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Abstract

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. What’s already known about this topic?
  7. What does this study add?
  8. Acknowledgments
  9. References

Summary Background  Provoked vestibulodynia is difficult to treat. The beneficial effects of botulinum toxin A are being considered because of the muscular anomalies observed in this pathology.

Objective  To evaluate the efficacy of botulinum toxin A in the treatment of provoked vestibulodynia.

Methods  Patients aged between 18 and 60 years presenting with provoked vestibulodynia (according to the 2003 International Society for the Study of Vulvar Disease classification) received 50 U of botulinum toxin A bilaterally in the bulbospongiosus muscle under electromyographic monitoring. Pain was evaluated by a visual analogue scale (VAS), quality of life was evaluated by the Dermatology Life Quality Index and sexual function by the Female Sexual Function Index.

Results  Twenty patients received the injections. Sixteen patients presented with a muscular hyperactivity on electromyography. After 3 months, 80% of the patients improved in terms of pain. Mean ± SD VAS values significantly decreased from 8·37 ± 1·22 (range 4·5–10) to 2·57 ± 2·67 (0–9; < 0·0001) at month 3 and to 3·90 ± 2·92 (0–9; < 0·001) at month 6. Quality of life and sexual function improved significantly during the first 6 months (< 0·0001). After 3 months, 13 patients (out of 18 for whom intercourse was not possible before the injections; 72%) were able to have sexual intercourse.

Conclusion  Botulinum toxin A seems to be an effective and safe treatment for provoked vestibulodynia; 100 U botulinum toxin A significantly reduced pain 3 and 6 months after injections without side-effects. The treatment also improved quality of life and sexual function of patients. Botulinum toxin A appears to be a promising option for managing sexual pain disorder.

Vulvodynia is a common syndrome defined as a ‘chronic discomfort in the vulva described as a burning pain without objective findings or specific signs of a neurological disorder’.1 Some studies have estimated the incidence at almost 16% of the female population.2 Provoked vestibulodynia (PV), previously known as vulval vestibulitis,3 is the most common clinical form of vulvodynia. It is defined by pain in the vulval vestibule, triggered by a stimulus which is usually nonallergenic, such as wearing clothes or inserting tampons or a speculum.1 Dermatological examination of patients with PV is normal but sometimes a vestibular erythema is observed. Moreover, the patients never have fissuring, erosion or atrophic patches in the vulva. PV is responsible for introital dyspareunia which is a different pathology from vaginismus as the latter involves painful contraction of all perivaginal muscles in anticipation of any vaginal penetration.4 Guidelines for the management of vulvodynia have been published by the British Society for the Study of Vulval Diseases and they present evidence-based treatments.5 The usual treatments (tricyclic antidepressants, local anaesthetic agent, physiotherapy, etc.) are reputed to be relatively efficient.5–7 Only a minority of patients may be suitable for vestibulectomy.5 The aetiologies of this disease are under debate: infectious, inflammatory, neurological or muscular. The muscular hypothesis in the course of PV is the most strongly supported, as several studies have shown that patients have greater muscular hypertonia in the muscles in the superficial area of the perineum, which become painful.8 In vestibular tissue, intraepithelial nervous hyperplasia in C fibres is observed, as well as the presence of neurotransmitters such as glutamate and substance P; all these elements contribute to the abnormal transmission of sensory perceptions.9 Botulinum toxin A (BTA) could therefore be effective in the treatment of PV. On the one hand, it has transient paretic effects on muscular fibres, which become painful through hyperactivity, and on the other hand, it blocks the release of neuropeptides and neurotransmitters involved in the neuropathic part of this chronic pain syndrome.10 This treatment has been evaluated for vaginismus.4 BTA is also effective for pelvic floor spasm.11 Published reports on the use of BTA in vulvodynia are rare and the studies did not use standardized methods; they included variable dosages, different injection sites and use or nonuse of electromyography (EMG) for locating injection sites.

Therefore the objective of this investigation was to carry out an open pilot study to evaluate the efficacy of a particular dose of BTA in PV using a standardized and reproducible method.

Materials and methods

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. What’s already known about this topic?
  7. What does this study add?
  8. Acknowledgments
  9. References

Patients studied

Patients were recruited from those attending specialized consultations for vulval pathologies at Besançon University Hospital between October 2009 and July 2010. The study protocol was accepted by the local ethics committee (26 October 2009). Patients were women aged between 18 and 60 years presenting with PV (2003 International Society for the Study of Vulvar Disease classification). For all patients, pain was usually triggered by a nonallergenic stimulus and was responsible for introital dyspareunia. Pain occurred due to light pressure from a cotton swab on all or part of the vestibule. Patients presented with a vestibulodynia refractory to all conventional treatments (tricyclic antidepressants, biofeedback physiotherapy, psychological care including psychosexual approach) performed simultaneously or sequentially for at least 3 months for each patient. Vaginismus was excluded after physical examination and psychological consultation. The patients were either surgically sterile menopausal women, or were taking an effective form of contraception. Patients were given information about the study and informed consent was obtained.

A preinclusion assessment was carried out for each patient in order to rule out other causes of vulval pain. This included looking for sexually transmitted diseases, i.e. polymerase chain reaction (PCR) testing of urine for Chlamydia trachomatis, Treponema pallidum haemagglutination (TPHA)–Venereal Disease Research Laboratory (VDRL) test, human immunodeficiency virus (HIV) serology, hepatitis B serology, vaginal bacteriological and mycological sampling and a pelvic neurological clinical examination.

A medical history of vulvovaginal candidiasis and cystalgia was found in all patients. Clinical examination and PV diagnosis were carried out by the same clinician for all patients.

Botulinum toxin A administration method

Patients received an initial injection of BTA (Botox®; Allergan, Courbevoie, France) 1 mL (50 U BTA diluted in 1 mL) in the right and left bulbospongiosus muscles. The total dose injected was thus 100 U of BTA as determined by our previous experience. Treatment was administered by intramuscular injection under EMG monitoring (detection) using a sterile Bioject® needle (Bioject Biomedical Technologies, Tualatin, OR, U.S.A.) allowing for injection and analysis of EMG activity. All injections were carried out by the same clinician after the patient had inhaled nitrous oxide (Kalinox®; Air Liquide Santé, Puteaux, France), in the absence of contraindications and under the supervision of trained staff.

The details of the EMG examination were as follows: the aim was to help position the BTA treatment while looking for the greatest number of EMG traces attesting to muscular hyperactivity in one or several muscles in the bulbospongiosus muscle on the right- and left-hand sides. This was shown on EMG by visible and audible interference when the muscle was not expected to be generating electrical activity.

Visual analogue scale evaluation of pain

The visual analogue scale (VAS) was represented by a line increasing centimetre by centimetre from 0 (absence of pain) to 10 (most intense pain imaginable).12 Evaluating the pain was carried out before the injections and 3 and 6 months afterwards. The ability to have sexual intercourse before the injections and 3 and 6 months afterwards was also evaluated.

Sexual function evaluation

Sexual function was evaluated by the Female Sexual Function Index (FSFI), an autoquestionnaire including 19 items and evaluating six different aspects of sexuality: desire, arousal, lubrication, orgasm, satisfaction and pain. Patients with a score < 26·55 (cut-off) were likely to present with sexual dysfunction.13,14

Quality of life evaluation

Patients’ quality of life was evaluated by the Dermatology Life Quality Index (DLQI), an autoquestionnaire with 10 questions referring to the previous 7 days, which led to a score of between 0 and 30. Self-assessment included symptoms and perceptions (items 1 and 2), daily activities (items 3 and 4), leisure time (items 5 and 6), work/studies (item 7), interpersonal relationships and sexuality (items 8 and 9) and treatment (item 10).15 This scale has already been used to evaluate quality of life in PV.16

Statistical analysis

Student’s t-test was used to compare means on the paired series (VAS, FSFI, DLQI). The McNemar χ2 test was used to compare qualitative variables on paired series (ability to have sexual intercourse or not).

Results

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. What’s already known about this topic?
  7. What does this study add?
  8. Acknowledgments
  9. References

Twenty patients received an injection of 100 U BTA (Botox®; Allergan) in the bulbospongiosus muscles to treat PV.

Demographic data

The mean age of the patients at admission was 26 years (range 22–36) and 75% were married or cohabiting. Most were of caucasian origin (17/20, 85%), two were African (10%) and one Asian (5%). The study of their socioprofessional category showed that they were mostly students: 10/20, i.e. 50% (Table 1).

Table 1.   Demographic data and previous gynaecological history of the patients
CharacteristicsCases (= 20)
  1. Values are n (%) unless otherwise indicated.

Age (years), mean ± SD (range)26·8 ± 3·2 (22–36)
Ethnicity
 African-American0
 White17 (85)
 Hispanic0
 Asian1 (5)
 Other non-White2 (10)
Married/cohabiting15 (75)
Education
 < 10 years0
 > 10 years20 (100)
Socioprofessional category
 Student10 (50)
 Employed8 (40)
 Employed at executive level2 (10)
Gravida
 Nulligravida17 (85)
 Multigravida3 (15)
Parity
 Nulliparous17 (85)
 Multiparous3 (15)
Current oral contraception12 (60)

Associated factors

Serological screening for HIV and syphilis (TPHA-VDRL) as well as urinary Chlamydia PCR were negative for all patients before the injections (Table 2). Thirteen patients were vaccinated against hepatitis B. Eleven patients (55%) had a history of cystitis, and eight (40%) had had at least one episode of vulvovaginal candidiasis (microbiologically proven). No patients presented with episodes of vulvovaginal candidiasis or bacterial vaginosis when the injections were administered.

Table 2.   Clinical characteristics of patients with provoked vestibulodynia and results of preinclusion assessment
CharacteristicsCases (= 20)
  1. Values are n (%) unless otherwise indicated. HIV, human immunodeficiency virus; PCR, polymerase chain reaction; HBs, hepatitis B surface antigen.

Age at symptom onset (years), mean ± SD (range)20·8 ± 2·6 (18–24)
Sexually transmitted diseases serological screening (no. of positive tests)
 HIV0
 PCR Chlamydia0
 Positive anti-HBs13 (65)
Associated interstitial cystitis11 (55)
History of bacterial vaginosis9 (45)
Treatment for candidiasis more than once8 (40)
Infection before injections0
Pain duration (years), mean ± SD (range)7·6 ± 3·91 (3–17)
Diagnosis delay (years), mean ± SD (range)4·65 ± 4·5 (0–13)
Dyspareunia
 Primary13 (65)
 Secondary7 (35)
Vulval erethism18 (90)
Hyperactivity of bulbospongiosus muscles16 (80)

Characteristics of provoked vestibulodynia

The mean age at symptom onset was 20·8 years (range 18–24) (Table 2). The mean delay between symptom onset and diagnosis was 4·65 years (0–13). Seventeen patients were nulliparous (85%). In 13 patients (65%), dyspareunia provoked by vestibulodynia was of secondary origin, and was of primary origin in seven patients (35%) (the patients had never had sexual intercourse without pain). Eighteen of our 20 patients (90%) presented with a vulval erethism (i.e. an involuntary contraction of the perivulval muscles on gently touching the mucous membrane). Sixteen patients (80%) presented with muscular hyperactivity recorded on the painful muscles based on EMG examination.

Pain evaluation

Sixteen patients out of 20 (80%) reported an improvement in the pain 3 months after the injections, which was still the case 6 months later (Fig. 1). Before the BTA injections, the mean ± SD VAS value was 8·37 ± 1·22 (range 4·5–10) for all 20 patients. Three months after the injections of 100 U BTA, the mean VAS value for our 20 patients was 2·57 ± 2·67 (range 0–9; < 0·0001). After 6 months, the mean VAS was 3·90 ± 2·92 (0–9), i.e. a mean reduction of 3·52 (range 0–9), which was statistically significant compared with the mean value before the injections (< 0·001). Between 3 and 6 months, mean VAS values increased by 0·52 on average (−5 to 2·5; = 0·2).

image

Figure 1.  Visual Analogue Scale (VAS) score for each patient injected with botulinum toxin A and mean values at baseline, 3 months and 6 months.

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Before the BTA injections, sexual intercourse was impossible for 18 of 20 patients (90%). After 3 months, sexual intercourse was possible for 13 patients (72%) of the 18 for whom intercourse was not possible before the injections. There was a significant difference (< 0·001) when we compared the possibility of sexual intercourse before and after the injections. This result was confirmed after 6 months for all the patients who had improved. Of these 13 patients, eight (62%) had no more pain at all during sexual intercourse, compared with five (38%) who presented with a residual pain (identical result after 6 months).

Evaluation of sexual function

Fifteen patients were evaluated by the FSFI questionnaire before the injections and 3 and 6 months later. Before the injections, the mean ± SD FSFI score was very low [3·74 ± 2·94 (range 2–14)]. The inability to have sexual intercourse for 13 of the 15 patients significantly lowered the mean score of the questionnaire. After 3 months, this score significantly increased to 18·44 ± 9·66 (3·2–29·6) showing a clear improvement in sexual activity at the 3-month interval (< 0·0001). Five of the 15 patients (33%) had a score > 26. After 6 months, the mean ± SD score was 20·16 ± 10·24 (3·2–31·6; < 0·0001) and six patients (40%) had a score > 26.

Evaluation of quality of life

Quality of life according to the DLQI was evaluated before the injections and 3 months later for 15 patients. Before the injections, the mean ± SD DLQI was 19·46 ± 5·16 (range 12–26). Three months later, the DLQI score significantly decreased to 9·93 ± 7·48 (2–28; < 0·0001). Between 0 and 6 months, the mean DLQI significantly decreased to 8·85 (2–26; < 0·0001).

Side-effects

No side-effects apart from the pain on injection were observed for the 20 patients.

Discussion

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. What’s already known about this topic?
  7. What does this study add?
  8. Acknowledgments
  9. References

PV is increasingly recognized as a cause of sexual pain and is often difficult to treat. Among treatment strategies,5 BTA is a possible option owing to its modes of action. Our study shows that BTA may be considered an interesting therapeutic alternative for PV. Indeed 3 months after treatment, 80% of patients experienced a significant improvement in pain and nearly 72% were able to have sexual intercourse, which was impossible before the injections. Three and 6 months after the BTA injections, the decrease in pain was also significant compared with the VAS values at baseline. The efficacy of the treatment on pain was also associated with a significant beneficial effect on sexual function and quality of life. The mean value of the DLQI decreased between baseline and 3 or 6 months after the injections. Similarly, 6 months later, for 40% of patients, the value of FSFI questionnaire was higher than the fixed threshold of 26·55 for satisfying sexual activity.

Our study is original because of the specific methodology used to treat a relatively high number of patients fulfilling precise diagnostic criteria. The BTA injections in the bulbospongiosus muscles were all carried out by the same operator using EMG guidance for the tracking muscle. The dose of 100 U, which was determined by our previous experience, was administered to all patients. The use of BTA in vestibulodynia has already been evaluated in different clinical cases17–20 and small series.21,22 However, the doses used varied from 10 to 80 U, and the injection sites were often imprecise and numerous. The use of EMG detection is not constant in the search for muscular hyperactivity. In the only randomized double-blind study published, the authors used low doses of 20 U Botox® which did not significantly reduce pain and had no impact on sexual function and quality of life, but a significant improvement of pain was observed in both the group receiving 20 U Botox® and in the placebo group.23 In our experience, effective doses are 100 U per patient, i.e. 50 U on each side of the vestibule, and lower doses do not provide sufficient clinical improvement.

PV alters sexual function and the quality of life of patients. In our study, sexual function became impossible and quality of life was also distinctly impacted. Most studies using scales suggest that sexual function and the associated psychological distress are a consequence and not the cause of PV symptoms. Sackett et al.24 report that suffering linked to the syndrome of vulval vestibulitis leads to dramatic consequences on sexuality. Vestibulodynia has a negative impact on libido, satisfaction and the desire for intimate relationships. This leads to major frustration and to the appearance of depressive symptoms.24 In our study, we showed that sexual function and quality of life are significantly improved by BTA injections but that mean score values none the less remain low for FSFI and high for DLQI. This suggests that injections should be continued in order to control the pain as far as possible and in the long term, thus allowing patients to have confidence in their intimate relationships. Indeed, the duration of action of BTA is usually about 3 months but the first effects are observed after 3 weeks. Furthermore, we observed that the effects of BTA in our patients spread beyond the expected duration for the pain and quality of life or sexual activity.

The beneficial role of BTA is partly explained by its action on muscular disorders which are identified in PV and also by its antinociceptive effect on the mediators of pain. For our patients, muscular anomalies are corroborated by several clinical and paraclinical elements. Firstly, 18 of our 20 patients presented with a vulval erethism. The BTA injections also made sexual intercourse possible for 72% of patients in whom no penetration could be envisaged before due to painful tension of the clinically perceptible vestibule in the form of a tensed, thin muscular cord on both sides of the vestibule. The muscular involvement may explain the relative success of certain therapies, including biofeedback relaxation and physical therapies.5 Finally, 16 of 20 patients presented with a muscular hyperactivity on the EMG recording, which is unusual for a muscle normally at rest. Perhaps this abnormal hyperactivity can explain vulval erethism and vestibular cords. Reissing et al.8 reported the presence of muscular hyperactivity on the pelviperineal muscles even though this was not correlated with the intensity of pelvic pain. On the other hand, a negative correlation between pain duration and muscular activity was specified in the same study: electrical muscular hyperactivity reduces progressively and significantly with time.8 These authors point out that this EMG anomaly has been identified as a cause of chronic pain syndrome and thus partly explains the pain of PV. The aetiologies of hyperactivity, which are still little known, are multifactorial: accumulation of neurogenic metabolites, change in muscular blood flow, oedema, inflammation and ischaemia.25

The main effect observed in this study was the reduction of the painful perception of vestibulodynia symptoms.10In vitro and in vivo data have shown that BTA has an antinociceptive action through its effects on inflammation, axonal transport, on spinal ganglion inhibition and spinal and suprasegmental level inhibition.26 Therefore, in addition to a blockade at the extrafusal neuromuscular junction in the muscle fibre, BTA also reduces the excitatory drive to the α-motoneurons by reducing the intrafusal afferent signals from the muscle spindle to the spinal cord.10 Beyond these neuromuscular actions, BTA blocks the release of substance P in particular, but also glutamate, calcitonin gene-related peptide (CGRP), ATP, acetylcholine and noradrenaline.10,26–28 Furthermore, in PV, the sensation of painful perceptions may be altered.29 A significant increase in the vestibular innervation compared with healthy subjects was identified in biopsies of the posterior vestibule, which can correspond to nerve renewal or neuronal hyperplasia.30 The vanilloid receptors, VR1, expressed by the nociceptors in the vestibular mucus were also significantly increased in patients with vulvodynia compared with a control group.31 This receptor may be activated by capsaicin, a thermal stimulus, and by endogenous agonists such as anandamide, eicosanoids and leucotriene B4.31 Once activated, these receptors, which are sensitive to capsaicin, lead to a clinical burning sensation as felt in PV.32 It is produced at the same time as the release of neuropeptides (CGRP and substance P) leading ultimately to neurogenic inflammation. The action on these receptors by mediators of inflammation explains the fact that the clinical history of patients often begins with an infectious episode, particularly candidiasis (40% of patients in this study), which triggers the pain. It has been shown that BTA prevents the release of these neurotransmitters.27,28 It is a reminder that the action of BTA is also located on these receptors, which are present in large numbers in vulvodynia. The antalgic effect of BTA therefore breaks the circle of pain, thus allowing for the lessened central perception of symptoms and accounting for the prolonged action of BTA beyond 3 months.33

It was remarkable that BTA injections were well tolerated and no adverse events observed. The systematic use of Kalinox® has been very effective in controlling pain associated with injections. Few side-effects are reported: tenderness at the injection site or influenza-like symptoms.23

In conclusion, our results demonstrate that BTA seems to be an effective and safe treatment for PV. BTA should be carried out in subjects fulfilling precise diagnostic criteria for PV and using a specific technique and sufficient doses. These encouraging preliminary results have led us to conduct a randomized double-blind trial to evaluate the efficacy of 100 U of BTA compared with a placebo. Although the effect of further treatment should be investigated, BTA appears to be a promising option for managing sexual pain disorder.

What’s already known about this topic?

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. What’s already known about this topic?
  7. What does this study add?
  8. Acknowledgments
  9. References
  • • 
    There are currently few effective treatments for provoked vestibulodynia.
  • • 
    A few case reports and series have investigated the effects of botulinum toxin A in provoked vestibulodynia but precise criteria and specific techniques were not used.

What does this study add?

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. What’s already known about this topic?
  7. What does this study add?
  8. Acknowledgments
  9. References
  • • 
    For 80% of treated patients, botulinum toxin A 100 U injections are effective for pain, quality of life and sexual function.
  • • 
    The presence of muscular hyperactivity in the vast majority of patients suggests muscular involvement in this pathology.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. What’s already known about this topic?
  7. What does this study add?
  8. Acknowledgments
  9. References

The authors thank Frances Sheppard of the Clinical Investigation Centre of Besançon for translating the manuscript into English.

References

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. What’s already known about this topic?
  7. What does this study add?
  8. Acknowledgments
  9. References