatment of chronic anal fissure found that the BTX is the more effective option.
Footnotes
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.