Subjective and Objective Outcomes of Botulinum Toxin Type A Treatment in Vestibulodynia

Synopsis
Botulinum toxin type A may be effective in reducing coital pain in vestibulodynia with levator ani tenderness, but has little effect on vestibular allodynia. 

Objectives
To collect pilot data on the efficacy of intramuscular botulinum toxin type A (BTX/A) injection into the levator ani muscles to relieve coital pain, reduce pelvic floor tension and instability, and reduce vestibular hyperalgesia in vestibulodynia.

Study Design
Two subjects meeting diagnostic criteria for vestibulodynia were treated with 20 u and 40 u of BTX/A at 12-week intervals. Outcomes included a visual analogue scale (VAS), weekly coital pain diaries, surface electromyography (sEMG), and a vulvar algesiometer.

Results
BTX/A 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. The patient with greater pelvic floor tension had more reduction in diary-rated coital pain at 2 weeks post injection (29% v. 9%) and on the VAS at 12 weeks (15% vs. 3%).

Conclusion
BTX/A injections may be effective in reducing coital pain in vestibulodynia with levator ani tenderness, but has little effect on vestibular allodynia. The relationship between pelvic floor hypertonicity and decreased coital pain suggests vestibulodynia may be a variant of Chronic Regional Pain Syndrome. Dose and volume of BTX/A injected may be related to degree of relief.

 

Vulvodynia is a complex disorder characterized by vulvar discomfort. Its classification is based on the pain’s location, whether it is generalized or localized, and whether it is provoked, unprovoked, or mixed.¹ Provoked vestibulodynia, formerly known as vulvar vestibulitis syndrome (VVS), refers to discomfort from intercourse, clothing pressure, tampon insertion, or cotton-tipped applicator pressure on pelvic examination.

Although its etiology is unknown, vestibulodynia may be a variant of a chronic pain condition known as Complex Regional Pain Syndrome (CRPS). Complex Regional Pain Syndromes are painful conditions that usually affect the extremities and consist of a broad spectrum of sensory, autonomic, and motor features subdivided into two types.  Type I occurs in the absence of any identified peripheral nerve injury whereas Type II occurs in association with a known peripheral nerve injury.²  Because vestibulodynia often occurs without an identifiable cause or a proven neurological injury, it is more likely to resemble Type I CRPS.  However, one case report attributed equestrian dyspareunia to local pelvic trauma.³

In CRPS, hypertonic pelvic floor muscles initiate a process by which local visceral afferent nerve fibers release histamine and prostaglandins. The resulting inflammation produces irritation of the vulvar tissue.  This results in tissue tenderness and leads to further reflex spasms of the pelvic muscle resulting in positive feedback that exacerbates the condition. Two reports have demonstrated that biofeedback-induced pelvic muscle relaxation is associated with reduced vestibular pain in women with vestibulodynia.^4,5 These data support the hypothesis that hypertonic and unstable muscles in the pelvic floor are a contributing factor in perpetuating vulvar pain.  Therefore, other interventions that would reduce muscle tone may also be an effective treatment for this condition.

Botulinum toxin type A (BTX/A) inhibits release of acetylcholine from the presynaptic region of the neuromuscular junction, producing chemodenervation that results in reduced muscle tone.^6-8  Thus, BTX/A  would break the cycle of hypertonic and unstable pelvic floor muscles stimulating nerve conduction and further spasm. Three case reports and one open-label study have reported reduced coital pain following BTX/A injection. ^9-12  BTX/A doses varying from 10-80 u produced pain relief in 2-14 days and lasted from 3-36 months. Vestibular pain was associated with levator ani tenderness in two of the case reports and in the open label study.^9,11,12  Coital pain completely resolved in the three case reports.^9-11  The open-label study reported similar findings of a significant reduction but incomplete resolution of coital pain.¹²

Although these studies provide encouraging evidence of BTX/A relieving coital pain in women with vulvar pain, many methodological weaknesses were present.  Although vestibulodynia was diagnosed in three case reports,^9-11 only one confirmed the diagnosis with a cotton swab test. ¹⁰   The open label study enrolled women with chronic pelvic pain and dyspareunia but did not differentiate women with vestibulodynia.¹² Needle electromyography (EMG) confirmation of  pelvic muscle placement was not performed in the open study¹² and in only two of the case reports.^9,11 None of the studies prospectively rated symptoms using a diary.  Direct measures of pelvic floor tension, such as surface electromyography (sEMG), and objective measures of vestibular tenderness were not performed in any report.

Prompted by the success reported in earlier studies treating vulvar pain, and a need for a more rigorous experimental design, we evaluated the effect of two different doses of BTX/A on relieving coital pain under EMG guidance in women who met diagnostic criteria for vestibulodynia using objective endpoints.

Materials and Methods
Two women, with vestibulodynia underwent BTX/A injections into the pelvic floor. The University Institutional Review Board approved the treatment and subjects provided written informed consent. Each patient was seen over four visits, which included screening, baseline  and two separate BTX/A administrations spaced 12 weeks apart. Patients received 20 u BTX/A at baseline and 40 u 12 weeks later. They were evaluated 12 weeks post-injection of both doses for treatment response. 

During screening, diagnosis of localized, provoked vestibulodynia was confirmed by 1) moderate-to-severe pain during attempted penetration and 2) moderate-to-severe pain limited to the vulvar vestibule as confirmed by a cotton-swab test.¹³ Symptoms of vaginitis, suspicious lesions on pelvic exam, a previous vestibulectomy, an active neurological disorder, significant ongoing medical conditions, current major depression, an abnormal physical exam or laboratory values were not present.  

One week after screening, baseline evaluations of patient-rated pain, muscle hypertonicity and vestibular tenderness were obtained and BTX/A was administered. Weekly diaries were collected, and the patients completed a Visual Analogue Scale (VAS) retrospectively documenting the “average” coital pain rating since the last visit. They were dispensed weekly diaries to take home, and instructed to return at 12 weeks for another BTX/A injection and a final follow-up visit at week 24.

Botulinum toxin A (Allergan, Irving, CA, USA) was prepared by adding 2 ml of normal saline to 100 u of freeze-dried drug giving a standard dilution of 5 u per 0.1 ml. Injections were drawn up in a 1 ml graduated syringe. The site was covered with local anesthetic cream (EMLA, Astra Pharmaceuticals, Herts, UK) for approximately 30 minutes prior to injection. The pubococcygeal position of the levator ani muscle was palpated and the site was confirmed using EMG guidance through monopolar needle electrodes (SEI S.N.C., Cittadella, Italy). Depending on dose, the patients received a total of 20 to 40 u of BTX/A, with either a total of 0.4 ml or 0.8 ml solutions divided into two injections and injected transvaginally at the 5 and 7’oclock positions into the levator ani.

Electromyographic (EMG) Signals were recorded (Phasis ESAOTE Biomedica, Florence, Italy) and bandpass filtered at 20 Hz-5 kHz. The recording parameters were a sweep of 100 msec at a gain of 200 µV/div at a bandpass of 20 Hz to 5k HZ on a commercial electromyograph (Phasis ESAOTE biomedical, Florence, Italy). BTX/A was injected into tissue with the highest electromyographic potentials using multiple injection points to enhance efficacy.⁷

A weekly diary was used to prospectively evaluate the effectiveness of treatment by documenting pain severity after each coital episode using a 10 cm visual analogues scale (VAS) where 0 = no pain at all, at any time, during or after intercourse, and 10 = the worse pain ever experienced with intercourse. At the 12week follow-up visits patients completed a VAS scale using the same scale described in the weekly diary. Objective measures included surface electromyography (sEMG) to measure pubococcygeal muscle hypertonicity, and a vulvar algesiometer to measure vestibular tenderness.                       

Surface EMG has been shown to have diagnostic value in identifying women with vestibulodynia over normal controls if three of the four criteria are met: 1) instability of muscle (>0.20 SD), 2) poor muscle recovery after contraction (> 2 seconds) and 3) elevated resting baseline (> 2 µV), and either 1) reduced frequency (< 115 Hz) or 2) reduced muscle contraction strength (< 17 µV).⁵ Surface EMG assessment included one 60 s resting baseline; 5 phasic, flicking, contractions with 10 s rest between each phasic contraction; five tonic, 10 s contractions with 10 s rest between each tonic contraction; one 60 s endurance contraction; and one 60 s resting baseline (Myotrac3, Thought Technology, Montreal, Canada, with Glazer protocol software and bandpass filtration of 20-400 Hz).^4,5 Relaxation periods were measured with resting signal amplitudes, standard deviations and coefficients of variance. Recruitment and recovery times, amplitudes, standard deviations, and coefficients of variance and power density spectral frequencies measured contractions.

Vestibular tenderness has been objectively measured using the vulvar algesiometer.¹⁴ Although there is no clear cutoff score between normal and abnormal scores on the algesiometer,¹⁵ significant treatment effects have been shown in women with vestibulodynia.¹⁴ Lower readings correspond to decreased force exerted by the vulvar algesiometer and greater vestibular tenderness (e.g., the more tender the vestibule, the less force can be tolerated), with scores ranging from 4 (lowest threshold, worst pain) to 28 (no pain). Paraurethral and posterior vestibular areas are assessed by a vulvar algesiometer,^14,15  starting with the minimum force and increasing the force by 1 reading until the patient reports pain similar to coitus, or to a maximum of eight force levels (in millinewtons).

VAS scores, sEMG, and algesiometer were obtained at baseline, 12, and 24 weeks post injection and weekly diaries were returned at each follow-up visit.

Results

Case 1
A 24-year old married Caucasian woman, gravida 0, presented with a 5-year history of insertion dyspareunia, which had recently worsened. Current medications included fluoxetine for generalized anxiety disorder, an oral contraceptive, and guaifenesin and calcium citrate for vulvar pain. She had observed no improvement with either guaifenesin or calcium citrate, and had previously observed mild improvement with topical lidocaine. On pelvic exam, she had  moderate pain at the 1, 5, 7, and 11-oclock positions with a cotton swab test, levator muscle tenderness, and vestibular erythema. Cervical cultures and wet mounts were negative for candidiasis, chlamydia, gonorrhea, trichomonas, and bacterial vaginosis, and all laboratory values were normal.

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