University of Groningen
The Genito-Pelvic Pain/Penetration Disorder Paradigm and Beyond Spoelstra, Symen Kornelis
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The Genito-Pelvic Pain/Penetration Disorder Paradigm and Beyond
Theoretical and empirical perspectives
Symen Kornelis Spoelstra Printing of the thesis was financially supported by: University of Groningen, University Medical Center Groningen (UMCG), Ahmas Foundation Groningen
Cover image: Ollyy | www.shutterstock.com Lay-out: Nikki Vermeulen | Ridderprint BV Printing: | www.ridderprint.nl
ISBN: 978-94-6299-520-8
© 2017 Symen Kornelis Spoelstra All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means without written permission of the author and the publisher holding the copyright of the published articles.
The Genito-Pelvic Pain/Penetration Disorder Paradigm and Beyond
Theoretical and empirical perspectives
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op
woensdag 22 februari 2017 om 16.15 uur
door
Symen Kornelis Spoelstra geboren op 21 november 1979 te Leeuwarden Promotores Prof. dr. W.C.M. Weijmar Schultz Prof. dr. H.B.M. van de Wiel
Beoordelingscommissie Prof. dr. R. Basson Prof. dr. H.W. Nijman Prof. dr. M.D. Waldinger
Paranimfen Dr. C. Borg Dr. E.R. Nijhuis
“Het doet het mysterie geen kwaad er een beetje meer van te weten”
Richard Feynman, 1918-1988
TABLE OF CONTENTS
Scope of the thesis
Chapter 01 General introduction 13 A woman with coital pain: new perspectives on provoked vestibulodynia Accepted for publication as a chapter in the book Bio-Psycho-Social-Obstetrics and Gynaecology
PART I Treatment
Chapter 02 Anticonvulsant pharmacotherapy in generalized and 39 localized vulvodynia; a critical review of the literature J Psychosom Obstet Gyneacol 2013;34(3):133-138
Chapter 03 Long-term results of an individualized, multifaceted 53 and multidisciplinary therapeutic approach to provoked vestibulodynia J Sex Med 2011;8(2):489-496
Chapter 04 Transcutaneous electric nerve stimulation as an 69 additional treatment for women suffering from therapy-resistant provoked vestibulodynia: a feasibility study J Sex Med 2015;12(1):228-237
PART II Pathophysiology
Chapter 05 Female genito-pelvic reflexes and their sexual 89 implications: an overview Submitted for publication
Chapter 06 Dynamic clinical measurements of voluntary vaginal 107 contractions and autonomic vaginal reflexes J Sex Med 2014;11(12):2966-2975
Chapter 07 The distinct impact of voluntary- and autonomic 125 pelvic floor muscles on genito-pelvic pain/penetration disorder Submitted for publication PART III Reflection
Chapter 08 Throwing the baby out with the bathwater: 141 the demise of vaginismus in favor of genito-pelvic pain/penetration disorder Arch Sex Behav 2014;43(7):1209-13
PART VI Conclusion
Chapter 09 Summarizing discussion and future perspectives 155
Chapter 10 Nederlandse samenvatting 167
PART V Appendices
A. List of abbreviations 183 B. Co-authors and their affiliations 187 C. Dankwoord (acknowledgements) 191 D. Curriculum Vitae 199 E. Publication overview 203
SCOPE OF THE THESIS
Scope of the thesis | 11
This thesis focuses on two female sexual pain disorders: vaginismus and dyspareunia. In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; American Psychiatric Association, 2013) these two disorders have been merged into a new ‘diagnosis’: Genito-Pelvic Pain/Penetration Disorder (GPPPD).
We place the term diagnosis between inverted commas for several reasons: • The DSM does not provide ‘diagnoses’ in the normal nosological manner. It clusters and categorizes symptoms, but does not describe the etiology in terms of underlying pathophysiology; • Merging of the disorders gives the impression that vaginismus and dyspareunia are identical. Although it is generally believed that these two phenomena lie on a phenotypical continuum, there is much debate concerning the differentiation of the underlying pathology; • As a consequence of the different etiological views - and therefore the lack of a formal diagnosis – a broad spectrum of treatment modalities has emerged, many of which represent a certain school (medical, psychological, psychosomatic, etc.) each with its own ‘claim for fame’. Although these form very interesting subjects for scientific debate, this situation has a paralysing effect on painstaking clinicians who want to provide treatment which they can account for to their patients.
In order to evaluate the clinical management of provoked vestibuldodynia (PVD) and to gain more insight into the pathology of vaginismus and dyspareunia, this research project was launched. To emphasize the importance of establishing sound etiological bases for medical professionals, we took the scientist practitioner stance: ‘building the bridge from two sides’ and ‘on-the-job-experience’.
Aims
- To evaluate the clinical management of provoked vestibulodynia - To gain more insight into the pathophysiology of vaginismus and dyspareunia, in casu, explore the role of genito-pelvic reflexes - To discuss the new DSM-5 classification genito-pelvic pain/penetration disorder 12 | SCOPE OF THE THESIS
OUTLINE OF THE THESIS
Chapter 1 describes the symptoms, aetiology, pathogenesis, differential diagnosis and treatment of provoked vestibulodynia based on the case history of a young woman with provoked vestibulodynia.
Chapter 2 provides an overview of the efficacy of anticonvulsant pharmacotherapy for generalized and localized vulvodynia. Relevant studies were evaluated with the Oxford Centre for Evidence-Based Medicine – levels of evidence.
Chapter 3 presents the long-term results of an individualized, multifaceted and multidisciplinary therapeutic approach to vulvar pain, sexual functioning, sexually related personal distress and relational sexual satisfaction in women with provoked vestibulodynia.
Chapter 4 evaluates the additional value of transcutaneous electric nerve stimulation (TENS) to the multidimensional treatment for provoked vestibulodynia.
Chapter 5 describes the state of the art on female genito-pelvic sexual reflexes. A literature search provided insight into genito-pelvic reflexes and their assumed sexual implications.
Chapter 6 demonstrates dynamic clinical measurements of voluntary vaginal contractions and induced autonomic vaginal reflexes in asymptomatic women.
Chapter 7 presents the genito-pelvic reflex hypothesis: a new theory about the role of genito-pelvic reflexes in genito-pelvic pain/penetration disorder.
Chapter 8 focuses on the debate concerning the demise of vaginismus in favour of genito-pelvic pain/penetration disorder in the DSM-5. Pros and cons are discussed.
Chapter 9 provides a summarizing discussion and suggestions for future research on genito-pelvic pain/penetration disorder.
Chapter 10 summarizes the findings of this thesis in Dutch. CHAPTER 1 A Woman with Coital Pain: New Perspectives on Provoked Vestibulodynia
Symen K. Spoelstra Harry B.M. van de Wiel
Accepted for publication as a chapter in the book Bio-Psycho-Social-Obstetrics and Gynaecology
General introduction | 15
INTRODUCTION AND AIMS 1 Provoked vestibulodynia (PVD) is characterized by pain at the vulvar introitus, in particular the vulvar vestibule, provoked by touch, pressure, and vaginal penetration. Although distinct and interesting hypotheses have been put forward, the pathogenesis of PVD still remains largely unknown. In general, the etiology is considered to be multifactorial. Problems arise in PVD when normal protective functions “overreact”: when normal behavior or a psychophysiological state is too extreme, too prolonged, or too intense. This attention to contextual appropriateness is one of the key principles of psychosomatic obstetrics and gynecology. It is therefore the major reason why PVD symptoms should always be put into a biopsychosocial perspective.
DEFINITION IN LAY TERMS
Provoked vestibulodynia (PVD) is characterized by pain at the vulvar entrance, in particular the vulvar vestibule, provoked by touch, pressure, and vaginal penetration.
DIDACTIC GOALS
After reading this chapter, you will: • Be able to recognize PVD as a sexual as well as a chronic pain problem • Know that its onset often has the character of an acute disease but that this disease easily turns into a chronic pain syndrome through the particular psychological makeup of the patient or couple • Be aware of the most recent insights into diagnostic and therapeutic options in PVD • Know that a multidimensional treatment provides the best options for long-term success • Know that the key element of this treatment is to end the vicious circle of pain and fear • Be able to inform patients and partners about diagnostics and therapeutics, including complications or disturbances that may occur throughout the treatment process • Know that even after what can be considered as successful treatment, the motto at the resumption of intercourse remains: “Handle with care!”. 16 | CHAPTER 1
Case History
Bianca Olive, a 30-year-old woman, para 2, enters your consultation room alone. She is referred by her general practitioner (GP) for gynecological examination. Her main problem is pain during sexual intercourse, which started after the birth of her second child, about 2 years ago. At that time she also suffered from some vaginal discharge. Her GP treated her with antimycotic vaginal suppositories against vaginal infection. The treatment alleviated her complaints for a few weeks but then the pain returned. She describes the pain as a very intense burning pain starting from the moment of penetration. The pain is always present during sexual intercourse and it can even hold on for hours afterward. She is using OAC (ethinyl estradiol 30 ug/levonorgestrel 150 ug), no other medication or drugs. Bianca has no history of illnesses or sexual or physical abuse.
FACTS AND FIGURES: EPIDEMIOLOGY, CLASSIFICATION, AND DIFFERENTIAL DIAGNOSIS Epidemiology The prevalence of PVD is unclear and depends on a number of intermediating variables, such as age, cultural background or ethnicity, and setting: • Age: with regard to the prevalence of dyspareunia, there appears to be a bimodal age distribution that varies from 14 to 34 % in younger (premenopausal) women and from 6.5 to 45 % in older women [1]. In premenopausal women, PVD is the most frequent cause of chronic painful sexual intercourse [2]. • Cultural background/ethnicity: the prevalence of dyspareunia in Northern European countries seems low, whereas in the USA, relatively high prevalence figures have been reported. Historically, PVD was primarily considered to bea disorder that only affects white Caucasian (young nulliparous) women [3]. However, it has become increasingly clear that the lifetime prevalence of PVD is the same regardless of ethnicity [4]. • Setting: a prevalence of 3–18 % has been reported in the general population, 3–46 % in general practice populations, and 10–20 % at outpatient gynecology clinics [5].
Besides these more general mediators, time frame (as specified by researchers), comorbidity, and the physician’s initiative in bringing up the topic seem to play important roles in determining the prevalence [1]. General introduction | 17
Classification 1 For several decades, there has been debate about the classification and terminology of vulvar pain in general. Its origin lies merely in the many different dimensions that are used to underpin the classification process, such as quality, quantity, localization, origin, and duration of the pain or (more generally speaking) discomfort: • Quality: where the International Society for the Study of Vulvovaginal Diseases (ISSVD) refers to the pain as burning, others describe the pain as sharp (knifelike). • Quantity: the degree of vulvar pain experienced varies per patient. PVD is characterized by hyperalgesia, i.e., increased response to a painful stimulus, and allodynia - the experience of pain in response to a normally not painful stimulus. • Localization: depending on the anatomical site of the pain, vulvodynia can be divided into a generalized and a localized subtype. The generalized form is far less common and has been understudied. The more customary localized subtype chiefly occurs in the vulvar vestibule. The locus of the allodynia is limited to specific areas and is symmetrical in the majority of women. It occurs particularly at the 5 o’clock and 7 o’clock positions exteriorly to the hymenal ring [3]. In a very small percentage of women, the hypersensitivity is localized in the anterior part of the vulva. These cases in particular are usually therapy-resistant. • Origin: vulvar pain can be divided into provoked, unprovoked, and mixed. The most common presenting symptom of provoked vestibulodynia is severe vulvar pain during sexual intercourse. In extreme cases, sexual intercourse is virtually impossible. However, the pain also can occur during other forms of penetration, such as the insertion of a finger, vibrator, tampon, or speculum. Furthermore, the pain can occur during nonsexual activities, such as cycling or horse riding. • Duration: PVD can be divided into a primary form and a secondary form. In the primary form, the pain has been present since starting intercourse or tampon use, whereas in the secondary form, there has been a period of pain-free intercourse or tampon insertion prior to the onset of symptoms. After intercourse, the pain may last for several hours to several days and mainly occurs during micturition.
There is long-term ongoing debate about whether vaginismus can be differentiated from dyspareunia/PVD categorically, dimensionally, or not at all [6]. In 2013, the diagnosis of genito-pelvic pain/penetration disorder (GPPPD) was introduced in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), to replace the diagnoses of dyspareunia and vaginismus [7]. GPPPD is defined as: 18 | CHAPTER 1
A. Persistent or recurrent difficulties with one (or more) of the following: – Vaginal penetration during intercourse – Marked vulvovaginal/pelvic pain during vaginal intercourse/penetration attempts – Marked fear/anxiety about vulvovaginal or pelvic pain in anticipation of, during, or as a result of vaginal penetration – Marked tensing or tightening of the pelvic floor muscles during attempted vaginal penetration B. The symptoms in criterion A have persisted for a minimum duration of approximately 6 months. C. The symptoms in criterion A cause clinically significant distress in the individual. D. The sexual dysfunction is not better explained by a nonsexual mental disorder or as a consequence of a severe relationship distress (e.g., partner violence) or other significant stressors, and it is not attributable to the effects of a substance/ medication or other medical conditions.
There is a lifelong and acquired subtype of GPPPD. Furthermore, based on the degree of distress in criterion A, GPPPD is categorized into mild, moderate, and severe. Up to date, the validity and reliability of the GPPPD diagnosis has not yet been established. Regardless of the new DSM diagnosis, the debate on the classification of dyspareunia and vaginismus still continues [6].
Differential Diagnosis The diagnosis of PVD is based on exclusion, which is largely established through client history. The most important differential diagnoses are: • Recurrent vulvovaginal candidosis: – In a proportion of women, PVD simply starts with recurrent vulvovaginal infections. It is likely that PVD develops because these women continue to have sexual intercourse with the accompanying pain, despite having an infection. • “Ordinary” dyspareunia: – If there is insufficient sexual arousal, then there will be insufficient lubrication. Penetration may become painful and lead to “the anticipation of pain,” also in the absence of chronic inflammation. The difference between “ordinary” dyspareunia and PVD is found in the number of times that there is sufficient sexual arousal, without the experience of pain. Moreover, sometimes in women with PVD, penetration may succeed without pain. That’s because in women with sufficient General introduction | 19
arousal (and orgasm), the pain threshold temporarily increases. However, in these cases the pain continues thereafter. (See Chap. 20 for discussion on insufficient 1 sexual arousal) • Vaginismus and other overactive pelvic floor dysfunctions: – Although vaginismus can be accompanied by pain, its main characteristic is involuntary contraction of the vaginal sphincter, which makes penetration impossible. (See Chap. 17 for discussion of vaginismus) • The presence of anogenital dermatoses: – Chronic disorders of the female genital skin may interfere with sexual contact, because they cause pain. Examples are lichen sclerosus, Zoon’s vulvitis, mucosal lichen planus, etc. Diagnostic uncertainty can be ruled out by vulvoscopy or by taking a biopsy and performing histological examination. (See Chap. 19 for discussion of the sexual consequences of lichen sclerosus)
ETIOLOGY AND PATHOGENESIS
Before discussing the etiology of PVD, some critical comments must be made from a biopsychosocial perspective about syndrome diagnoses in general. This perspective is summarized under the label “functional complaints.”
Functional Complaints Although this is often forgotten in health care, the two main characteristics of syndromes such as PVD - i.e., pain and fear - are extremely important aids to human survival. In the case of threat or actual danger, high levels of fear and/or pain are “healthy reactions to an unhealthy situation.” The same holds true for somatic stress reactions, such as increases in muscle tension, heart rate, blood pressure, etc. With (the threat of) sexual harassment and violence, the vaginal sphincter should contract, and the genital area should become hypersensitive, including an inflammatory reaction, to protect against and inhibit hostile invasion or reduce the negative consequences should this occur. In essence, these are normal psychophysiological reactions. Therefore, the question of pathology does not lie in the phenomenon itself, but in its appropriateness, i.e., the match between action and reaction. Problems arise when normal protective functions “overreact”: when normal behavior or a psychophysiological state is too extreme, too prolonged, or too intense. This attention to contextual appropriateness is one of the key principles of psychosomatic obstetrics and gynecology. It is therefore the main reason why symptoms should always be put into a biopsychosocial perspective. 20 | CHAPTER 1
Etiology Although distinct and interesting hypotheses have been put forward, the pathogenesis of PVD still remains largely unknown. In general, the etiology is considered to be multifactorial. PVD is generally considered to be a chronic pain syndrome, because clusters of characteristics, especially symptoms and risk factors, often coincide, such as: • The typical vicious circle of chronic pain and psychosomatic complaints • Comorbidity with other pain syndromes, such as fibromyalgia and the irritable bowel syndrome • Comorbidity with pelvic floor dysfunction
Other observations have also been made that give PVD a more chronic pain disease-like character, such as: • The presence of a peripheral and central neuropathic process [8, 9] • Accompanying pathology in terms of increases in mast cells and nerve tissue in the vestibulum [10, 11] • Histology of the vestibule showed markedly increased mast cells as well as pain nociceptors [12], such that touch was perceived as painful • Lower pain thresholds in nongenital parts of the body [13], which supports the notion that PVD is characterized by central pain center dysfunction
An explanation for the “hybrid” character of PVD - i.e., disease combined with syndrome - might be found in its chronological development. What often starts as an ordinary acute disease (vaginal infection) or normal reaction to an averse stimulus (having intercourse without sexual arousal) gradually turns into a chronic pain syndrome. It is believed that psychological and social variables play an important role in why this occurs and why no normal adaptation takes place.
Psychological Factors Many studies have been performed on the relationship between PVD and psychological characteristics of the patient and/or couple. Dimensions have been distinguished such as intrapersonal variables, interpersonal variables, social variables, and variables related with sexual behavior. Some of the studies focused on the psychosomatic perspective, i.e., the psychological makeup as the cause of the complaints or the contributing factor. Other studies concentrated on the somatopsychological perspective, i.e., the effects of PVD on the psychosocial functioning of the patient and/or couple. Although General introduction | 21
conclusions were often drawn about cause–effect, most epidemiological studies were performed without any clear starting hypotheses, which makes causal inferences highly 1 speculative.
Intrapersonal Variables Psychological morbidity is significantly higher in PVD-affected women than in asymptomatic women. Many studies reported high levels of anxiety, depressive symptoms, somatization disorders, and hypochondrial symptoms. However, no convincing evidence is found of a psychological cause for the vestibular pain [14]. Epidemiological studies reported higher prevalences of comorbid anxiety disorders and depression in women with vulvodynia compared to healthy control groups [15]. With regard to obsessive–compulsive behavior, inconsistent results were found [16]. Additionally, PVD-affected women are more prone to specific personality traits, such as shyness, perfectionism, harm avoidance, increased tendency to catastrophize, hysterical personality, reward dependency, low self-esteem, and fear of negative evaluation than asymptomatic women [1, 5].
Interpersonal Variables Women with PVD were found to have more negative feelings toward sexual-partner contact, but their marital satisfaction with the nonsexual aspects of the relationship was similar to that in normative groups. Nevertheless higher pain ratings in women with PVD were associated with lower marital adjustment and higher levels of harm avoidance and reward dependence [1].
Sexual Behavior Women with PVD demonstrated impaired sexual functioning, namely, lower levels of sexual desire, arousal, frequency of intercourse, lower sexual pleasure, and erotophobia [15, 17]. They experienced more difficulties with sexual arousal and lubrication during partnered sexual activities than during masturbation [1]. Childhood physical abuse and sexual abuse were found to be potential risk factors for the development of PVD [17].
Vicious Circle Pain is a complex sensation that encompasses sensory, affective, and cognitive features. Similar to many other chronic (pain) syndromes, PVD starts like or as an ordinary disease, e.g., a vaginal infection, cystitis, etc. Whereas normally recovery occurs, symptoms fade 22 | CHAPTER 1
away or are treated successfully; in chronic syndromes, a vicious circle develops. In the case of pain during sexual intercourse, this circle may have several different components, such as: • PAIN Fear PAIN • PAIN No genital sexual response (blood flow, transudation, etc.) PAIN • PAIN Pelvic floor muscle hypertonia PAIN • PAIN Inflammation PAIN • PAIN Elevated nerve density PAIN Once the circle has developed, in no time these strings of components become a toxic cocktail of stress reactions: PAIN stress reactions PAIN.
In order to complete the circle, there must be a stimulus that provokes the pain response. This means that the consequences of PVD must be intrusive. Fortunately, the psychosocial impact of chronic pain has been well documented, and the burden is indeed devastating. Feelings of hopelessness, depression, and anxiety are common [18]. Chronic pain can be debilitating and demoralizing. Pain associated with sexuality can decrease self-esteem and disrupt relationships [19]. Coital pain is not the patient’s only problem. Some women who considered themselves cured of coital pain reported fear of intercourse due to the long-term experience of painful intercourse [20]. This information about the consequences of PVD enables us, while making use of the biomedical perspective, to combine medical knowledge with insights into psychological finality. This combination model not only makes PVD easy to grasp for health-care providers but also for patients and partners. A key factor in this model is the role of the vicious circles. As mentioned previously, in chronic pain syndromes, none of the so-called risk factors, or the general stress reaction patterns, are pathological in themselves. On the contrary, each phenomenon is a sound reaction to danger or threat. The question is why normal adaptation does not take place, when the context makes it clear to the woman that she is not being “threatened.”
Relevant questions in the light of PVD are as follows: When is “attempting to have intercourse” part of normal adaptive behavior, and when is it a neurotic habit and thereby a serious sign of threat? What does it mean when some women try to break through the pain while having intercourse? And if you want to break through the pain as a form of desensitization, why choose the most difficult and complex way of doing so, by having intercourse? General introduction | 23
It is therefore important to obtain a clear view of the interaction between all those involved, preferably when faced with problems that require collaboration. In other 1 cases, the present may be safe, but memories of the past are so intrusive that they interfere with current functional behavior. Especially sexual encounters, with their focus on emotional openness and closeness, are vulnerable to this type of interference from the past, as, for example, research into cancer survivorship has shown [21]. So even when there is no clear-cut post-traumatic stress disorder, sensitization may take the place of adaptation. In order to grasp this sort of understandable but still problematic coping behavior, thorough exploration of the personal (sexual) history of the patient and/or the couple is needed.
Case History: Continued
Bianca Olive is devastated. Until now, nothing has alleviated her complaints. Instead, they have worsened. She fears that her relationship will end due to the painful sexual encounters. She admits that, once in a while, she let her husband penetrate, while she tries to hide her pain from him. Recently, it was too painful and they stopped all sexual activity. Even intimacy is difficult for her now, afraid as she is, that intimacy “turns into sexual intercourse.”
SPECIFIC DIAGNOSTIC ASPECTS Aims and Strategies Owing to the lack of any clear etiology, the vicious circle of pain, and the prospect that the complaints are functional, it is not surprising that PVD is difficult to treat or, in other words, PVD is highly therapy-resistant. This has consequences on the treatment aims and strategies that can be used to fulfill the aims: • Aims: it is wise to not strive for immediate success in terms of pleasurable sexual intercourse, but to focus instead on breaking the vicious circle of pain. • Strategies: given the multitude and heterogeneous character of the intermediating variables (the elements in the vicious circle), many options are available. This plurality enables us to tailor the treatment to the individual characteristics and needs of the patient and/or couple (Table 1). In order to be able to do so, a number of preconditions must be met, such as the presence of a multidisciplinary team. 24 | CHAPTER 1
TABLE 1. Multidimensional and multidisciplinary approach of PVD
Careful history taking (in a safe atmosphere/setting) An educative gyneco-sexological examination that the patient is able to follow with a hand mirror (and when applicable with the partner present) Providing information about provoked vestibulodynia (PVD), its natural course, treatment options, and a treatment plan Involvement of the patient and partner in the decision process about potential treatment options Prescription of an inert cream (simple eye ointment or petroleum jelly 20 % in cetomacrogol) to protect the vestibular area and to urge the woman to touch the painful area (mucosal desensitization) (local corticosteroids are contraindicated) Vaginal EMG biofeedback, pelvic floor physiotherapy (by a registered pelvic floor physical therapist) with the aim of alleviating pelvic floor hypertonia Homework assignments that comprised self-exploration of the genitals and biofeedback by means of digital control, or with the aid of vaginal dilators and lubricants, together with a temporary coitus prohibition A hygienic protocol, e.g., no vaginal douching, no press-on panty liners Normalizing, reframing, and encouraging sexual activity without penetration to avoid development of feelings of guilt If appropriate, individual sexological counseling that aims to improve the woman’s self- image, body image, and autonomy, with the aid of a registered psychologist/sexologist If appropriate, sexological partner-relation therapy that primarily aims to improve physical and noncoital sexual contact, with the aid of a registered psychologist/sexologist If appropriate, nerve stimulation by means of transcutaneous electrical nerve stimulation If appropriate in some cases of persistent PVD, surgical intervention (vestibulectomy) as an additional form of treatment to facilitate breaking the vicious circle of irritation, pelvic floor muscle hypertonia, and sexual maladaptive behavior (end-of-line treatment)
Psychosocial Aspects/Biopsychosocial Approach Research into the treatment of PVD still pays too little attention to the biopsychosocial model. From this perspective, all the phases of the treatment process are interdependent. It is only for didactical reasons that we discuss the phases separately, according to the following standard categorization [22]: • Problem and patient orientation • Diagnostic phase • Indication and differential diagnosis • Informed consent and shared decision-making
It is important to note that these stages are interdependent-like buttoning up a white lab coat: If you start at the wrong buttonhole or miss one, the coat will not fit properly! After the aforementioned phases, the therapeutic phase and the follow-up and evaluation phase will follow (described later in the section on Specific Therapeutic Aspects). General introduction | 25
Problem and Patient Orientation The acquaintance phase is especially important when dealing with patients who are 1 coping with chronic illness. These patients are often at the end of their tether, because they have been looking for treatment for many years. In women with PVD, a quest of 5 years or more is no exception [19], and the mean number of physicians consulted prior to diagnosis is three [4]. PVD patients are likely to be feeling ashamed about having to reveal their very intimate problems to yet another health-care provider. During history taking, it is important to decrease the woman’s anxiety level by selecting a low-pressure setting, somewhere in private, with the woman fully clothed and not sitting on an examination table [19]. An important first step toward recovery is for patients to understand and accept their diagnosis. Providing clear and concise information is essential (psychoeducation). Over the years, women with PVD are likely to have received misinformation or ambivalent information from the different health-care providers [23].
PVD has a highly negative impact on quality of life. Patients are often young women at the start of their sexual life, when the couples’ problem-solving skills (as a duo) still need time to develop. A negative male attitude toward PVD was found to be a significant predictor of decreased dyadic adjustment and sexual satisfaction, as well as increased psychological distress, although it failed to predict sexual functioning. These findings indicate that partners should be involved in the treatment of PVD [24]. It is likely that facilitative male partner responses will improve sexual functioning, whereas solicitous and negative responses may be detrimental. Psychological interventions that target partner responses can help to improve the sexual functioning of the affected couple [25, 26]. However, it is suggested that PVD is not necessarily associated with general relationship maladjustment of the woman and her partner [27].
Especially the lack of a clear or acceptable cause is experienced as an extra burden. All in all, this supplementary stress makes the patient (hyper)sensitive to the course of events during the first encounter. A reassuring but sensitive approach combined with ample communication about the current emotions and feelings often helps a lot. Whereas in acute situations, swift medical action can be a blessing; in these cases, it is essential to take your time. Festina lente (make haste slowly)! 26 | CHAPTER 1
Diagnostic Phase As there are no clear causal pathways in the case of syndrome diagnoses, the diagnosis of PVD is mostly determined by exclusion. Even then PVD is difficult to recognize, because if the women is sufficiently sexually aroused, intercourse can still be pleasurable, even in the presence of PVD. In some cases, the pain manifests itself after sexual intercourse.
Case History: Continued
After she has given her consent, Bianca Olive is gynecologically examined, while she watches herself with a hand mirror. Her vulvar skin is reddish. There is no visible vaginal discharge. Upon request, it is difficult for her to relax her pelvic floor muscles. There are two bright red spots at 5 and 7 o’clock visible in the vulvar introitus, which are extremely painful when touching them with a wet cotton swab. Careful examination, after explicit permission of Bianca, with one gloved, lubricated finger, reveals firmly tightened levator muscles, eliciting the pain she recognizes when starting penetration.
Indication and Differential Diagnosis Because there is no clear etiology and there are so many targets (i.e., risk factors to deal with), in the eyes of beginners or outsiders, the indication process and the differential diagnosis appear to be “trial and error driven.” However, in the hands of an experienced clinician, the complaints and behavior of the patient become usually quite easily meaningful, and thereby a diagnostic and therapeutic pathway emerges for all involved. However, between sharing a rationale and complying with a treatment regime often lies a great distance - at least for the patient. This makes patient education more than a moral but a legal obligation. In case of PVD, it is a sine qua non.
Informed Consent and Shared Decision-Making In many countries, informed consent is already a legal condition to start treatment, while shared decision-making is rapidly gaining ground as a moral condition. However, research has shown that in practice, neither of these conditions are adequately met [28]. This can even be a problem when treating illness with a clear biomedical cause. We know that adherence to lifestyle changes is extremely low in most chronic illnesses such as rheumatic arthritis, multiple sclerosis, etc., but in the case of chronic sexual problems, it is almost nil. We therefore pay ample attention to both conditions as follows: General introduction | 27
Informed Consent 1 In medical practice, understanding why things happen does not guarantee therapeutic success. Moreover, even when success is possible, the way to achieve it is not always the solution the patient is seeking. In some situations, as we already pointed out when discussing the etiology of PVD, a reaction or symptom can have a protective function. In such cases, it is very difficult to eradicate, because the problem is also a solution. It is precisely this functional characteristic that raises the (ethical) question of whether health professionals should try to resolve the problem. Especially when there is no clear biomedical pathology, it is important to discuss and deliberate explicitly with the patient about the aims of the treatment process and the potential positive and negative consequences. In the case of PVD, the following possible aims could be discussed: • Promoting quality of life in general • Promoting quality of sexual life in particular, with or without intercourse • Reducing morbidity and complaints • Attempting to make intercourse non-harmful and as pleasurable as possible Sometimes a patient’s grasping of the situation, or gaining a clearer understanding, resolves the problem or the request for help. If the request for help persists, the elements that make up the vicious circle need to be clearly explained, and special attention must be paid to the need for full symptom prevention.
Shared Decision-Making It should be clear to all those involved that the only way to resolve this sexual variant of the old “chicken and the egg dilemma” is to establish a different means of “sexual self-management.” The object of this self-management should not be the act of sexual intercourse, but full symptom prevention. The term “self-management” in itself stresses that this can only be achieved with the active involvement and participation of the patient and/or couple. Just like many other lifestyle issues, such as eating, drinking, physical activity, etc., sexual habits are difficult to change. Besides informed consent and sexual literacy, shared decision-making is a sine qua non for the treatment of PVD. Therefore, preferably during the whole process, but at least when you have established the diagnosis of PVD, explain to the patient what you are going to do and repeatedly ask for her consent. Keep in mind that in psychological terms, these patients are at risk anyway. They may also have been “mistreated” medically and been traumatized for years. If a gynecological examination is needed, do it in an educational way, and give maximum control to the patient. Ask her whether she wants her partner, if present, to be 28 | CHAPTER 1
involved; ask her if she would like to use a hand mirror to see what is happening. Listen to her answers carefully, and look closely at how the patient and her partner interact as a couple. Having to make changes to their sexual lifestyle will put extra stress on the relationship. Therefore, careful observation might provide important information about the need to reconsider some treatment aims or procedures. In the end, it should be clear exactly which aims have been set, for which reasons and which procedures are needed. The patient should not only be informed but should also be the one who has made the decision to start treatment. This means that the patient and/or couple should be sexually literate in general, but particularly about the most important therapeutic options regarding PVD.
SPECIFIC THERAPEUTIC ASPECTS Therapeutic Phase In terms of the actual treatment, it is of eminent importance to keep in mind that the primary aim is not the reuptake of intercourse, but full symptom prevention: breaking the vicious circle! As stated previously (see the section on Aims and Strategies), several different, but not mutually exclusive, strategies can be used.
Follow-Up and Evaluation Phase The importance of follow-up and evaluation lies in the opportunity to make adjustments to the current case and to learn from it, in order to improve the approach to future cases (reflection). Given the complex nature of PVD, a number of possible pitfalls canbe distinguished and thereby points for evaluative reflection.
Examples of Patient-Related Topics for Reflection • Some patients are unwilling to adopt a psychosocial stance and insist on receiving somatic treatment. If this occurs, it is important to realize that it is unbearable for many patients that their PVD complaints are rooted in more fundamental psychological or interpersonal (sexual) problems. This means that our good news, i.e., that we have solved the puzzle, is perceived by the patient as bad news. When discussing future action, the rules of a bad news consultation should be followed. Do not try persuasion, but ask questions about the patient’s emotions and what the message means to her. • Make a decision in the multidisciplinary meeting regarding who will be the one to talk with the patient. General introduction | 29
• Sometimes young patients are accompanied by one of their parents, or a dominant partner, whose ideas and behavior interfere with the treatment process. 1 It is important to address these types of disturbance first, before actual treatment can start. An elegant strategy is to relate PVD to the theme of autonomy versus dependency. • Some patients feel very embarrassed about discussing intimate details with a health-care professional. Having sexual problems and being forced to talk about them is a way of expressing who they really are as a person. Unmasking themselves - and often their partner as well - makes people extremely vulnerable. It is easy to implicitly presume that the partner is the ideal co-therapist or that he will at least provide social support for the patient. However, for him, treatment also means being exposed, and moreover, it is the start of an intimate triangular relationship. Owing to the fact that health-care professionals in sexology often deliberately act as “the ideal partner,” their therapeutic behavior alone may induce intense feelings of jealousy, anger, etc. Beware of this transference, also on the part of the partner, and if it happens, eradicate the disturbances first before starting actual treatment.
CRITICAL REFLECTION AND CONCLUSIVE REMARKS
When dealing with syndrome diagnoses such as PVD, it is always the match between the patient and the professional that in the end determines failure or success. This does not mean that it is unimportant to follow a clear road from hello to goodbye. On the contrary, but as a health professional, one has to be able to discover or, better, to co-create with the patient the pathway that serves her best. Moreover, many patients look back at the treatment process as “a difficult yet rewarding process of personal and relational growth.” 30 | CHAPTER 1
Case History: Continued
After getting dressed and at the desk, Bianca Olive learns about the vicious cycle she has entered. She acknowledges that it has been a long time since she had experienced sexual excitement and lubrication - afraid of the coming pain. She understands that she needs to quit the attempts for penetration until she has more control of her pelvic floor musculature. She will bring her husband for the follow-up visit, in order to talk about the mechanism of the complaints. In the meantime she will start pelvic floor physical therapy and apply emollients to smoothen her irritated skin. She is willing to find out alternative sexual stimulation. Some leaflets and websites are provided to her, so she can orientate herself on which aspects might stimulate her in an erotic sense if desired. During the standard telephone follow-up evaluation 6 months later, Bianca says that she now realizes how sexually ignorant she and her partner were at the beginning of the therapy. Together they are now exploring a whole new dimension in their relationship that goes beyond having intercourse.
TIPS AND TRICKS
1. During the problem and patient orientation phase: • Realize that when dealing with syndrome diagnoses such as PVD, a patient- physician relationship of excellent quality is of utmost importance. Therefore, keep in mind that “There is no second chance to make a first impression” and “The medium is the message.” 2. During the diagnostic phase: • Combine empathy with moral neutrality; try to put apparently problematic phenomena, such as pain and fear, into a functional perspective without “blaming the victim.” • In the case of a vicious circle, shift the focus from the normal elimination of causes to breaking the circle. • Before you share your ideas about the ultimate diagnosis and treatment options with the patient, inform the patient that you will discuss and check them within the multidisciplinary team. Listen carefully to all the arguments, because they will probably reoccur in your discussions with the patient. • Be aware of the possible influences of sexual traumata. Ask proactively about previous sexual traumata! General introduction | 31
3. When talking things over with the patient: • Be careful using terms with “psy” in them (psychic, psychogenic, psychosomatic, 1 or even psychologist), because they mean bad news to most patients who are suffering from a syndrome diagnosis. • Do not impose your solutions; offer them as neutral options. 4. During the therapeutic phase: • PVD is a multifactorial disorder that should be treated in a multidimensional way in accordance with etiological factors, the risk profile, and context. • If you try to follow a stepped care model, beware: the more you become involved in the treatment process, the greater the intimacy and the stronger the bonding. Do not wait too long before referring the patient on. • When referring, make it clear that you are not doing it due to the complexity or magnitude of the complaints but due to the limitations of your professional repertoire. 5. During the follow-up and evaluation phase: • Even with timely referral, intimacy will have developed during the treatment process; therefore, attention should be paid to the way the patient, the couple, and/or the professional “return to normal.” • When looking back on successful treatment, parallel lines can be drawn between effective coping with PVD and other often coexisting problems, such as fibromyalgia, etc. 32 | CHAPTER 1
TEST YOUR KNOWLEDGE AND COMPREHENSION
1. The lifetime prevalence of PVD is the same regardless of ethnicity. A True B False
2. In women, with sufficient arousal (and orgasm), the pain threshold temporarily increases. A True B False
3. Evidence is found of a primary psychological cause for PVD. A True B False
4. In women with PVD, the marital satisfaction with the nonsexual aspects of the relationship is similar to that in normative groups. A True B False
5. Childhood sexual abuse is found to be a potential risk factor for the development of PVD. A True B False
6. Which of the following statements referring to allodynia in women with PVD is not true? The allodynia areas: A Chiefly occur in the vulvar vestibule B Are limited to specific areas C Always coincide with local redness D Are symmetrical in the majority of women General introduction | 33
7. Choose the option that is contraindicated in the treatment of PVD. A Local corticosteroids 1 B Penetration prohibition C Pelvic floor physiotherapy D Multidisciplinary approach
8. The primary aim of the treatment of PVD is: A The reuptake of intercourse B Full symptom prevention C Recovery of sexual response D Removal of negative feelings toward sexual-partner contact
9. What is the most essential condition for the treatment of PVD? A Sharing a rationale B Shared decision-making C Complying to treatment D Patient education
10. What is the mean number of physicians consulted prior to the PVD diagnosis? A 1 B 2 C 3 D 4
Answers 1. True 6. C 2. True 7. A 3. False 8. B 4. True 9. D 5. True 10. C
ACKNOWLEDGMENTS
We would like to thank Prof. dr. W.C.M. Weijmar Schultz, emeritus professor of Psychosomatic Obstetrics and Gynaecology, for his comments on this chapter. 34 | CHAPTER 1
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24. Jodoin M, Bergeron S, Khalifé S, Dupuis 27. Smith KB, Pukall CF. A systematic review 1 MJ, Desrochers G, Leclerc B. Male partners of relationship adjustment and sexual of women with provoked vestibulodynia: satisfaction among women with provoked attributions for pain and their implications vestibulodynia. J Sex Res. 2011;48:166–91. for dyadic adjustment, sexual satisfaction, 28. Leclercq WKG, Keulers BJ, Houterman and psychological distress. J Sex Med. S, Veerman M, Legemaate J, Scheltinga 2008;5:2862–70. MR. A survey of the current practice of 25. Rosen NO, Bergeron S, Sadikaj G, Glowacka the informed consent process in general M, Delisle I, Baxter ML. Impact of male surgery in the Netherlands Patient. Saf Surg. partner responses on sexual function in 2013;7:4. women with vulvodynia and their partners: a dyadic daily experience study. Health Psychol. 2014;33:823–31. 26. Rosen NO, Bergeron S, Sadikaj G, Glowacka M, Baxter ML, Delisle I. Relationship satisfaction moderates the associations between male partner responses and depression in women with vulvodynia: a dyadic daily experience study. Pain. 2014;155:1374–83.
PART I Treatment
CHAPTER 2 Anticonvulsant Pharmacotherapy for Generalized and Localized Vulvodynia: a Critical Review of the Literature
Symen K. Spoelstra Charmaine Borg Willibrord C. M. Weijmar Schultz
J Psychosom Obstet Gyneacol 2013;34(3):133-138 40 | CHAPTER 2
ABSTRACT
Anticonvulsant therapy has occasionally been recommended to treat vulvodynia. However, convincing evidence to support this therapeutic option is lacking. The goal of this study was to critically review studies published on the effectiveness of anticonvulsants for the treatment of vulvodynia. Evaluation of the methodological quality of relevant publications was the main outcome measure. MEDLINE, PubMED and Cochrane were used to identify studies published in English between January 1999 and February 2013. Searches were performed between December 2012 and February 2013. Articles were appraised with the Oxford Centre for Evidence-Based Medicine – Levels of Evidence. Eight relevant studies were identified: two case reports, three retrospective studies, two non-randomized prospective studies and one open- label pilot trial study. Gabapentin formed the main focus (87.5%) to reduce vulvar pain; success rates ranged from 50 to 82%. Lamotrigine was used in one study (12.5%) to relieve symptoms; satisfaction was reported in 82%. These results seem promising, but the majority of studies have several methodological weaknesses regarding sample size and design. Insufficient evidence was available to recommend anticonvulsants for the treatment of vulvodynia. Further studies are necessary with double-blind, randomized-controlled designs to investigate the effectiveness of anticonvulsant therapy for vulvodynia. Anticonvulsant pharmacotherapy for generalized and localized vulvodynia | 41
INTRODUCTION
Vulvodynia refers to a condition of vulvar discomfort, most often described as burning pain, which occurs in the absence of any relevant visible findings or a specific, clinically 2 identifiable, neurological disorder [1]. According to the literature, the condition affects approximately 16% of the female population at some point in their lives [2]. Depending on the localization of the pain, vulvodynia can be subclassified into generalized (pain in the whole vulva) or localized (pain in a specific area). The most common types of localized vulvar pain are vestibulodynia, clitorodynia and hemivulvodynia. Vulvar pain interferes with sexual, psychological and relational functioning [3], but the presenting complaint is often restricted to sexual functioning. Epidemiological studies reported a higher prevalence of co-morbid depression and anxiety disorders in women with vulvodynia than in healthy control groups [4]. Conflicting results were found regarding obsessive-compulsive behavior [5–7]. It is unclear whether depression and anxiety disorders are the cause or consequence of vulvodynia. Women with vulvodynia were also found to have negative feelings towards sexual-partner contact, but their marital satisfaction with the non-sexual aspects of the relationship was similar to that in normative groups [8,3]. The etiology and pathophysiology of vulvodynia are not fully understood. One ongoing hypothesis, the ‘‘neuromatrix pain theory’’ [9] suggests that chronic pain is produced by output from a widely distributed neural network in the brain rather than by sensory input evoked by injury, inflammation or other pathology. According to this theory, somatic sensory input is only one component of the matrix of pain. It is believed that injury, pathology and even chronic stress can affect this neuromatrix [9]. Consequently, vulvar pain in vulvodynia might be due to alterations in the neural network, in the absence of a physical cause. This theory suggests that neurogenic inflammation and the accompanying pain are chronic sequels to central and peripheral sensitization, which results from the bidirectional influence of peripheral input and the nervous system [8]. Quantitative sensory testing around the vagina in women with vulvodynia showed painful responses to normally innocuous tactile stimuli and increased pain responses to noxious stimuli [10,11]. As characteristics of a neuropathic disorder, this increased sensitivity to pain (hyperalgesia) and the painful experience of normal tactile stimuli (allodynia) might be caused by less efficient pain modulation processing due to local neurogenic inflammation, or peripheral and/or central sensitization. A multidimensional, multifaceted, individualized treatment approach is the main recommendation for vulvodynia patients, with specific attention to five main areas: 42 | CHAPTER 2
the mucous membrane, the pelvic floor, the experience of pain, sexual/relational functioning, and psychosocial adjustment [8,3]. Although first-line pharmacological treatment for generalized and localized vulvodynia generally comprises a tricyclic antidepressant, such as amitriptyline, very few studies have confirmed its efficacy in vulvodynia [12]. This is an important question, because tricyclic antidepressants have serious side-effects, including weight gain, fatigue, tachycardia and seizures, which limit their clinical applicability and affect patient compliance. Consequently, in the 1990s, an attempt was made to find alternative pharmacological treatment modalities for vulvar pain in vulvodynia [13]. Based on the assumption that vulvodynia is a neuropathic pain condition, the drugs used to treat neuropathic pain were tested in patients with local as well as generalized vulvodynia [14]. It should be noted that the administration of pharmacological treatment always has a placebo analgesic effect [15]. In 1996, it was reported that the anticonvulsant gabapentin (GBP), with antiepileptic and antinociceptive effects, was a highly effective treatment for a variety of chronic pain conditions, particularly neuropathic pain [16]. It is claimed to be effective for chronic pain conditions, such as postherpetic neuralgia, sympathetic dystrophy, trigeminal neuralgia, diabetic neuropathy, migraine, acute pain in herpes zoster infection and other types of neuropathic pain [17]. GBP has also occasionally been recommended for the treatment of vulvodynia [18]. However, there is no convincing evidence to support its use in these patients. Although the precise mechanism of GBP action remains unknown, several theories have been put forward, including (1) selective activation of the heterodimeric GABA (B) receptor subunits GABA (B1a) and GABA (B2), (2) selective enhancement of the N-methyl-D- aspartate current at GABAergic interneurons, (3) blockage of the a-amino-3-hydroxy- 5-methyl-4-isoxazo-lepropionic acid-receptor-mediated transmission in the spinal cord, (4) binding to the L-alpha-amino acid transporter, (5) activation of adenosine triphosphate-sensitive K(+) channels, (6) activation of hyperpolarization-activated cation channels, (7) modulation of Ca(2+) current by selective binding to the specific binding site of [3H]gabapentin (the alpha 2/delta subunit of voltage-dependent Ca(2+) channels) and, last but not least, a placebo effect [15,19,20]. Thus, the exact mechanism of GBP action to relieve chronic vulvar pain in vulvodynia is not entirely clear. Within the neuromatrix pain theory, with peripheral and central sensitization, GBP might inhibit afferent pathways to the central nervous system and thereby reduce vulvar pain perception [8]. Pharmacotherapy with GBP is a good choice, owing to its low side- Anticonvulsant pharmacotherapy for generalized and localized vulvodynia | 43
effect profile (most common side-effects are drowsiness, nausea and dizziness) and its minimal interaction profile with other medication [13]. GBP should not be discontinued abruptly, but tapered-off gradually, because it can lead to withdrawal-related side- effects. 2 GBP is a precursor of pregabalin. Jerome et al. administered pregabalin in their case report [21]. It showed equivalent efficacy to gabapentin, but at much lower doses [22]. When gabapentin was applied topically, a significantly smaller amount of active drug was required than when it was taken orally. In addition, the topical route of delivery reduced systemic absorption [23]. By changing the route of administration, the occurrence of possible adverse side-effects seemed to decrease [22]. Our literature search identified only one study on another anticonvulsant, lamotrigine, for the management of vulvodynia. Glutamate is a candidate neurotransmitter in spinal cord nociceptive pathways. It is believed to be involved in chronic pain, such as central sensitization and wind up, which can be inhibited by N-methyl-D-aspartate receptor (NMDA) antagonists. If lamotrigine can inhibit the pathological release of glutamate, it has the potential to be antinociceptive and prevent the mechanism responsible for establishing chronic pain [24]. In addition, lamotrigine appears to have antidepressant properties and an anxiety-reducing effect [25,26]. Until now, no convincing evidence has been published on the therapeutic effectiveness of anticonvulsants in the treatment of vulvodynia. Therefore, the goal of this study was to perform a critical review of the literature on the effectiveness of anticonvulsant pharmacotherapy for vulvodynia.
METHODS Literature search strategy MEDLINE, PubMED and Cochrane were searched in the period from December 2012 to February 2013 to identify studies on anticonvulsant treatment published between January 1999 and February 2013. All studies published in English on the specific subject of anticonvulsant treatment for vulvodynia, regardless of their methodological quality, were included in our review. The search strategy included the following words: vulvodynia, anticonvulsants, gabapentin, lamotrigine, treatment, dyspareunia, multidimensional approach and a combination of these words. Relevant articles, i.e. on the specific subject of anticonvulsant treatment for vulvodynia, were selected from these searches and the reference lists were checked for additional sources. 44 | CHAPTER 2
Grading the quality of the evidence Three reviewers independently graded the quality of the evidence in each of the articles, using pertinent diagnostic and therapeutic questions from the Oxford Centre for Evidence-Based Medicine – Levels of Evidence (March, 2011). (http:// www.cebm.net/ mod_product/design/files/CEBM-Levels-of-Evidence-2.1.pdf) This grading system is internationally accepted, as it ensures that the best available evidence is used in patient care. The scale is built according to a hierarchy, in which level 1 is the highest level of evidence, including high-quality, randomized-controlled trials, while level 5 is the lowest level of evidence, so-called expert opinion. The grading of recommendations is conducted as follows: (A) consistent level 1 studies, (B) consistent level 2 or 3 studies or extrapolations from level 1 studies, (C) level 4 studies or extrapolations from level 2 of 3 studies, (D) level 5 evidence or troubling inconsistent or inconclusive studies of any level.
RESULTS
The literature search identified eight relevant studies for inclusion in this review: two case reports, three retrospective studies, two non-randomized prospective studies and one open-label pilot trial study. Seven out of these eight studies focused on the efficacy of gabapentin (87.5%), while one study focused on lamotrigine (12.5%) (see Table 1). Patients with generalized and localized vulvodynia received anticonvulsant therapy in six studies, whereas two studies exclusively examined the efficacy of anticonvulsants for the generalized subtype of vulvodynia. Age ranged from 17 years in the study by Harris et al. to 65 years in the study by Jeon et al. Sample size was small, except in the three studies by Harris et al. (N = 152), Boardman et al., who administered GBP topically (N = 51) and Jeon et al. (N = 62) (see Table 2). Gabapentin dosage varied between the studies. The majority of studies administered an initial oral dose of 300 mg per day and increased it steadily every week, with intervals of 300 mg per day, to a maximum of 1200 mg per day. However, in the studies by Ventolini et al. and Harris et al., the maximum daily dose was 2700 mg and 3000 mg, respectively. Outcome measures in the studies focused mainly on the determinants vulvar pain and sexual functioning, i.e. reduction in vulvar pain and satisfactory sexual intercourse, while Meltzer-Brody et al., Jerome et al. and Bates et al. also focused on anxiety and depression. Follow-up duration was not documented in four out of the eight studies (50%). The retrospective study by Harris et al. had the longest follow-up of 30 months, while Bates et al. and Jerome et al. had follow- up periodes of 2 and 6 months, respectively. Anticonvulsant pharmacotherapy for generalized and localized vulvodynia | 45
2 Women had clinically had clinically Women robust and significantly in pain and reductions (at mood symptoms visit). week the 8 with Satisfaction was relief symptom 82%. 26 women received received women 26 gabapentin;13(50%) with GBP improved weeks) 4 (after A total of 50 (80.6%) of total A were 62 patients out of pain Vulvar satisfied. decreased (VAS) score 8.6 before from 3.2 after to treatment (p<0.001) treatment Results Not documented Not documented Not documented Follow-up Reduction Reduction in pain, and anxiety depression Achievement Achievement painless/ of acceptable sexual intercourse Vulvar pain Vulvar Outcome Outcome measure(s) Specified Not specified Not specified Selection criteria Generalized Generalized and localized vulvodynia Generalized Generalized and localized vulvodynia Generalized Generalized and localized vulvodynia Vulvodynia Vulvodynia (sub)type Open label Open label trial pilot study Non- Non- randomized prospective study cohort Retrospective Retrospective study Design Initial daily dose of 25 dose of daily Initial 2 for mg lamotrigine 50 to increased weeks, weeks 2 for mg/day to and subsequently 100, 200, 300 and 400 each dose mg/day, week. an additional for Dosage schedule: daily weeks during first 2 the for daily and twice weeks 6 remaining Starting 300 mg GBP 300 mg GBP Starting and titrated daily symptoms to according at 5 days every 300 mg of increments mg daily 2700 up to Initial daily GBP dose GBP daily Initial flexibly 300 mg/day, of depending increased to (up on response at for 900mg daily), least 2 months Anticonvulsant Anticonvulsant treatment N = 17 (mean N = 17 yr) age 41 N = 26 N= 62 (mean yr; age 45.7 yr) 31-65 range Sample characteristics (N, age) Meltzer- al., Brody,et 2009 [24] Ventolini, et et Ventolini, al., 2009 [27] Jeon, et al., et Jeon, 2013 [20] Authors [ref] Authors Anticonvulsant treatment studies treatment 1 | Anticonvulsant Table 46 | CHAPTER 2 80% reduction in pain 80% reduction 12 (after symptoms and anxiety weeks) These symptoms. over continued beneftis period a six months Symptoms resolved by by resolved Symptoms least 80% in 64% of at the patients 80% reported at least at 80% reported 50% improvement 8 (at in pain scores Evaluable weeks). vulvodynia localized sexual patients: in functioning improved reinstituted (6/9 17/20 intercourse; vaginal reported 11 patients intercourse increased frequency) Results 6 months 6 months 30 months Not documented Follow-up Reduction in Reduction pain intensity and anxiety symptoms Symptom Symptom relief Reduction in Reduction pain vulvar and changes in sexual functioning Outcome Outcome measure(s) Not specified Specified Specified Selection criteria Generalized Generalized vulvodynia Unprovoked Unprovoked generalized vulvodynia Generalized Generalized and localized vulvodynia Vulvodynia Vulvodynia (sub)type Case report Retrospective Retrospective review of files medical Retrospective Retrospective study Design Dose of 150 mg Dose of times/ three pregabalin day Range GBP dose was was dose GBP Range in 100 – 300 mg/day divided doses. 300 common: Most 900 to mg increased weeks. 3 over daily required 49 patients 13 1200 mg daily. 1500 required patients patients 17 mg daily. 1800 mg daily. required required 13 patients to doses (up higher 3000mg daily) 2%, 4% or 6% topical 6% topical 2%, 4% or of amount Small GBP. (approximately crème times daily) three 0.5ml Anticonvulsant Anticonvulsant treatment N = 1 (age 62 yr) 62 (age 1 = N N = 152 (range N = 152 (range yr; mean 17-85 yr) age 41 N = 51 (19 with N = 51 (19 generalized vulvodynia with and 32 localized vulvodynia) age Mean generalized: yr; mean 52.4 age localized: yr 32.9 Sample characteristics (N, age) Jerome, 2007 2007 Jerome, [21] Harris, et al., et Harris, [14] 2007 Boardmann, et et Boardmann, al., 2008 [23] Authors [ref] Authors Anticonvulsant treatment studies treatment 1 | Anticonvulsant Table Anticonvulsant pharmacotherapy for generalized and localized vulvodynia | 47
2 14 patients (82%) 14 patients or partial had either pain relief complete four to two (after at treatment weeks from doses ranging 1200 600 mg to mg in divided daily those 14 doses). Of had 7 patients patients; and 7 relief, significant had complete patients were Benefits relief. 32 up to maintained weeks Patient 1: dramatic 1: dramatic Patient in improvement pain symptoms, anxiousness, and depression Patient activity. sexual 2: considerable in improvement symptoms Results Between 26 - Between weeks 32 Patient Patient 1: twelve months 2: two Patient months Follow-up Vulvar Vulvar pain relief: excellent, good, poor, none Patient 1: Patient symptom reduction (pain, anxiety, depression, sexual problems) 2: Patient improvement in symptoms Outcome Outcome measure(s) Not Specified Not specified Selection criteria Generalized Generalized and localized vulvodynia Generalized Generalized and localized vulvodynia Vulvodynia Vulvodynia (sub)type Case reports Case reports Design GBP 300 mg/day for 1 for 300 mg/day GBP weekly Increased week. 300 mg twice/day, to times/ 300 mg three 300 mg four to day, daily Once times/day. 1200 mg/ dosage of reached, was day for dosage maintained wks least 12 at Patient 1: GBP was 1: GBP Patient 1200 mg/day to titrated 300 mg 2: GBP Patient times/day. three Anticonvulsant Anticonvulsant treatment N = 17 (range (range N = 17 yr; 26-82 median age: yr) 62 N = 2 (patient N = 2 (patient yr; 1 age: 33 2 age: patient yr) 30 Sample characteristics (N, age) Ben-David Ben-David & Friedman, 1999 [13] Bates & Bates Timmins, 2002 [28] Authors [ref] Authors Anticonvulsant treatment studies treatment 1 | Anticonvulsant Table = gabapentin GBP 48 | CHAPTER 2 C B B C B B C C Grade of of Grade recommendation 3 3 3 3 4 4 4 4 Level of evidence + + + - - - - +/- analysis statistical statistical Appropriate Appropriate + + ------group Comparison ------Blinding ------Randomization 1 2 N 17 17 51 62 26 152 Sample size Ben-David& Friedman, 1999 [13] Friedman, Ben-David& Bates& Timmins, 2002 [28] Bates& Authors Boardmann, et al.,2008 [23] et Boardmann, [14] al.,2007 et Harris, [21] 2007 Jerome, Jeon, et al., 2013 [20] et Jeon, Ventolini, et al., 2009 [27] et Ventolini, al., 2009 [24] et Meltzer-Brody, Methodological analyses of the studies on anticonvulsant therapy the studies on anticonvulsant of analyses 2 | Methodological Table Anticonvulsant pharmacotherapy for generalized and localized vulvodynia | 49
Success rates varied between the studies. Jeon et al. reported that 80.6% of their patients were ‘‘satisfied’’ after GBP therapy. Ventolini et al. reported improvement in 50% of the patients. Meltzer-Brody et al. observed (clinically) significant robust reductions in pain and negative effect (at the 8 week follow-up visit). Boardman et al. reported at 2 least 50% improvement in vulvar pain scores in 28 out of the 35 women (80%); in their group with localized vulvodynia, sexual functioning improved in 17 out of the 20 women (six out of nine had reinstituted vaginal intercourse, while 11 patients reported increased intercourse frequency). Harris et al. claimed that symptoms had resolved by at least 80% in 64% of the patients. Jerome mentioned 80% reduction in pain symptoms (after 12 weeks) and anxiety symptoms. Bates et al. reported dramatic improvements in pain symptoms, anxiousness and depressive feelings, as well as in the resumption of sexual activity.
DISCUSSION
Antidepressants are used to treat neuropathic pain, depression and anxiety. At present, tricyclic antidepressants are the first-line pharmacological treatment for vulvodynia. As in all chronic pain conditions that might be explained by the neuromatrix pain theory it is unclear whether these drugs treat the cause of the pain or its consequence. Anticonvulsant pharmacotherapy has also occasionally been used to treat generalized and localized vulvodynia [13,14,23,24]. However, there is limited evidence of the efficacy of anticonvulsant pharmacotherapy in vulvodynia. Critical evaluations are warranted, because this treatment option may have specific advantages, such as greater efficacy, fewer side-effects, better clinical applicability and greater patient compliance than treatment with tricyclic antidepressants. In this comprehensive review, a total of eight relevant studies were found on anticonvulsant pharmacotherapy for vulvodynia. Most of the studies focused on the anticonvulsant gabapentin. Only one study focused on lamotrigine. Success rates with gabapentin to reduce vulvar pain ranged from 50 to 82%; satisfaction with symptom relief with lamotrigine was 82%. It was notable that although carbamazepine is also prescribed in daily clinical practice, we did not find any studies on its use in the treatment of vulvodynia. The majority of the studies in our review had several methodological weaknesses, such as the absence of (1) large sample size, (2) inclusion and exclusion criteria, (3) control group or placebo group, (4) double-blind evaluation, (5) validated measures of pain and sexual functioning and (6) long-term follow-up. Using the Oxford Centre for Evidence- 50 | CHAPTER 2
Based Medicine Guidelines, the levels of evidence for recommendations in this review were Level 3/4, grade B/C (www.cebm.net). Therefore, based on our analysis of the currently available literature, there is insufficient evidence to recommend anticonvulsant intervention for the management of vulvodynia. In our opinion, patient care should be as ‘‘evidence-based’’ as possible, but not at the expense of a ‘‘patient-based’’ comprehensive approach. It is essential to combine clinical expertise with the needs of each individual patient. This is particularly important in the case of treatment for refractory problems, such as localized and generalized vulvodynia. Therefore, although there is no strong scientific evidence to support the use of anticonvulsants, their prescription based on the clinical expertise of the gynaecologist should not be eliminated altogether, especially in specific therapy-resistant cases. It is possible that different subtypes of vulvodynia react differently to the same anticonvulsant. Therefore, in future research, it would be interesting to distinguish between patients with generalized and localized vulvodynia. Studies might focus on gabapentin and lamotrigine, but also on carbamazepine in the management of vulvodynia. Furthermore, correction must be made for the placebo effect. It is widely acknowledged that the (double-blinded) administration of placebo treatment can lead to the expectation of pain relief and result in significant placebo analgesic effects [15].
CONCLUSION
Based on the results of the present critical review of the literature, there is insufficient evidence to recommend anticonvulsants for the treatment of vulvodynia. Prospective studies and double-blind, randomized-controlled studies are urgently needed to investigate the effectiveness of anticonvulsant therapy in the management of (refractory) vulvodynia.
ACKNOWLEDGEMENTS
We would like to thank J. Abma-Hill for editing the English. Anticonvulsant pharmacotherapy for generalized and localized vulvodynia | 51
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26. Gabriel A. Lamotrigine adjunctive treatment 28. Bates CM, Timmins DJ. Vulvodynia–new in resistant unipolar depression: an open, and more effective approaches to therapy. descriptive study. Depress Anxiety 2006;23: Int J STD AIDS 2002;13:210–2. 485–8. 27. Ventolini G, Barhan S, Duke J. Vulvodynia: a step-wise therapeutic prospective cohort study. J Obstet Gynaecol 2009;29:648–50. CHAPTER 3 Long-Term Results of an Individualized, Multifaceted, and Multidisciplinary Therapeutic Approach to Provoked Vestibulodynia
Symen K. Spoelstra Jeroen R. Dijkstra Mels F. van Driel Willibrord C.M. Weijmar Schultz
J Sex Med 2011;8(2):489-496 54 | CHAPTER 3
ABSTRACT
Introduction. Although it is highly recommended to use a multifaceted approach to treat provoked vestibulodynia (PVD), the large majority of treatment studies on PVD used a one-dimensional approach.
Aim. To evaluate the long-term treatment outcome of a multifaceted approach to vulvar pain, sexual functioning, sexually related personal distress, and relational sexual satisfaction in women with PVD.
Methods. Retrospective questionnaire survey 3–7 years after treatment.
Main Outcome Measures. Sexual functioning, sexually related personal distress, and relational sexual satisfaction were measured using the Female Sexual Function Index (FSFI), the Female Sexual Distress Scale (FSDS), and the Dutch Relationship Questionnaire (NRV), respectively. An additional questionnaire assessed socio-demographic variables, intercourse resumption, and the level to which the women would recommend the treatment to other women with PVD. Post-treatment vulvar pain scores were obtained using a visual analog scale (VAS). Pretreatment scores were reported in retrospect on a separate VAS.
Results. The questionnaires were completed by 64 out of 70 women (91%). Mean follow-up was 5 years (range 3–7). Comparison of the mean pretreatment and post- treatment VAS scores showed a significant reduction in vulvar pain. Pain reduction was reported by 52 women (81%), whereas no change and pain increase were reported by 7 women (11%) and 5 women (8%), respectively. Post-treatment, 80% of the women had resumed intercourse. Only 5 women (8%) reported completely pain-free intercourse. Comparisons with age-related FSFI and FSDS Dutch norm data showed that scores for sexual functioning in the study group were significantly lower, while scores for sexually related personal distress were significantly higher. There were no significant differences in relational sexual satisfaction ratings between the study group and the NRV Dutch norm data.
Conclusion. These retrospective data on long-term treatment outcome support the hypothesis that a multifaceted approach to PVD can lead to substantial improvements in vulvar pain and the resumption of intercourse. Long-term results of a multidimensional approach to provoked vestibulodynia | 55
INTRODUCTION
Provoked vestibulodynia (PVD) was originally described by Skene in 1889 [1]. It is believed to be the most frequent cause of chronic, superficial burning vulvar pain at intercourse in premenopausal women [2]. PVD affects 12% of women in the general population [3] and has been estimated to affect 15% of women who visit gynaecological outpatient 3 clinics[4]. The vulvar pain is associated with sexual, psychological, and relational distress [5]. Friedrich defined PVD as vulvar pain at attempted vaginal entry (e.g., intercourse, tampon, and finger insertion), tenderness to pressure with cotton tips within the vulvar vestibule, and vestibular erythema in various degrees [6]. However, erythema is not a strong and reliable diagnostic criterion, because its presence and severity are subject to clinical judgement [7]. Other information is usually taken into account to diagnose PVD in addition to Friedrich’s criteria, e.g., the presence of symptoms for at least 3–6 consecutive months and the exclusion of other causes of acquired superficial dyspareunia [8]. The etiology of PVD is considered multifactorial, including physical factors (inflammatory reactions, infections, antigen, genetic, and hormonal influences) and psychosexual factors. Hypertonicity of the pelvic floor muscles has also been demonstrated [9]. According to the neuro-matrix theory, pain results from activity in the neural network rather than directly from sensory input evoked by injury, inflammation, or other pathology [10]. Dysfunction of the neuronal system (neuropathic pain) should also be considered in the pathogenesis of PVD [11–16]. There is no consensus about the treatment approach to PVD. During the International Consultations on Sexual Dysfunctions in 2004, a multidimensional and multidisciplinary approach was advocated, with specific attention to six main areas: the mucous membrane, the pelvic floor, the experience of pain, sexual and relational functioning, psychosocial adjustment, and genital/sexual abuse [17] Nevertheless, the majority of treatment studies on PVD used a one-dimensional approach. Until now, only three studies have been published on a multifaceted and multidisciplinary treatment approach. However, their follow-up period was limited (8, 30, and 6 months, respectively) [18–20]. In most of the studies on PVD, the success rate of treatment was exclusively related to the degree of persistent coital vulvar pain. Other factors that might influence overall treatment outcome, e.g., quality of sexual functioning, sexually related personal distress, 56 | CHAPTER 3
relational sexual satisfaction, awareness that painless intercourse can be achieved, and intercourse resumption, have rarely been analyzed [21]. In the present study, we evaluated the outcome of a multifaceted and multidisciplinary treatment approach, while taking into consideration multiple domains of functioning that are affected by this distressing pain problem.
AIM
The purpose of our study was to evaluate the long-term treatment outcome of an individualized, multifaceted, and multidisciplinary therapeutic approach to coital vulvar pain, sexual functioning, sexually related personal distress, and relational sexual satisfaction in women diagnosed with PVD.
METHODS
A retrospective questionnaire was administered to 64 women diagnosed with PVD who had received individualized, multifaceted, and multidisciplinary treatment (Table 1) at the University Medical Center in Groningen (UMCG) between 2002 and 2006. Based on the results of a prospective randomized and multifactorial study at the UMCG (the Netherlands) in 1996, we concluded that an individualized, multifaceted, and multidisciplinary therapeutic approach is the treatment of choice for women diagnosed with PVD [18]. An integrated approach was taken: thorough evaluation of the complaint and a tailored course of action that consisted of conservative local measures (i.e., vaginal electromyogram [EMG] biofeedback and pelvic floor physiotherapy, sex therapy, and/or psychotherapy), and in some cases - after careful deliberation with the patient and when applicable also the partner - surgical intervention [22,23]. This approach was conducted by a multidisciplinary team consisting of a coordinating gynecologist/ sexologist, registered pelvic floor physiotherapists, and registered psychologists and sexologists. All the women received steps 1–9 and if appropriate, step 10, 11, or 12. Therefore, psycho- therapy and surgery did indeed form part of the multifaceted approach. At the time of treatment, the women were either sexually active without penetration or sexually abstinent. At the first visit, all the women were seen by a gynecologist/sexologist (W.W.S) at the gynecological department of the UMCG. After an educative gynecosexological examination and, if appropriate, cultures, vulvoscopy, and dermatological consultation (to exclude other causes of superficial vulvar pain), the diagnosis was confirmed. To take part in the present study, women were required to meet the following inclusion Long-term results of a multidimensional approach to provoked vestibulodynia | 57
criteria: (i) self-reported, superficial vulvar pain at attempted vaginal entry (e.g., intercourse, tampon- and finger insertion); (ii) tenderness of the vestibular area even upon light touching with a cotton tip; (iii) presence of symptoms for at least 6 consecutive months; and (iv) exclusion of all other causes of acquired superficial dyspareunia (including vaginismus). Although erythema is usually present, it was not an inclusion criterion. 3 In February 2009, women who met our inclusion criteria were invited by phone to participate in this study by an independent researcher. Participants gave informed consent. Between March 2009 and April 2009, a letter of introduction and a battery of questionnaires (visual analog scale [VAS], Female Sexual Function Index [FSFI], Female Sexual Distress Scale [FSDS], and Dutch Relationship Questionnaire [NRV]) were sent to the participants to obtain data on the long-term post-treatment situation. Upon receipt the completed questionnaires, all relevant patient data were retrieved and transferred into an anonymous, password-protected, database. The identity of the participants was protected by study-specific, unique patient codes; true identity was only known to one dedicated data manager. According to Dutch regulations, these precautions meant that no further institutional review board approval was needed (http://www. federa.org/).
VAS To obtain pretreatment coital vulvar pain measurements, the women were asked to indicate their score in retrospect on a horizontal VAS. Post-treatment outcome scores were reported on a separate VAS. The VAS is widely recognized as a quantitative index of pain [24,25]. It consisted of a 10-cm line anchored at the end points with the words “no pain” at 0 and “worst possible pain ever experienced” at 10.
FSFI The participants filled in the FSFI to obtain long-term outcome data. It is a brief, self- report measure of female sexual function composed of six subscales: desire, arousal, lubrication, orgasm, satisfaction, and pain. Total FSFI score can range from 2 to 36. Lower scores indicate poorer sexual functioning. A Dutch language version of the FSFI was used. The internal consistency of the FSFI within our sample was high (Chronbach’s alpha = 0.96). In accordance with Ter Kuile et al. we report the total score, because the discriminative value of the total FSFI score is on par with the combined use of the six subscales. For comparison purposes, norm values were used that were obtained from 58 | CHAPTER 3
108 Dutch women without sexual problems during validation of the Dutch version. Mean age of the comparison population was 27.1 years (SD 9.4) [26–28].
Table 1. The multifaceted and multidisciplinary therapeutic approach
1. Careful history taking 2. An educative gyneco-sexological examination that the patient was able to follow with a hand mirror (and when applicable with the partner present) 3. Providing information about provoked vestibulodynia (PVD), its natural course, treatment options, and a treatment plan 4. Involvement of the patient and partner in the decision process about potential treatment options 5. Prescription of an inert cream (simple eye ointment) to protect the vestibular area and to urge the woman to touch the painful area (mucosal desensitization) 6. Vaginal EMG biofeedback, pelvic floor physiotherapy (by a registered pelvic floor physiotherapist) with the aim of alleviating pelvic floor hypertonia 7. Homework assignments that comprised self-exploration of the genitals and biofeedback by means of digital control, or with the aid of vaginal dilators and lubricants, together with a temporary coitus prohibition 8. A hygienic protocol, e.g., no vaginal douching, no press-on panty liners 9. Normalizing, reframing, and encouraging sexual activity without penetration to avoid development of feelings of guilt 10. If appropriate, individual sexological counseling that aimed to improve the woman’s self- image, body-image, and autonomy, with the aid of a registered psychologist/sexologist 11. If appropriate, sexological partner-relation therapy that primarily aimed to improve physical and noncoital sexual contact, with the aid of a registered psychologist/sexologist 12. If appropriate in some cases of persistent PVD, surgical intervention (vestibulectomy) as an additional form of treatment to facilitate breaking the vicious circle of irritation, pelvic floor muscle hypertonia, and sexual maladaptive behavior [18]. Surgery was performed by a gynecologist/sexologist (W.W.S).
FSDS The participants filled in the FSDS in relation to their experience over the previous 30 days to assess sexually related personal distress in the long-term. The FSDS consists of 12 items about negative feelings and problems that were bothersome or had caused distress during the past 30 days. Total FSDS score can range from 0 to 48. Higher scores indicate greater sexual distress. A Dutch language version of the FSDS was used. The internal consistency of the FSDS full scale score within our sample was high (Chronbach’s alpha = 0.96). For comparison purposes, norm values were used that were obtained from 108 Dutch women without sexual problems during validation of the Dutch version [29]. Long-term results of a multidimensional approach to provoked vestibulodynia | 59
NRV NRV was used to obtain data on various aspects of the women’s intimate relationship. It consists of 80 items, divided into five subscales: independence, emotional solidarity, identity, conflict handling, and sexuality. The total NRV score provides a general impression of the quality of the relationship. In this study, we only report the total score 3 on the scale “sexuality” (SE). Low scores indicate lower sexual satisfaction and poorer sexual compatibility. The internal consistency of the NRV within our sample was high (Chronbach’s alpha = 0.82). For comparison purposes, we used a specific norm group of 2,059 women without dyspareunia, whose mean age was 45.3 years (SD 12.9) [30].
Statistical Analysis Data were analyzed using the statistical analysis program SPSS, version 16.0 (SPSS Inc., Chicago, IL, USA). To test for significant differences in vulvar pain between the pretreatment VAS score and the post-treatment VAS score, paired T-tests were used. Significant differences in the FSFI, FSDS, and NRV scores between our participants and the (age-related) norms from the comparison groups were tested by calculating 95% confidence intervals.
RESULTS Patient Characteristics A total of 70 women met our inclusion criteria. An independent researcher approached them by telephone and 64 (91%) agreed to participate and gave informed consent. Four women dropped out because they found the questions too intimate and two more dropped-out due to lack of motivation. Mean follow-up was 5 years (range 3–7). Characteristics of the women (N = 64) at the time of our questionnaire survey are shown in Table 2. There were no significant correlations between the socio-demographic characteristics of the participants and the outcome variables. All of the women (N = 64) had received treatment steps 1–9 (as shown in Table 1.), while 27 women (42%) had also received psychotherapy and 15 women. (23%) had undergone surgery. Mean duration of treatment was 148 weeks. 60 | CHAPTER 3
Table 2. Characteristics of the study population at the time of the questionnaire survey
Study population (N=64) Mean (range) or N Data % Age (yrs) 29.3 (20-39) --- Duration of symptoms (years) < 2 9 14 3-5 30 47 6-10 15 23 > 10 10 16 Vestibulodynia Primary 38 59 Secondary 26 41 Civil state Married 23 36 Single 8 13 Living together 29 45 Relationship, but not living together 4 6 Highest education University 12 18 Higher education 24 38 Secondary education 28 44 Sexual abuse Yes 16 25 No 48 75 Tricyclic antidepressants Yes 3 5 No 54 84 Other medication 7 11 Use of oral contraceptive Yes 26 41 No 27 42 Other contraceptive 11 17 Nulliparous Yes 21 33 No 43 67
Coital Vulvar Pain Table 3 shows the VAS vulvar pain scores pretreatment and post-treatment, and also the vulvar pain reduction after treatment. Paired T-tests revealed significant reductions in pain (P < 0.001). Vulvar pain reduction following individualized, multifaceted treatment was reported by 81% (N = 52) of the women; 11% (N = 7) reported no change, and 8% (N = 5) reported Long-term results of a multidimensional approach to provoked vestibulodynia | 61
increase in pain. Post-treatment, 80% of the women had resumed intercourse. Only five women reported completely pain-free intercourse.
Table 3. Visual analog scale vulvar pain scores pretreatment, post-treatment, and vulvar pain reduction after treatment (mean score and SD)
Patient population 3 (N=64) Vulvar pain pre-treatment 7.4 (SD 1.4) Vulvar pain post-treatment 3.8 (SD 2.8) Vulvar pain reduction 3.6 (SD 2.9)*
*P < 0.001
Sexual Functioning, Sexually Related Personal Distress, and Relational Sexual Satisfaction Table 4 shows the FSFI, FSDS, and NRV-SE scores post-treatment. Quality of sexual functioning on the FSFI was significantly lower than the norm in the age-related Dutch comparison group, while sexually related personal distress on the FSDS was significantly higher. There were no significant differences in relational sexual satisfaction between the study population and the norm in the Dutch NRV comparison group.
Table 4. Sexual functioning (FSFI), sexually related personal distress (FSDS) and relational sexual satisfaction (NRV-SE) in the study population and comparison groups (mean score and SD) Study population Comparison group(s) (N=64) 19.7 (SD 3.5) 31.2 (SD 3.9) FSFI 18.5-20.1* (N=108) 18.6 (SD 13.2) 5.1 (SD 6.4) FSDS 14.5-21.0* (N=108) 8.0 (SD 2.7) 7.8 (SD 3.2) NRV-SE 7.4-8.8* (N=2,059) *95% confidence interval. FSFI = Female Sexual Function Index; FSDS = Female Sexual Distress Scale; NRV-SE = Dutch Relationship Questionnaire-Sexuality.
Recommendation of the Treatment to Other Women with PVD A high percentage (80%) of the women reported that they would recommend similar multifaceted and multidisciplinary treatment to other women with PVD. 62 | CHAPTER 3
DISCUSSION
Since 1996, a multifaceted therapeutic approach has been recommended for the treatment of PVD [17,18,22]. However, the majority of treatment studies on PVD used a one-dimensional approach [17,18,22,31–37]. Although a one-dimensional approach is preferable to asses the therapeutic outcome of one specific intervention, its singularity will also undoubtedly affect the ultimate results. These one-dimensional studies, with pain reduction during intercourse as the most important outcome criterion, demonstrated that vaginal EMG biofeedback combined with pelvic floor physiotherapy, cognitive behavioral therapy, and vestibulectomy are useful interventions. Success rates were 50–70%, 40–50%, and 61–93%, respectively [17]. An explanation for the high success rates of vestibulectomy is that women might consider the radical removal of painful structures as the maximum acknowledgement of their PVD. However, in the literature, 9% of vestibulectomy participants reported increased pain at long-term follow-up [22]. In this study, we evaluated the long-term treatment outcome of an individualized, multifaceted, and multidisciplinary therapeutic approach. Significant vulvar pain reduction was observed between pretreatment and post-treatment in 52 women (81%). However, seven women (11%) reported no change and five women (8%) reported an increase in vulvar pain. Post-treatment, 80% of the women had resumed intercourse, but only five women reported completely pain-free intercourse. Thus, even after a “successful” therapy outcome (81% pain reduction), intercourse remained a hypersensitive act in the majority of these women [19]. This was also reflected in our findings that the quality of sexual functioning was significantly lower than the FSFI norm, while sexually related personal distress was significantly higher than the FSDS norm. However, we did not find any significant differences in relational sexual satisfaction between the study population and the NRV comparison group, which might mean that these women were able to adapt to the circumstances, despite the persistence of vestibular pain. Many women with PVD stress that their partner becomes angry and frustrated at the infrequency and low quality of their sex life. This results in loss of excitement and intimacy for both partners [38]. Avoidance reactions are common, and may obstruct the sexual rehabilitation [39]. In our opinion, strengthening of the intimacy aspects of the sexual relationship continues to be a crucial element in the recovery process of women with PVD. Long-term results of a multidimensional approach to provoked vestibulodynia | 63
Ultimately, the couple will need to renegotiate their sexuality and intimacy after the diagnosis of PVD, in the same way gynecological cancer patients do [40,41]. Thus, they need to find a way to continue their sexual relationship, despite the presence of symptoms. There is evidence that psycho-educational interventions can improve sexual functioning 3 under these circumstances [35]. Although we did not measure this impact, we believe that our multifaceted treatment offers all the ingredients to achieve improvement from this angle. It was striking, for example, that 80% of our participants would recommend the multifaceted approach to other women with PVD. PVD probably encompasses mechanisms of neurogenic inflammation as well as neuropathic pain (as is also the case in other related pain conditions). Such a combination may lead to the development of sexual pain disorders, with less efficient pain modulating processing [17]. At present, we do not have the tools to completely correct disturbances in pain modulating processes. Thus, the pain may persist to a greater or lesser extent, despite the removal of all the factors related to the development, maintenance, or exacerbation of PVD symptomatology. This might explain the persistence of low scores on sexual functioning after treatment. In our opinion, it is important that women with PVD should be fully informed about this inability prior to starting treatment. Until now, only three studies have been published on the multifaceted therapeutic approach to PVD [18–20]. Schover et al. employed structural collaboration between a gynecologist and a psychologist to evaluate and treat 32 women with PVD. Their comprehensive treatment approach comprised local excision of vulvar lesions and consultations with the psychologist, including Kegel exercises, vaginal dilation, and couple therapy [19]. After a mean follow-up of 8 months, the success rate was 40–60%. This somewhat disappointing result might have been caused by the short duration for the psycho-sexual intervention, which, on average, was only two or three consultations. Weijmar Schultz et al. treated 48 women with PVD in the first phase of their study using behavioral therapy (with or without preceding surgery). In the second non-randomized part of the study, the women and their partners were given the choice of whether or not to include surgery. The nonsurgical approach was chosen first by 82% of the women. At 2 to 3 years after treatment, 79–89% of the women reported positive effects from the intervention: their complaints had disappeared, diminished, or (although unchanged) were considered to be less of a problem. The differences in outcome between the treatment groups were not statistically significant [18]. 64 | CHAPTER 3
Backman et al. offered standardized physiotherapy and psychosexual therapy to 24 patients with PVD. A midwife supervised exercises for mucosal desensitization and reestablishment of the pelvic floor muscle function. Follow-up measurements were performed after 6 months. The mean number of appointments with the psycho-sexual counsellor was 12 (range 4–24), while the mean number with the midwife was 12 (range 9–26). Surgery was not an option. In the group of 24 women, 19 (79%) considered themselves to be cured or greatly improved [20]. In our study the mean duration of individualized, multifaceted and multidisciplinary treatment was 148 weeks, which was considerably longer than other studies. This may have been due to our specific population of patients, who were referred from all over the Netherlands due to “therapy-resistance”. The present study has a number of shortcomings. It was retrospective; there was a lack of pre-treatment measures in the questionnaires; and there was no control group. Therefore, the outcome of the study should be interpreted as purely “preliminary.” Nevertheless, the results make a significant contribution, given the scarcity of existing research into the multifaceted treatment approach. In addition, the positive effects of an individualized, multifaceted, and multidisciplinary approach to PVD are emphasized and in comparison with other studies, the duration of follow-up was longer. The study clearly demonstrates that PVD goes far beyond the experience of pain. Long- term, randomized, multifaceted, and prospective studies are needed and should not be restricted exclusively to pain reduction, but should also include other factors that influence treatment outcome, e.g., the quality of sexual functioning, sexually related personal distress, relational sexual satisfaction, awareness that painless intercourse can be achieved, and intercourse resumption.
CONCLUSIONS
Our individualized, multifaceted, and multidisciplinary treatment approach to PVD led to vulvar pain reduction in the long-term in more than 80% of the women. We also found that 80% had resumed intercourse and 80% would recommend a similar multifaceted therapeutic approach to other women with PVD. Although these data were gathered in retrospect, they support the hypothesis that an individualized, multifaceted, and multidisciplinary therapeutic approach can have positive long-term effects. However, even after what can be considered as “successful” therapy outcomes, intercourse remained a hypersensitive act in the majority of women. Therefore reinforcement of Long-term results of a multidimensional approach to provoked vestibulodynia | 65
the intimacy aspects within the sexual relationship may constitute a major theme in the treatment of PVD.
ACKNOWLEDGEMENTS
We gratefully acknowledge Astrid Pascal, Anneke Kuyk, Charmaine Borg, Vijaya Faber, 3 Janneke van der Velde, and Mike Balkema for their comments on an earlier version of the manuscript. 66 | CHAPTER 3
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CHAPTER 4 Transcutaneous Electrical Nerve Stimulation as an Additional Treatment for Women Suffering from Therapy-Resistant Provoked Vestibulodynia; a Feasibility Study
Marleen S. Vallinga Symen K. Spoelstra Inge L.M. Hemel Harry B.M. van de Wiel Willibrord C.M. Weijmar Schultz
J Sex Med 2015;12(1):228-237 70 | CHAPTER 4
ABSTRACT
Introduction. The current approach to women with provoked vestibulodynia (PVD) comprises a multidimensional, multidisciplinary therapeutic protocol. As PVD is considered to be a chronic pain disorder, transcutaneous electrical nerve stimulation (TENS) can be used as an additional therapy for women with otherwise therapy-resistant PVD.
Aims. The aims of this study were to evaluate whether TENS has a beneficial effect on vulvar pain, sexual functioning, and sexually-related personal distress in women with therapy-resistant PVD and to assess the effect of TENS on the need for vestibulectomy.
Methods. A longitudinal prospective follow-up study was performed on women with therapy-resistant PVD who received additional domiciliary TENS. Self-report questionnaires and visual analog scales (VASs) were completed at baseline (T1), post- TENS (T2), and follow-up (T3).
Main Outcome Measures. Vulvar pain, sexual functioning, and sexually-related personal distress were the main outcome measures.
Results. Thirty-nine women with therapy-resistant PVD were included. Mean age was 27 ± 5.6 years (range: 19 to 41); mean duration between TENS and T3 follow-up was 10.1 ± 10.7 months (range: 2 to 32). Vulvar pain VAS scores directly post-TENS (median 3.4) and at follow-up (median 3.2) were significantly P ( < 0.01) lower than at baseline (median 8.0). Post-TENS, sexual functioning scores on the Female Sexual Functioning Index questionnaire had improved significantly P( = 0.2); these scores remained stable at follow-up. Sexually-related personal distress scores had improved significantly post-TENS (P = 0.01). Only 4% of the women who received TENS needed to undergo vestibulectomy vs. 23% in our previous patient population.
Conclusion. The addition of self-administered TENS to multidimensional treatment significantly reduced the level of vulvar pain and the need for vestibulectomy. The long-term effect was stable. These results not only support our hypothesis that TENS constitutes a feasible and beneficial addition to multidimensional treatment for therapy- resistant PVD, but also the notion that PVD can be considered as a chronic pain syndrome. TENS in women with therapy-resistant provoked vestibulodynia | 71
INTRODUCTION
Provoked vestibulodynia (PVD) is a subtype of vulvodynia characterized by pain in a certain area of the vulva [1,2]. The main complaint of woman with PVD is vulvar pain during sexual intercourse, although the pain can also be triggered by other forms of pressure, such as wearing tight clothes or inserting a finger or tampon [3]. PVD is the most common cause of dyspareunia before menopause [4]; it affects 16% of women in the general population [5]. 4 Friedrich defined PVD as vestibular pain at attempted vaginal penetration, vulvar vestibular pain on touching with a wet cotton tip (positive touch test), and varying degrees of vestibular erythema [6]. However, erythema does not appear to be a useful diagnostic criterion, because the clinical judgment of its presence and severity is subjective [7]. In daily clinical practice, two other criteria are considered relevant: symptoms should be of at least three to six consecutive months’ duration and other causes of acquired superficial dyspareunia must be ruled out [8]. Besides its influence on sexual functioning, PVD can strongly affect other quality of life aspects, e.g., psychological and relational functioning [9,10]. The etiology of PVD is still not fully understood. Traditionally, it was classified as a sexual dysfunction, but in the light of prevailing theories, which lean toward neurogenic inflammation and changes in local innervation and central pain processing [11], PVD is more likely to be a chronic pain disorder [4,12,13]. Owing to the lack of any clear etiology, PVD is considered to be a heterogeneous, multisystemic, and multifactorial disorder that should be treated with an individualized, multidimensional, and multidisciplinary approach [3,14]. The multidimensional treatment protocol encompasses six main areas [15]: the mucous membrane, the pelvic floor, the experience of pain, sexual and relational functioning, psychosocial adjustment and, if applicable, genital/sexual abuse. If none of these lines of action provide the desired result, the final treatment option at our clinic is vestibulectomy. Spoelstra et al. found that after multidimensional treatment, vestibulectomy had been necessary as a last resort in 23% of the women [16]. From a medical perspective, this high-impact surgery is an ultimum refugium, because it is irreversible and invasive. The purpose of vestibulectomy is to remove the painful tissue from the vulvar vestibule, presumably including pain receptors or pro-inflammatory molecules [3]. Some studies reported success rates of 61–94% for vestibulectomy [17]. Bergeron et al. encountered in their patient population (n = 29) a deterioration in vulvar pain at long-term follow-up in 9% of cases [7]. 72 | CHAPTER 4
We therefore searched for a less intrusive treatment for PVD than vestibulectomy to enhance the therapeutic power of the multidimensional approach. One option is (domiciliary) transcutaneous electrical nerve stimulation (TENS) because of its positive effects in other chronic pain conditions [18] and its low impact. Possible complications of TENS are known to be skin irritation, electrode adherence problems and difficulty attaching the electrodes, skin rash, and a burning sensation at the electrode site [18]. TENS is believed to have two mechanisms for relieving pain. The first is the gate- control theory, which postulates presynaptic inhibition of pain signals by stimulation of non-nociceptive afferent neurons [19]. Activation of βA -nerve fibers might attenuate pain signals from nociceptor C-fibers on interneuronal and spinal levels. The second mechanism is believed to use the descending pain suppression pathway, which originates in the cortex and is therefore called supraspinal inhibition [20–22]. The first to study electrical stimulation (ES) in the management of sexual pain disorders were Nappi et al. [23]. They found that after weekly intravaginal ES with a probe in their patient population of 29 women with vestibular pain, dyspareunia, or vaginismus, the vestibular pain significantly declined. At present, only three short-term studies have been published on the use of TENS for PVD [24–26]. The effect of treating PVD with TENS was first studied by Murina et al. [24]. Placebo TENS was compared with functional TENS in a randomized controlled trial (RCT) on women with vestibulodynia with 3 months follow-up. They used a vaginal probe to administer functional or sham TENS in a clinical setting, twice a week. A significant difference in vulvar pain reduction was found between placebo and functional TENS [24]. In an evaluative study, Dionisi et al. [26] found that weekly biofeedback in combination with TENS and functional ES led to improvements in vulvar pain in 76% of the subjects. They also used an endo-vaginal probe to administer TENS. The visual analog scale (VAS) was used to measure vulvar pain directly post-TENS treatment. In 75.8% (110/145) of the women in this study, vulvar pain lowered after TENS treatment. Recently, Murina et al. performed an RCT in which all the subjects received domiciliary TENS treatment and either a combination of palmitoylethanolamide (PEA) + transpolydatin or a placebo. In contrast with the University Medical Center Groningen (UMCG) protocol, which recommends TENS treatment three times daily, these subjects were advised to use TENS three times weekly. Vulvar pain and dyspareunia scores were significantly lower posttreatment than at baseline. Additional treatment with PEA and transpolydatin was only effective in the subjects with recent onset PVD or relapse. It was concluded that TENS (self-administered in a home setting) can be of benefit in the management of vestibulodynia [25]. However, in the existing studies on TENS for PVD, it is not clear TENS in women with therapy-resistant provoked vestibulodynia | 73
whether the women had completed multidimensional treatment before receiving TENS. Owing to the multisystemic and multifactorial nature of PVD, the effectiveness of treatment should not only depend on vulvar pain and dyspareunia reduction but also on the ability to resume and experience satisfactory sexual intercourse and to reduce sexually-related distress. Until now, knowledge about the long-term feasibility of domiciliary TENS is lacking. The present study aims to determine whether domiciliary TENS is a feasible additional 4 treatment in the multidimensional approach to women with therapy-resistant PVD.
MATERIALS AND METHODS Study Design A longitudinal non-placebo controlled cohort study was performed to test the feasibility of TENS as an additional treatment for an end-of-the-line population with therapy- resistant PVD.
Participants The study was comprised of 39 women between the ages of 19 and 41, who were diagnosed with PVD by an experienced gynecologist annex sexologist at the UMCG. They received supplementary domiciliary TENS treatment between July 2009 and August 2013. A certified pelvic floor physiotherapist instructed the women on the proper use of TENS. Eligible candidates were required to be able to read and speak the Dutch language and be willing to give signed informed consent. Exclusion criteria were a cardiac pacemaker and/or pregnancy. All the women diagnosed with PVD underwent multidimensional treatment according to the UMCG protocol, which was based on the results of two studies at the UMCG in 1996 and 2011 [15,16]. The treatment was also in accordance with the recommendations of the 3rd International Consultation on Sexual Medicine (2009). Patients who did not experience sufficient pain reduction on completion of the multimodal approach received additional (domiciliary) TENS treatment. They answered questionnaires directly before starting TENS (T1 = baseline) and at the end of TENS (T2 = post-TENS) to measure vulvar pain, sexual functioning, and sexually related personal distress. At long-term follow-up between January and August 2013 (T3), the women were asked to complete the same questionnaires and a separate general questionnaire on demographic and clinical characteristics (see Figure 1). All the questionnaires were coded and upon receipt, transferred to an anonymous database. The key to the codes was held by the data manager. 74 | CHAPTER 4
Approval for the study was requested from the institutional review board, but as there were no interventions besides questionnaires, the institutional review board considered this study to be an evaluation of standard health care. Consequently, this study did not fall under the legislation of the Dutch law on medical research into humans.
Diagnosis Satisfactory PVD Multidimensional effect approach
Pre- No benefit treatment T1
TENS Post- treatment T2 No benefit Satisfactory effect
Operation No operation Follow-up T3
Figure 1 | Flowchart of the study design. Women diagnosed with PVD underwent multidimensional treatment. TENS was offered when this approach did not achieve sufficient pain reduction. Questionnaires were completed pre-TENS (T1), post-TENS (T2), and at follow-up(T3) to measure vulvar pain, sexual functioning, and sexually-related personal distress. PVD = provoked vestibulodynia; TENS = transcutaneous electrical nerve stimulation.
TENS Procedure PRIMO PRO equipment from CEFAR Medical AB (Malmö, Sweden) was used. This device had a dual channel setup. Adhesive electrodes were applied to the labia majora (on intact, clean, and non-greasy skin) in a V-shape (caudally on both sides of the introitus; cranially angled toward the groin). The electrodes used were oval and are 4.0 by 6.5 centimeters. If women had trouble with these electrodes, i.e., they did not adhere to the skin or caused mild skin irritation, then alternative electrodes were used that were square and 5.0 by 5.0 centimeters. There was no known difference in efficacy between electrodes, only size and adhesive substance. But difference in size was not considered to be relevant as long as the electrodes are placed over the nerves that innervate the introitus of the vagina. TENS frequency was 80 Hz with a pulse duration of 50 or 180 microseconds. Women started with 180 microseconds pulse duration; if this duration proved too sensitive for women, setting was changed by the physiotherapist to 50 microseconds for the remaining treatment. Pulse intensity was increased to the maximal TENS in women with therapy-resistant provoked vestibulodynia | 75
level that was still comfortable. To ensure good adherence of the electrodes and prevent irritation by “waxing” the skin, women were advised to shave the labia majora once a week and not to use the TENS device on the day of shaving to prevent irritation. After initial administration of the TENS by a pelvic floor physiotherapist, the women received one or two instruction sessions. The number of sessions depended on how swiftly each individual learned the procedure. They then applied the TENS treatment themselves two to three times a day at home at their own convenience, for a total duration of 90 4 minutes per day. Patients were instructed to continue the treatment for at least 12–16 weeks. The women returned to the physiotherapist after 6–8 weeks to evaluate the TENS treatment. If a patient no longer required TENS (i.e., the complaints had diminished to her satisfaction), the treatment was stopped. Patients were free to choose their own application protocol, for instance, twice a day for 45 minutes. The total duration of treatment and the amount of time spent per week depended on how the women experienced the TENS treatment. Recommended use of TENS was three times daily for a total duration of 90 minutes. Time until benefit varied per woman and was not recorded objectively. After their last appointment with the physiotherapist, the patients kept the TENS equipment. They were then free to use it according to their needs and wishes. Some patients told the physiotherapist that they still used TENS occasionally when their symptoms required. Thus, the patients became independent and were given the means to direct their own treatment. No data were gathered on the use of TENS after long-term follow-up (T3).
Questionnaires Demographic and Clinical Variables A single investigator collected all the data. General demographic and clinical data were obtained at prospective follow-up using a general questionnaire. These data included inter alia, age, marital status, and the use of medication and/or contraception. Additional data were obtained on pregnancy, childbirth and complications during and/or afterward, the presence of dyspareunia at the first (attempt at) sexual intercourse, current pain level during sexual activity and/or intercourse, and whether the women were able to have satisfactory intercourse at follow-up (T3). The women were also asked posttreatment at follow-up (T3) if they would recommend TENS treatment to other women with PVD.
Vulvar Pain The McGill Pain Questionnaire–Dutch language version (MPQ-DLV) was used to evaluate the severity of pain and pain perception. The MPQ-DLV contains a VAS and 20 groups of 76 | CHAPTER 4
three to four pain-descriptive words arranged in progressive intensity. Overall intensity of vulvar pain was assessed on a 10-cm VAS on which the subject had to place a mark to indicate her pain level. Zero centimeter means no pain while 10 cm means the worst possible pain imaginable. The minimum VAS score was defined as the lowest level of vulvar pain experienced during the last (attempt at) sexual intercourse. Maximum VAS score was defined as the highest level of vulvar pain experienced during (attempts at) sexual intercourse. The VAS is a wellknown and widely used quantitative method to measure pain [27]. Domain scores on sensory, affective, and evaluative domains of pain were calculated using the number and order of intensity of the descriptive words. The MPQ-DLV is a reliable instrument to measure pain [28]. Total scores can range from 0 to 78. A higher score indicates increased pain and more severe pain perception.
Sexual Functioning Sexual functioning was evaluated using the Female Sexual Functioning Index (FSFI). This is a brief self-report index, which consists of six domains: sexual desire, arousal, lubrication, orgasm, satisfaction,and genital pain. The Dutch version of the FSFI questionnaire is a reliable and valid measurement tool [29]. The total score can vary from 2 to 36. Lower scores indicate poorer sexual functioning. The cutoff score for differentiating between women with and without sexual dysfunction is 26.55 [30].
Sexually-Related Personal Distress The Dutch version of the Female Sexual Distress Score (FSDS) was used to assess personal distress associated with sexual problems. It is known to be a reliable and valid instrument [29]. The total score can range between 0 and 48. Higher scores indicate more personal distress; 15 is the cutoff score of the FSDS [31].
Statistical Analysis IBM SPSS statistics for Windows version 20.0 (Released 2011 IBM Corp, Armonk, NY, USA) was used to analyze the anonymized data from the women with PVD who received additional TENS between July 2009 and August 2013 after standard multidimensional treatment and completed one or more questionnaires at two or more of the data collection times. Quantitative comparisons of the baseline (T1), post-TENS (T2), and follow-up (T3) values on the MPQ-VAS, FSFI, and FSDS were made using nonparametric tests for repeated measures. The scores obtained at the three data collection times mostly had TENS in women with therapy-resistant provoked vestibulodynia | 77
an abnormal distribution. This was tested using q–q plots and histograms. To prevent difficulty with interpretation, all the values were compared using a nonparametric test: Wilcoxon signed-rank test. All the tests were two tailed; significance level was P < 0.05.
RESULTS
A total of 39 women with therapy-resistant PVD were included in this prospective follow- up study. 4 Patient characteristics (at T3) are shown in Table 1. Mean age was 26.7 ± 5.6 years (range: 19 to 41). In 35% of the women, the total duration of symptoms was 3–5 years; in 19%, the duration was shorter, while in 46% the symptoms had been present for more than 6 years. Mean duration of TENS was 6.2 ± 4.0 months (range: 1 to 12).
Table 1 Characteristics of the study population at T3
Study population % Mean or N Age (years) 19-41 26.7 - Duration of symptoms (years) <2 6 19 3-5 11 35 6-9 7 23 9> 7 23 Duration of treatment (months) 1.0-12.0 6.2 - Primary/ lifelong PVD 11 35 Nulliparous 28 90 Medical history Recurrent vaginal candidiasis 7 23 Irritable bowel syndrome 2 6 Depression 4 13 Vestibulectomy 3 10 Civil status Married 4 13 Relationship, living apart 6 19 Living together 9 29 Divorced 1 3 Single 11 35 Highest education level University 5 16 Community college 15 48 Secondary education 8 26 High school 3 10 Negative sexual experiences 10 33 Use of oral contraceptives 13 42 Medication use Tricyclic antidepressants 1 3 Selective serotonin re-uptake 3 10 inhibitors PVD = provoked vestibulodynia; T3 = follow-up 78 | CHAPTER 4
In 65% of the women, the complaints had started after initially pain-free intercourse (secondary PVD). In our study population, 23% (7/31) had a history of recurrent vaginal candidiasis; three women (10%) had undergone vestibulectomy prior to TENS; 13% (4/31) were suffering from depression; and all but one of the women were using a selective serotonin reuptake inhibitor. None of the patients in this study reported pain or local irritation from the electrodes. Mean follow-up (T3) after completion of TENS (T2) was 10.1 ± 10.7 months (range: 2 to 32).
MPQ-DLV: VAS Table 2 shows the vulvar pain VAS scores at the most recent (attempt at) sexual intercourse. VAS, minimum VAS, and maximum VAS scores were significantly lower post- TENS (T2) than at baseline (T1) (median VAS from 8 at T1 to 3.4 at T2, P < 0.001; minimum VAS 5.3 to 2.1, P = 0.01; maximum VAS 8.3 to 6.1, P < 0.001). At follow-up (T3), the scores were not significantly different from those at post-TENS (T2)P ( = 0.74). Figure 2 shows a box plot of the VAS scores. There was a significant decrease in the VAS score after TENS and no significant increase at follow-up.
MPQ-DLV: Pain Descriptive Words At baseline (T1), the women who completed the MPQ-DLV to assess the intensity and characteristics of vulvar pain mostly described the pain as strained (44%), burning, ripping, and scorching (38%). Post-TENS (T2), the words chosen most often were stinging (33%), scorching, and burning (56%). At long-term follow-up (T3), burning (50%), strained (43%), and sharp (32%) were the most common. The scores per domain of the MPQ-DLV are shown in Table 2. Scores were given for the total number of words chosen (NWC-t) and for the sum of the ranks of the words (PRI-t). At post-TENS (T2), NWC-t and PRI-t were significantly lower than at baseline (T1) P( = 0.01 and P < 0.001, respectively). The scores remained at this post-TENS level at follow-up (T3) and were still significantly lower than at baseline (NWC-t,P = 0.02; PRI-t, P = 0.01). TENS in women with therapy-resistant provoked vestibulodynia | 79 P (n*) T2- T3 T2- .42 (12) .72 (16) .72 .81 (18) .73 (16) .73 1.0 (16) .52 (16) .74 (20) .74 .63 (16) .94 (18) .50 (16) .65 (18) .80 (16) .68 (18) P (n*) .07 (8) .07 T1- T3 .01 (22) .01 (22) .01 (22) .01 (22) .01 (25) .07 (22) .07 .49 (22) .02 (25) .08 (22) .06 (22) .00 (22) .00 (28) Statistics 4 P (n*) .01 (14) T1 - T2 T1 .12 (20) .14 (20) .15 (20) .01 (27) .01 (25) .10 (20) .00 (31) .02 (20) .02 (20) .03 (20) .00 (27) .00 (25) value = significance level, two tailed FSDS tailed two = value significance level, n 25 27 27 28 28 28 28 28 28 28 28 28 28 P 0, 3.9 3.7, 5.3 3.7, 2.1, 5.6 2.1, 6.7 3.6, 7.7 3.9, 5.4 4.4, 5.9 3.0, 4.2 0.6, 4.0 8.3, 24.3 6.0, 12.0 13.5, 33.5 21.0, 28.4 Quartiles Follow-up T3 Follow-up 5.2 3.2 2.4 2.0 4.8 4.8 4.6 3.6 9.5 5.9 21.0 23.4 18.0 Median Median n 31 22 22 22 22 22 22 22 27 27 20 26 26 0, 4.4 1.6, 5.2 1.9, 7.0 4.4, 5.7 1.0, 4.3 3.8, 5.4 3.6, 5.5 3.0, 4.4 3.0, 8.2 3.0, 13.0 6.0, 23.0 11.5, 31.8 18.0, 27.5 Quartiles Descriptive - TENS T2 Post 0 2.1 6.1 5.2 3.4 4.8 4.8 3.6 4.0 16.0 20.5 25.0 10.0 Median Median n 15 31 31 34 34 30 30 30 30 30 30 39 30 0, 1.2 2.7, 5.4 2.7, 2.1, 6.2 3.1, 5.6 1.6, 4.4 2.4, 4.2 7.3, 9.3 7.3, 2.4, 4.9 6.6, 8.8 9.0, 15.0 17.8, 32.0 17.8, 14.9, 22.9 27.0, 23.0 27.0, Quartiles Baseline T1 0 8 4.1 5.3 2.6 4.8 3.6 3.0 8.3 19.1 11.0 32.0 24.0 Median Median FSDS FSDS Total Total FSFI FSFI Total Pain Satisfaction Orgasm Lubrication Arousal FSFI Desire PRI-t NWC-t Max VAS Max Min VAS Min MPQ-DLV Score VAS Descriptive values are given as medians (50th percentile) and quartiles (25th and 75th percentiles) of the scores; difference between paired values was calculated analysis included in the statistical observations paired of *Number calculated was values paired between difference scores; the of percentiles) 75th and (25th quartiles and percentile) (50th medians as given are values Descriptive pairs used subjects in or the analysis; of n = number measures; related two between test signed-rank Wilcoxon with = Female Sexual Distress Score; FSFI = Female Sexual Functioning Index; MPQ-DLV = McGill Pain Questionnaire–Dutch language version; NWC-t = total number of of number total = NWC-t version; language Questionnaire–Dutch Pain McGill = MPQ-DLV Index; Functioning Sexual Female = FSFI Score; Distress Sexual Female = analog scale visual = VAS stimulation; nerve electrical TENS = transcutaneous chose; women words the of the ranks chose; PRI-t = sum of women the that words Scores on the three questionnaires at baseline (T1), post-TENS (T2), and follow-up (T3) and follow-up (T2), post-TENS baseline (T1), at questionnaires on the three 2 Scores Table 80 | CHAPTER 4
Figure 2 | Box plot of the VAS vulvar pain scores at baseline (T1), post-TENS (T2), and follow-up (T3). Box plot of the median, upper, and lower quartiles (box) and the minimum and maximum values within 1.5 times the interquartile range (whisker) and outliers (circles). TENS = transcutaneous electrical nerve stimulation; VAS = visual analog scale.
FSFI and FSDS Table 2 shows the median scores and quartiles on the FSFI and FSDS questionnaires at baseline, post-TENS, and follow-up. FSFI domain scores, FSFI total scores, and FSDS total scores were compared. Results of the statistical analysis are shown on the right side of Table 2; T2 and T3 values were both compared with baseline values. FSFI total score was significantly higher post-TENS (T2) than at baseline (T1) P( = 0.02). At post- TENS, there were significant increases in desire and arousal. At follow-up, the changes in desire and arousal were no longer significant. Instead, domain scores on satisfaction and pain reduction were significantly higher than at baseline (T1). The FSDS scores for sexually-related personal distress had improved significantly at post-TENS (T2) P( = 0.01). At T3, the median score was not significantly different from that at post-TENSP ( = 0.42). The percentages of women who had normal FSDS scores (i.e., below cutoff) increased from 13% at baseline to 35% post-TENS and to 36% at follow-up.
General Questionnaire Table 3 shows the results of the general demographic and clinical questionnaire completed by 31 women at follow-up (T3). Post-TENS, 19 (61%) of the women had resumed sexual intercourse. TENS in women with therapy-resistant provoked vestibulodynia | 81
Only 2 out of these 19 women (11%) reported completely pain-free sexual intercourse. However, 79% of these 19 women who completed the questionnaire reported that sexual intercourse was satisfactory. And 87% of the 31 women who completed the general questionnaire at follow-up (T3) would recommend the treatment to other women with PVD. Three of the 31 women underwent a vestibulectomy before TENS. Of the remaining 28 women, only 1 woman underwent additional vestibulectomy after TENS treatment. 4 Table 3 | Status quo post-TENS based on the general questionnaire and a medical file survey (n = 31)
Study population %
Pain during sexual activity 23 /30 77 Resumption of intercourse after TENS 19 /31 61 Intercourse completely pain-free 2/19 11 Able to enjoy intercourse 15/19 79 Subject would recommend TENS to other women with PVD 27 /31 87 PVD = provoked vestibulodynia; TENS = transcutaneous electrical nerve stimulation
DISCUSSION
The aim of this longitudinal non-placebo controlled cohort study was to demonstrate that domiciliary TENS is a feasible and beneficial additional treatment for women with therapy-resistant PVD, i.e., that it leads to pain reduction, less need for surgery, and better sexual functioning. We found that compared with baseline (T1), vulvar pain had decreased significantly post- TENS (T2). At follow-up (T3) (mean duration: 10.1 months), vulvar pain scores were still significantly lower than at baseline (T1). Scores on the MPQ showed that pain intensity perception was significantly lower post-TENS (T2) and that it remained at the same low level at long-term follow-up (T3). Sexual functioning improved significantly after TENS and only deteriorated slightly in the long-term. At follow-up (T3), sexual functioning scores were also significantly higher than at baseline (T1). Before they started TENS, our population of women reported having a high level of personal distress as a result of their PVD related sexual problems. After TENS (T2), this distress level was significantly lower (P = 0.01). The addition of TENS to multidimensional treatment meant that ultimately, only 4% of our study population needed vestibulectomy, in contrast with 23% previously [16]. These results confirm our hypothesis that TENS forms a feasible addition to multidimensional treatment for women with therapy-resistant PVD. This low-impact treatment yielded very positive results. 82 | CHAPTER 4
Our results of TENS on sexual functioning and vulvar pain 10 months post-TENS were in agreement with those reported in the placebo controlled study by Murina et al. [24] after a mean follow-up of 3 months. In the two studies, median VAS scores for vulvar pain decreased significantly. Whereas we used a domiciliary selfadministered TENS protocol with cutaneous electrodes for 90 minutes per day, Murina et al. [24] sent their patients to a physiotherapy clinic where TENS was performed twice a week with a vaginal probe. Our population had a longer history of PVD symptoms (81% had been experiencing symptoms for more than 3 years vs. a mean of 16.8 months in the study by Murina et al. [24]) and the complaints had proved to be relatively more resistant to other (multidimensional) treatment options. In addition, our findings expand upon those of previous studies, as TENS was also beneficial and feasible when applied cutaneously and as a last resort. We opted to apply TENS in a domiciliary protocol because this is patient friendly, cost-effective, and the women could be expected to be more relaxed in their home environment. The results of the present study confirmed the conclusion drawn by Murina et al. [25] that TENS is of significant benefit in the management of PVD, also when applied in a home setting. In addition, we evaluated several extra dimensions to examine the feasibility of domiciliary TENS: the ability to resume intercourse, experience satisfactory intercourse, and reduce sexually-related personal distress. Positive effects of TENS were found on all these dimensions. These are very promising findings, particularly for women with therapy-resistant PVD when taking into account the multisystemic and multifactorial nature of PVD. In 2011, Spoelstra et al. used a comparable broad set of end points to evaluate the effects of multidimensional treatment without the addition of TENS in women with PVD. They observed decreased vulvar pain in 81%, but 23% still had to be referred for vestibulectomy [16]. In the present study, 87% of the women perceived a decrease in vulvar pain and only 4% ultimately needed to undergo surgery. There could be some overlap between the population in the present study and that of Spoelstra et al. in 2011 [16]. In theory, participants in the study by Spoelstra et al. who did not experience sufficient relief (19%) could have been included in the present study. Although some of the population characteristics were different (primary PVD: 59% vs. 35%, nulliparous: 33% vs.90%), all the women had received multidimensional treatment according to the UMCG protocol. Therefore, comparison of the two studies provides valuable information. Probably the most important limitation of the present study was the lack of a placebo control. It is widely acknowledged that the blind administration of a placebo, which gives TENS in women with therapy-resistant provoked vestibulodynia | 83
patients the expectation of pain relief, often has a significant placebo analgesic effect [32]. In the literature, several placebo RCTs have been published on TENS treatment for various types of chronic pain. Oosterhof et al. did not observe any significant difference between TENS and sham TENS in patients with chronic pain. Remarkably enough, they did not find any evidence of long-term placebo effects of sham TENS [33]. In contrast, Murina et al. did find a significant difference in vulvar pain reduction between sham TENS and TENS in women with vestibulodynia [24]. Sluka and Walsh 4 also found that TENS decreased hyperalgesia in animal research, which is less subject to placebo effects [20]. The strong placebo effect found in other PVD treatment studies suggests that women’s realization of the availability of treatment constitutes a powerful psychological component. New sham TENS devices are currently being developed that will enable placebo RCTs on the effectiveness of domiciliary TENS in women with (therapy-resistant) PVD. This study population comprised women with a relatively long duration of symptoms. A relatively high percentage of them had a medical history of depression or recurrent vaginal yeast infections. Compared with the 12-monthly rate of mood disorders in Dutch women aged between 18 and 44 years (7.1%) [34], our population had a relatively high rate (13%). In the present study, nonspecific factors might also play a role - as is the case in all therapies - such as perceived control or attention from the therapist [35]. Additional therapeutic effects might have arisen from the personal attention of the pelvic floor physiotherapist who trained the women to perform the self-administered domiciliary TENS [3,15]. A limitation of this study is the fact that women were highly responsible for their own treatment. Owing to the domiciliary use of TENS, it was not possible to determine the compliance rate. However, the therapist had the impression that most women who underwent this treatment were very motivated to follow the treatment as was prescribed. In some cases, she did check proper use when she doubted compliance dedication to therapy. Also, the very act of placing the cutaneous electrodes could promote familiarity with the genital area and in itself be therapeutic. Another important aspect could be (perceived) control as one of the main nonspecific therapeutic factors [35]. The strong placebo effect found in studies on the treatment of PVD suggests that women’s realization of the availability of treatment holds a powerful psychological component. Our hypothesis that TENS would be beneficial to women with therapy-resistant PVD was supported by the reductions in vulvar pain, (partial) recovery of sexual functioning, reduced sexually related personal distress, and the very high rate of positive 84 | CHAPTER 4
recommendations of TENS to fellow sufferers. This study showed that TENS treatment was a feasible addition to the multidimensional, multifaceted treatment approach. All patients with therapy-resistant PVD should be offered TENS before their gynecologist considers the last resort of vestibulectomy. Even if future research shows a large placebo effect, this does not undermine the benefit of TENS and the absence of irreversible complications for women with therapy-resistant PVD, many of whom have had debilitating symptoms for many years. In this group of women, any effect, however small, represents a giant leap forward in the challenge of treating PVD.
CONCLUSION
In women with therapy-resistant PVD, TENS was a feasible and beneficial additional treatment option. It led to significant decreases in vulvar pain and improvements in sexual functioning in the short and long-term. By adding TENS to the multidimensional treatment approach to PVD, it is possible to reduce the need for invasive and irreversible vestibulectomy. TENS in women with therapy-resistant provoked vestibulodynia | 85
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CHAPTER 5 Female Genito-Pelvic Reflexes and their Sexual Implications: an Overview
Symen K. Spoelstra Esther R. Nijhuis Willibrord C.M. Weijmar Schultz Janniko R. Georgiadis
Submitted for publication. 90 | CHAPTER 5
ABSTRACT
The female reproductive system includes an active and responsive genital tract that shows involuntary activity triggered by sexual arousal, genital stimulation and/or orgasm. This pelvic and perineal somatic and autonomic reflex muscle activity (‘genito- pelvic reflexes’) may be an important constituent of the female sexual response. The aim of this study was to review the literature critically on female genito-pelvic reflexes and their sexual implications. Only a small number of studies (fifteen), practically all from one research group, have been published on female genito-pelvic reflexes and their sexual implications. In most studies female genito-pelvic reflexes are suggested to enhance sexual performance or to play a role in sexual dysfunction. However, there is a lack of hard evidence that supports these assumptions. More neurophysiological research is needed to confirm the implications of these genito-pelvic reflexes for sexual (dys)function. Female genito-pelvic reflexes and their sexual implications | 91
INTRODUCTION
Female genital responses rely on an active and responsive genital tract that shows involuntary activity triggered by – or associated with – sexual arousal, genital stimulation and/or orgasm [1-2]. This pelvic and perineal reflexive muscle activity (‘genito-pelvic reflexes’) may be an important constituent of female sexual (dys)functioning. A reflex is defined as an automatic stereotyped response to a specific stimulus, mediated by the central nervous system. It requires an intact reflex arc, i.e. a receptor, an afferent and efferent limb, an integrative centre and an effector [3]. However, this definition 5 neither restricts reflexes to the spinal cord nor to skeletal (striated) muscles, which is highly relevant for sexual reflexes. In mammals other than humans, sexual genital responsiveness is under heavy brainstem and diencephalic control [4,5]. In humans it is likely that, even when more expanded cortical and voluntary control is present [6,7], automated or primordial neural control systems give rise to reflexive-like pelvic muscle activity [8]. In line with their embryonic origin, the perineum and pelvic floor are innervated by somatic nerves originating in the sacral spinal cord. This includes all the striated pelvic floor muscles, the genital skin, the anal canal, and the vulva including clitoris, labia and vaginal introitus. The main somatic nerve of the perineum is the pudendal nerve, which has somatosensory and somatomotor tributaries, and which divides into three main branches (inferior rectal, perineal, dorsal penile/clitoral) at the level of the levator ani muscle. The muscles that embryonically derive from the cloacal sphincter (external anal and urethral sphincter, superficial transverse perineal muscle, bulbocavernosus muscle, and ischiocavernosus muscle) are all innervated by pudendal nerve fibres originating in a specialized sacral motor neuronal pool called Onuf’s nucleus [9,10]. As Onuf motoneurons innervate striated muscles but also are known to be relatively unaffected by somatic motoneuron diseases like amyotrophic lateral sclerosis [11], they have been proposed to be of a mixed somatic/autonomic type [12]. Interestingly, the pudendal nerve seems less involved in the innervation of the levator ani muscle. A separate nerve, the ‘levator ani nerve’ [13], arising from the ventral ramus of the third and fourth sacral nerves, is held to innervate the pelvic diaphragm. In at least 50% of cadavers studied, the pudendal nerve also contributed to innervation of the levator ani muscle, especially in regards to the medial portions (puborectal and pubococcygeal muscles) [14]. Pelvic viscera, including cavernous tissues, contain smooth muscle that is innervated by the autonomic nervous system. Sympathetic innervation derives from preganglionic 92 | CHAPTER 5
motoneurons in the last three thoracic and the first two lumbar spinal cord segments. Post-ganglionic sympathetic fibres may reach the pelvic viscera either via the paired hypogastric nerve which originates from pre-aortic sympathetic ganglia or via branches originating from the sacral continuation of the sympathetic chain ganglia [15]. Thus, the former nerves descend into the pelvis while the latter reach the pelvis viscera from posteriorly. The parasympathetic pelvic splanchnic nerves arise from preganglionic motoneurons in the sacral segments to reach the pararectal pelvic parasympathetic ganglia [15]. The role of the parasympathetic vagal nerve in pelvic innervation is controversial. At the level of the pararectal parasympathetic ganglia the sympathetic and parasympathetic nerve systems become entangled – and probably also interact – to form inferior hypogastric plexuses. Visceral sensory information travels together with the autonomic nerves to enter the spinal cord at corresponding levels. Most of vaginal sensory fibres travel in the parasympathetic pelvic splanchnic nerve [15] or along with the sympathetic fibres arising from sacral sympathetic ganglia. However, the fact that paraplegic women may still perceive deep vaginocervical stimulation and may reach orgasm by virtue of this stimulation strongly suggests that a part of deep vaginal and cervical sensory information travels with the sympathetic hypogastric nerve [16] or possibly even the parasympathetic vagal nerve [17]. A decennia ago, Levin reviewed 6 genital reflexes and described their sexual functionality [1,18]. However, until now, the literature is very scare on the subject of genito-pelvic reflexes and their sexual implications. One of the reasons for scarcity is that measuring reflexes in the human pelvic region is very complicated. In general, electromyography and pressure measurements are used to obtain partly indirect information about genito-pelvic reflexes. Pelvic- and perineal muscles provide poor access for techniques such as surface (non-selective) or intramuscular needle electromyography (selective) techniques that are known to measure reliable estimates of skeletal muscle force [19]. In the case of autonomic reflexes that involve visceral smooth muscles the situation is even more complex, because the physiological properties of smooth muscle do not allow reliable inference of muscle force or activity [20]. Therefore, indirect measures (e.g. measuring intravaginal pressure with a solid state pressure transducer in combination with a balloon-like device) in this research field are used. The aim of the present study is to give an overview of all available studies on female genito-pelvic reflexes and their proposed sexual implications. Female genito-pelvic reflexes and their sexual implications | 93
METHODS
PubMED was used to identify relevant genito-pelvic reflex studies published between January 1979 and May 2013. Search terms were: female genito-pelvic reflexes, vaginal reflexes, female sexual reflexes and female pelvic floor reflexes. All studies published in English that dealt specifically with genito-pelvic reflexes and their sexual implications were included, regardless of their methodological quality. In addition, references lists of identified studies were searched. 5 RESULTS First sightings of pelvic reflexes In 1966, C.A. Ringrose, a Canadian gynaecologist, observed several reflexes or ‘neuromuscular phenomena’ in the pelvis while taking routine Pap smears. According to Ringrose, securing of the vaginal and cervical samples elicited reflexive contractions. Although these reflexive contractions varied in the degree of intensity, their presence or absence could be perceived clearly by the naked eye. Ringrose was the first to describe, categorize and document the incidence of these reflexes in a group of 137 women who did not have any vaginal complaints. The reactions observed while scraping of the cervix or lateral wall of the upper third of the vagina, were categorised into five groups: 1) no response, 2) contraction of the bulbocavernosus muscle (BCM) on touching the cervix (i.e. cervix-BCM reflex), 3) contraction of the adductor muscles of the thigh on touching the cervix (i.e. cervix-adductor reflex), 4) contraction of the BCM on touching the vagina (vagino-BCM reflex) and 5) contraction of the adductor muscles on touching the vagina (i.e. vagino-adductor reflex). Given the fact that the majority of the women with three or more of these reflexes were in their pre-ovulatory phase, Ringrose suggested that oestrogens influence pelvic reflexive contractions, whereas progesterone attenuates reflex activity. Out of these reflexes, the vagino-BCM reflex had the highest incidence. It was present in 47 out of the 137 women unilaterally and in 22/137 women bilaterally. Ringrose considered that the presence of pelvic reflexes indicated intact vaginal- and cervical receptors, but also noted that the women without pelvic reflexes nevertheless reported satisfactory sexual functioning [2].
Clitoro-pelvic reflex In 1979, Gillan & Brindley published an article entitled ‘Vaginal and pelvic floor responses to sexual stimulation’. Originally, the main purpose of their study was to evaluate the 94 | CHAPTER 5
vaginal vascular responses to vibratory stimulation, recorded as changes in vaginal light reflectance averaged over a cardiac cycle and as thermal conduction froma heated vaginal thermometer. However, during their experiments they were the first to discover that clitoral vibratory stimulation caused reflexive sustained contraction of the pelvic floor muscles. On one occasion, pelvic floor activation by clitoral stimulation was sustained (no orgasm occurred) for 3.5 minutes, without any decline in surface electromyographic(EMG) activity. Gillan & Brindley found that after orgasm, pelvic floor EMG activity remained increased for at least 2 minutes. They called this phenomenon the clitoro-pelvic floor reflex, but did not provide clues as to which particular pelvic floor muscle could be chiefly responsible for the phenomenon. The study confirmed orgasmic contractions and their curiously non-uniform time sequence. According to the authors, the slow relaxation of the pelvic floor muscles after orgasm was a new observation. In this study, vibratory stimulation of the clitoris was performed using a pneumatically coupled stimulator, while pelvic floor EMG measurements were obtained using stainless steel wire electrodes. The experiments were done on a large number of women with a sexual dysfunction. The total number of women and their specific sexual dysfunction was not reported. The authors considered the clitoro-pelvic floor reflex to be the counterpart of the vagino-BCM reflex described by Ringrose. However, Gillan & Brindley stated that in contrast with the phasic vagino-BCM reflex, the clitoro-pelvic reflex was a well-sustained tonic contraction. Unfortunately, the authors did not speclate about the sexual implications of this reflex [21].
Vagino-cavernosus reflex In 1993, Ahmed Shafik, an Egyptian pelvic surgeon and researcher, published his first study on female genito-pelvic reflexes. Data were obtained from 17 asymptomatic, sexually active women with a mean age of 36.6 years. A vaginal balloon, connected to a catheter, was inserted 3-4 cm into the vaginal canal and concentric needle electromyographic electrodes were inserted into the bulbocavernosus muscle (BCM) and ischiocavernosus muscle ICM). Then air was rapidly pumped into the vaginal balloon, in increments of 50 ml up to a total volume of 300 ml, and any reflexive muscle contractions in both cavernosus bodies were recorded on the EMG equipment. It was found that the two muscles acting on the main cavernous bodies, the BCM and ICM, immediately contracted at a rapid distension volume of only 50 ml. Shafik called this two-muscle contraction the vagino-cavernosus reflex. This reflex could be reproduced and did not arise after anaesthetization of the vagina. Shafik suggested that this reflex Female genito-pelvic reflexes and their sexual implications | 95
occurs during sexual intercourse and/or vaginal penetration and could enhance clitoral and penile erection. The BCM crosses the clitoris in V-form and, on contraction, it is believed to potentiate clitoral erection by two mechanisms: 1) compression of the deep dorsal vein of the clitoris and 2) compression of the corpus cavernosus. Simultaneously, contraction of the bulbus portion of the muscle would compress the bulbus vestibuli. In combination with compression of the cavernosus tissue resulting from ICM contraction, this would enhance clitoral erection. Shafik also speculated that reflexive contractions may help to milk semen from the penile urethra into the vagina, while the penis is being withdrawn from the vagina after ejaculation and that BCM contraction, during penile 5 penetration, would enhance male penile erection [22].
Vagino-levator reflex Two years later, in 1995, Shafik reported again a new reflex, probably based on data from the same group of 17 of asymptomatic women (mean age 36.6 years): the vagino-levator reflex. In accordance with Shafik’s previous reflex study, he usedan EMG concentric needle electrode and a vaginal balloon. On the lateral site to the anal orifice, the EMG electrode was inserted into the levator ani muscle. Shafik reported increased EMG activity in the levator ani muscle on vaginal distension at 50 ml, the mean duration of EMG activity was 2 seconds, whereas at 300 ml inflation, mean duration was approximately 8 seconds. EMG responses did not occur when the vagina or levator ani muscle was anaesthetized. Shafik proposed that this reflex leads to vaginal widening, vaginal elongation (ballooning) and uterus elevation (tenting). He concluded that this reproducible reflex might lead to genital responses that facilitate sexual performance, i.e. upon penile thrusting, levator ani contraction leads to widening of the vaginal introitus (in contrast with the puborectalis reflex), vaginal elongation and ballooning of the upper vagina, as well as uterine elevation (the tenting effect). However, Shafik did not investigate whether the different parts of the levator ani muscle contributed differently to this reflex [23].
Vagino-puborectalis reflex In 1995, Shafik studied reflexes in the puborectalis muscle in 14 asymptomatic women (mean age 34.8 years) using an inflatable condom-ended catheter (inserted 4-5 cm into the vagina) and a concentric needle electrode inserted in the puborectalis muscle. With air in steps of 50 ml up to a maximum volume of 300 ml, the vaginal balloon was filled. Meanwhile EMG activity in the puborectalis muscle was recorded. Inflating balloon (from 96 | CHAPTER 5
100 to 300ml) increased the EMG up to 8 seconds. Shafik found that vaginal distension evoked contraction of the puborectalis muscle (i.e. a momentary increase in EMG activity) and he named this the puborectalis reflex. After anaesthetization of the vagina with lidocaine gel or (the following day) anaesthetization of the puborectalis muscle with lidocaine injections, there were no responses from the puborectalis muscle to vaginal distension. The results were reproducible in each individual subject. Shafik speculated that during vigorous penile thrusting, the vagina distends and activates two reflexes: the vagino-bulbocavernosus reflex and the vagino-puborectalis reflex. Simultaneous contraction of the two muscles narrows both the vaginal canal and the vaginal introitus, leading to stronger penile erection. He also suggested that the penile sensation from the female muscle contraction is in itself an important erotic stimulus [24].
Vagino-clitoral reflex In 1995, Lavoisier and co-workers used Doppler ultrasonography to evaluate the response of the clitoral arteries to vaginal pressure stimulation in 10 healthy women, aged 20 to 28 years. A sterile, rigid, cylindrical pressure probe (diameter 2.5 cm; length 13 cm) was used as a stimulator. The distal part of the probe was packed in a rubber balloon that was capable of being filled, connected to a pressure transducer. Hydraulic balloon inflation and pressure monitoring occurred simultaneously. Vaginal pressure stimulation was performed using two methods: 1) cyclic insertion-withdrawal of an already situated vaginal pressure probe and 2) inflation and deflation of a stationary inflated vaginal pressure probe. The authors found that pressure stimulation along the superficial third of the vagina resulted in increased blood velocity and increased flow into the arteries of the clitoris in 90 percent of the women. They named this the ‘vagino- clitoral reflex’. They hypothesized that during the insertion and withdrawal movements of sexual intercourse, the glans penis experiences pressure stimulation that triggers both blood flow enhancement into the cavernous arteries and reflex contractions of the ischocavernosus muscle (ICM), resulting in increased intracavernosus pressure and penile rigidity. Similarly, vaginal stimulation triggers vascularization of the clitoris, with increased erotic pleasure, and muscular-reflexive responses, which enhances perivaginal blood flow and tone. On the basis of his findings, Lavoisier suggested that sexual synergy occurs during intercourse, in which vascular and muscular (reflexive) responses in both sexes are reciprocally reinforce [25,1]. Female genito-pelvic reflexes and their sexual implications | 97
Vagino-vesicourethral reflex In 2001, Shafik and El-Sibai aimed to study the effect of increased vaginal pressure (as in penile thrusting) on the bladder and urethra in 26 asymptomatic female volunteers with a mean age of 36.7 years. In steps of 10 ml, up to a maximum volume of 80 ml, carbon dioxide was pumped into a condom situated in the vagina and connected to a catheter. In response to this vaginal distension, bladder as well urethral pressure was measured by means of a microtip catheter connected to a transducer. In a range of 30 ml up to 80 ml vaginal distension, decreased bladder pressure and increased urethral pressure was reported. The duration of this effect was 4 seconds. This reproducible vesico-urethral 5 pressure response to vaginal distension was labelled the vagino-vesicourethral reflex. When the bladder, urethra and vagina were individually anaesthetized, no pressure responses were observed. During sexual intercourse, this reflex is evoked by penile thrusting and leads to bladder dilatation/relaxation and increased urethral sphincter activity, most likely in order to prevent urinary leakage. According to Shafik, urinary incontinence during sexual intercourse in patients with various neuropathic conditions might be explained by reflex disorders [26].
Vagino-anorectal reflex In the same year, Shafik and El-Sibai investigated how anorectal function was affected by increased vaginal pressure, following the same inflating procedure. In 24 healthy female volunteers, mean age 39.2 years, rectal and anal responses to vaginal distension were recorded in increments of 10 ml, up to a maximum volume of 80 ml using a two-channel microtip catheter connected to a transducer. At 30 ml and up to 80 ml, vaginal distension resulted in increased anal pressure (suggestive of anal sphincter contraction) and decreased rectal pressure (suggestive of rectal muscle relaxation). After anaesthetization of the vagina, and the internal sphincter, external sphincter and rectum, no vagino-anorectal reflex was observed during vaginal distension. Shafik speculated that repeated penile thrusting compresses the anorectum and shifts its contents towards the anal canal. Then the rectum dilates to accommodate any additional contents from the sigmoid colon, while the anal sphincter contracts to guard against the leakage of flatus or other rectal contents. He hypothesized that the vagino- anorectal reflex prevents the passage of flatus and faeces during sexual intercourse. This reflex could be inhibited in patients with diabetes mellitus or caudal equine lesions, resulting in faecal leakage during sexual intercourse [27]. In 2005, four years after his first description of the vagino-anorectal reflex, Shafik tested the hypothesis that this reflex 98 | CHAPTER 5
functions to prevent escape of flatus and faeces during sexual intercourse. His study population comprised 23 sexually active women, with a mean age of 33.7 years. Needle EMG activity was recorded in the internal anal sphincter, external anal sphincter and rectum. Meanwhile in steps of 50-300 ml, a vaginal balloon was inflated with 300 ml air. The results revealed that vaginal distension reduced the rectal pressure and increased the internal sphincter EMG activity. However, external sphincter EMG activity did not show any response. Shafik postulated that penile thrusting evokes rectal and internal anal sphincter contraction, which is suggestive of the vagino-anorectal reflex. He concluded again that this reflex contributes to preventing the leakage of rectal contents during sexual intercourse [28].
Clitoro-uterine reflex In 2005, Shafik and colleagues recruited 23 healthy women (mean age 36.7) to test the hypothesis that during sexual intercourse, uterine erection, elevation and enlargement are mediated by reflexes resulting from penile stimulation of the glans clitoris. Uterine and glans clitoris pressures were recorded during glans clitoris stimulation electrically and mechanically with a pencil electrode using a manometric tube. The main goal of the study was to gain insight into uterocervical responses during sexual intercourse. Shafik confirmed the results of previous studies, in which electrical waves were seen on EMG to emanate from the uterus. These waves were believed to be responsible for the motor activity of the uterus [29-31]. At present, there is no consensus regarding the source of the uterine electrical waves [32]. Slow waves were detected by the uterine electrodes, whereas no waves were observed from the glans clitoris. Nevertheless the study results suggested a reproducible reflex between glans clitoris stimulation and the uterus, which the authors referred to as the clitoro-uterine reflex. After cervical dilation and individual anaesthetization of the uterus and glans clitoris, the tests were repeated. Uterine electrical activity was recorded by means of a catheter attached to the uterine wall by suction, which was maintained during the test. Some participants needed sedation (intravenous diazepam) during cervical dilatation. Three electrodes were inserted into the uterus: two into the uterine mucosa (one above the other, 2 cm apart) and one into the cervix uteri (CU) mucosa (in about the middle of the cervical canal). During stimulation of the anaesthetized glans clitoris, no clitoro-uterine reflex was observed. The reflex also remained absent during anaesthetization of the uterus. No sexual implications were suggested [33]. Female genito-pelvic reflexes and their sexual implications | 99
Vagino-tubal reflex In 2005, Shafik and co-workers conducted a study on oviduct contractile activity during vaginal distension in 16 multiparous women (mean age 32.2 years), who were undergoing an abdominal hernia repair operation, or tubal ligation for sterilization. Vaginal pressure was measured using a cylindrical latex vaginal balloon; tubal pressure was measured by means of an open-tip urethral catheter, perfused with saline. The study revealed that 10 ml of vaginal distension caused an increase in ampullar and isthmic pressures and a decrease in intramural tubal pressure. Shafik named this phenomena the vagino- tubal reflex. Shafik suggested that these tubal pressure changes also occur during 5 sexual intercourse and are mediated by, what he called, the vagino-tubal reflex. In his opinion, the contractile tubal activity assists sperm-ovum transport and fertilization. The reflex was reproducible and disappeared after anaesthetic block of the vagina and anaesthetization of the oviduct, which was accomplished by infusing a solution of lidocaine in saline through the catheter already in situ [31].
Cavernoso-anal reflex In 2006, Shafik used EMG to measure how the internal and external anal sphincters responded to BCM and ICM contractions in seven healthy women (mean age 38.3 years) without any anorectal or gynaecological complaints. Prior to conducting the tests, the normality of the EMG activity of the BCM and ICM and the two anal sphincters had been verified in all participants. EMG needle electrodes were inserted into both cavernosus muscles and both anal sphincters. Electrical stimulation of the two cavernosus muscles caused increased EMG activity in the internal and external anal sphincters. The reflex was confirmed by its absence during anaesthetization of the cavernosus muscles, nor did anesthetized anal sphincters respond to cavernosus muscles stimulation. Shafik concluded that cavernosus muscle contraction evoked anal sphincter contraction, which seemed to be a reflex mediated through the cavernosa-anal reflex. He speculated that anal sphincter contraction acts to close the anal canal to prevent flatus or faecal leakage during sexual intercourse, in the same way as the vagino-anorectal reflex [34].
Ano-cavernosal excitatory reflex In 2006, Shafik performed a study on the relation between ICM contraction and external anal sphincter contraction. Measurements were obtained from eight asymptomatic women (mean age 36.8 years) using one EMG needle electrode inserted into the external anal sphincter and one into the ICM. The measurements showed that external anal 100 | CHAPTER 5
sphincter electro-stimulation produced an increase in ICM EMG activity, while voluntary anal squeezing also resulted in increased EMG activity in the ICM. This ICM contraction upon EAS contraction seemed to be mediated by a reflex that he referred to as the ‘ano- cavernosal excitatory reflex’. After anesthetization of the external anal sphincter (EAS) and ischocavernosus muscle (ICM) respectively, the reflex did not occur. According to Shafik, EAS contraction presumably acts to prevent the leakage of flatus or fluid stools during sexual intercourse, which might otherwise lead to coitus interruptus [35].
DISCUSSION
In general, genito-pelvic reflexes have been largely ignored in the literature. The aim of the present study was to review research into human female genito-pelvic reflexes and their sexual implications. Several different reflexes have been speculated to act on the female genital tract, and these reflexes have been framed in many different functional contexts, ranging from functional clitoral-vaginal interplay to the promotion of urinary and faecal continence during sexual intercourse. However, as these functional implications were not tested empirically the relevance of female genito-pelvic reflexes for sexual functioning remains largely unknown. Generally, some important critical comments should be made about the reviewed studies. In future research, these comments should be taken in consideration. Most importantly perhaps, it should be clear that the research method used (peripheral stimulation and measurement) is insufficient to reveal the neurophysiological characteristics of a given reflex-like response. That is, it does not reveal the integral parts of a reflex, namely the receptors, afferent and efferent nerves and synapse centre. One can of course derive that mechanical stimulation (e.g. pressure or moving touch) excites mechanoreceptors, but apart perhaps from the clitoris [36] the receptor constellation in the human vaginal tract is largely unknown. In a similar vein, vaginal afferent information may be conveyed by sacral parasympathetic nerves, by thoracolumbar sympathetic nerves, by sacral sympathetic nerves, and maybe even by the vagal nerve [15]. In addition, It is unclear whether different pathways would affect muscular responses via the same reflex centre. In analogy to men, some of the responses found in women could rely upon spinal circuits for genital reflexes. For instance, the male pelvic floor, especially the muscles acting on the urethra, shows rhythmic activity during ejaculation. Parallel, high frequency fluctuations in rectal pressure indicative of fast pelvic floor contractions havebeen found during orgasm in women. The characteristics of these contractions are strongly suggestive of subcortical control of pelvic motoneurons [37-38]. Possibly, female pelvic Female genito-pelvic reflexes and their sexual implications | 101
muscle contractions during climax rely on similar spinal control systems as those known to exist in men [4]. Genital responses that occur in spinal cord injured (SCI) women are suggestive that at least some of these reflexes are organized as spinal cord reflexes. SCI women are known to have lubrication and clitoral engorgement upon vulvar touch, while pelvic rhythmic contractions may be intact as well [39]. Nevertheless, the reflexes discussed in this review may be applicable to multiple levels of the central nervous system, and not only the spinal cord. Another limitation relates to the responses, which are measured from striated or smooth muscle. Striated muscle measurements clearly dominate in the studies reviewed, which 5 makes sense given the much more difficult accessibility of smooth muscle to EMG, leaving only the possibility for indirect measurement. As indicated earlier, muscles that derive from the embryonic cloaca (BCM, ICM, anal and urethral sphincters and possibly also the puborectalis) are controlled by motoneurons in a special sacral nucleus termed Onuf’s nucleus [9-10]. Onuf motoneurons can be considered as an intermediate type between somatic and autonomic [12]. Thus, whether responses of striated cloacal muscles must be considered autonomic or somatic is not entirely clear, while it leaves open the possibility that reflex responses of these muscles are controlled by a reflex centre distinct from responses of other striated pelvic muscles. Besides striated muscle activity, smooth muscle activity is important for sexual functioning such as clitoral and vaginal vasocongestion, vulvar and vaginal lubrication, and uterine motility [40]. Vaginal smooth muscles show continuous electrical activity, with spontaneous vaginal motility [21]. This activity, controlled by the autonomic nervous system, is increased at clitoral vibration and during menstruation [40]. Assumed functions of these contractions are clearing the vagina from ex-and secretion products, and possibly activating vaginal blood supply at sexual quiescence [41]. It is striking that most of the studies that were identified have been produced by the same research group, headed by the Egyptian pelvic surgeon Ahmed Shafik. The studies of Shafik have a stereotypic construction; electrical or pressure recording of muscular activity, induced by pressure (inflated balloon) or electrical stimulation. After anaesthetisation tests were repeated. In their studies, Shafik’s group consistently evaluated response reproducibility, the absence of responses during anaesthetization and the response latency. However, based on the demographics of the subjects in his studies, some of the studies seem to reflect the same subject cohort. The impression arises that different responses published in different papers (for example the vagino- cavernosus and vagino-levator reflexes) were actually part of the same experiment. 102 | CHAPTER 5
It would be important to know whether multiple reflexes were studied in the same subjects, or whether multiple reflexes were tested in different subjects. Until now, unfortunately, his studies have not been replicated by other research groups. Moreover, in the book ‘Bonk, the curious coupling of sex and science’ of Mary Roach is reported that Shafik used prostitutes in his studies [Mary Roach, 2008]. It is known that Masters and Johnson abandoned the use of prostitutes in their research when they found genital abnormalities in this group of women, probably from being continually stimulated to arousal without the relief of orgasm [Masters and Johnson, 1966]. Therefore, it can be questioned whether this study group is representable for other women. Levin pointed out that a short duration of the reflexes (seconds) could severely limit their functionality during coitus unless they were activated repeatedly [1,42]. The duration of the reflexes in the studies of Shafik ranged from 2-8 seconds. Gillan & Brindley stated that in contrast with the phasic vagino-BCM reflex, the clitoro-pelvic reflex was a well- sustained tonic contraction (ranging from 2.0 to 3.5 minutes) [21]. The latest is in line with a study of Broens et al. in which high resolution solid state circumferential catheters were used to measure intravaginal pressures during voluntary contractions and induced reflexive contractions in women without a sexual dysfunction. In their study voluntary contractions were characterized by low(decreasing) and fluctuating pressures of short duration (less than 1.5 minutes). In contrast, reflexive contractions were characterized by much higher (increasing) pressures of a relatively much longer duration (even longer than 6 minutes) [43]. At present, the literature on genito-pelvic reflexes and their sexual implications is very limited. The majority of studies on genito-pelvic reflexes have methodological shortcomings. These shortcomings could relate to; not reporting the reproducibility of the reflex, not performing anaesthetization to check the reflex in absence of an afferent arm, not performing manual examination of pelvic floor muscle strength and tone in order to confirm the absence of pelvic floor hypo- or hyperactivity and not reporting the duration of the reflexive contractions. With the exception of the study of Ringrose (N=137), subject cohorts were relatively small, while almost all the studies described in this overview were performed in sexually functioning women without sexual complaints. Only in Gillian and Brindley’s study measurements were performed in women with a sexual dysfunction. Unfortunately their specific sexual dysfunction was not reported [21]. We have the impression that participants were in a neutral state during the measurements, however, in most studies it is not reported whether participants were sexually aroused during the measurements. Therefore, studies are warranted that compare for example Female genito-pelvic reflexes and their sexual implications | 103
genito-pelvic reflexes between aroused and non-aroused sexually functioning- and dysfunctioning women.
CONCLUSIONS
The number of studies on female genito-pelvic reflexes and their sexual implications is very limited. These reflexes might be involved in clitoral and penile erection, milking semen from the male urethra during sexual intercourse, the tenting effect, and sperm- ovum transport. In several studies, it is suggested that female genito-pelvic reflexes 5 might play a role in preventing the leakage of faeces, flatus and urine during sexual intercourse. However, any substantial evidence for these sexual implications is lacking. In the future, more neurophysiological research as well case-control studies are needed to confirm the sexual implications of these genito-pelvic reflexes. 104 | CHAPTER 5
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CHAPTER 6 Dynamic Clinical Measurements of Voluntary Vaginal Contractions and Autonomic Vaginal Reflexes
Paul M.A. Broens Symen K. Spoelstra Willibrord C.M. Weijmar Schultz
Paul M.A. Broens and Symen K. Spoelstra are both first author.
J Sex Med 2014;11(12):2966-2975 108 | CHAPTER 6
ABSTRACT
Introduction. The vaginal canal is an active and responsive canal. It has pressure variations along its length and shows reflex activity. At present, the prevailing idea is that the vaginal canal does not have a sphincter mechanism. It is hypothesized that an active vaginal muscular mechanism exists and might be involved in the pathophysiology of genito-pelvic pain/penetration disorder.
Aim. The aim of this study was to detect the presence of a canalicular vaginal “sphincter mechanism” by measuring intravaginal pressure at different levels of the vaginal canal during voluntary pelvic floor contractions and during induced reflexive contractions.
Methods. Sixteen nulliparous women, without sexual dysfunction and pelvic floor trauma, were included in the study. High-resolution solid-state circumferential catheters were used to measure intravaginal pressures and vaginal contractions at different levels in the vaginal canal. Voluntary intravaginal pressure measurements were performed in the left lateral recumbent position only, while reflexive intravaginal pressure measurements during slow inflation of a vaginal balloon were performed in the left lateral recumbent position and in the sitting position.
Main Outcome Measures. Intravaginal pressures and vaginal contractions were the main outcome measures. In addition, a general demographic and medical history questionnaire was administered to gain insight into the characteristics of the study population.
Results. Fifteen out of the sixteen women had deep and superficial vaginal high- pressure zones. In one woman, no superficial high-pressure zone was found. The basal and maximum pressures, as well as the duration of the autonomic reflexive contractions significantly exceeded the pressures and the duration of the voluntary contractions. There were no significant differences between the reflexive measurements obtained in the left lateral recumbent and the sitting position.
Conclusion. The two high-pressure zones found in this study, as a result of voluntary contractions and, even more pronounced, as a result of reflexive contractions on intravaginal stimulation, support the hypothesis that the vaginal canal has an active and passive canalicular sphincter mechanism. Further investigation of this sphincter mechanism is required to identify its role in the sexual response and genito-pelvic pain/penetration disorder. Voluntary vaginal contractions and autonomic vaginal reflexes | 109
INTRODUCTION
The vagina does not simply act as a passive conduit for the passage of the penis, fetus, semen, and menses, but it is also a responsive, active canal with pressure variations along its length and contractile muscular activity [1]. The anal canal and the urethra both have sphincter mechanisms [2]. Shafik presented anatomical evidence on the existence of a vaginal sphincter; however, he could not provide physiological evidence because the vaginal sphincter was inaccessible and too thin to place electrodes in for testing [3]. The vaginal wall consists of outer longitudinal and inner circular smooth muscles. Contraction of the longitudinal smooth muscles shortens and widens the vagina, whereas contraction of the circular smooth muscles constricts the vagina [4]. Vaginal 6 smooth muscle motility is under the influence of the autonomic nervous system and is known to increase around menstruation, in order to evacuate the contents of the uterus and vagina. However, most women do not consciously feel these spontaneous contractions [5]. At present, it is not clear whether the vaginal wall itself is composed of striated muscles. The vaginal canal is anchored within a bed of powerful striated muscles, which can be divided into four groups. From superior to inferior, these layers are (i) the endopelvic fascia attached to the superior fascia of the levator ani muscle; (ii) the pelvic diaphragm/ the levator ani muscles, suspended from the fascia of the internal obturator muscle: the puborectalis muscle and the pubovisceral muscles (= the pubococcygeal muscle and the iliococcygeal muscle); (iii) the urogenital diaphragm/perineal diaphragm: the deep transverse perineal muscle (perineal membrane) and external urethral sphincters; and (iv) the superficial transverse perianal muscles and the muscles of the cavernous bodies: the bulbospongiosus muscles and ischiocavernosus muscles and the external anal sphincter [6]. There is wide interindividual variation in the size, power, and voluntary control of these striated muscles [7]. Intravaginal pressure variations occur along the length of the vaginal canal. The intravaginal pressure is a key parameter in the strength of the pelvic floor muscles in women [8]. Kegel was the first to measure this intravaginal pressure. In the 1950s, he introduced the “perineometer” to improve the strength of the pelvic floor muscles for the treatment of urinary stress incontinence in postpartum women. He observed that after the patients had completed his pelvic floor physiotherapy exercises, they not only reported relief from urinary incontinence but also improvement in sexual satisfaction [9]. Over the next 30 to 40 years, the perineometer was the gold standard to measure intravaginal pressure and hence pelvic floor strength. Although several different new 110 | CHAPTER 6
devices were introduced to measure intravaginal pressure [10–12], these techniques did not correct for the pressure created by the device itself. In the late 1960s and early 1970s, it became clear that infusion manometry, after correction for the balloon, was the only technique that could measure absolute pressure [8,13,14]. In 1992, Bø was the first to attempt to distinguish variations in pressure along the vaginal canal. She found the highest intravaginal pressure 3.5 cm from the vaginal introitus, using a vaginal balloon. However, this balloon measured an average pressure at only one level. Therefore, it was not possible to provide a pressure profile along the vaginal canal [15]. In 2005, Guaderrama et al. used infusion manometry to obtain vaginal pressure profiles in 14 asymptomatic women. They concluded that the intravaginal pressure was highest in the mid-zone over a length of 3–4 cm. Peak pressure occurred in the vaginal canal approximately 2 cm cranial to the hymen. In this vaginal high-pressure zone, the maximum pressure during voluntary contraction was significantly higher than the maximum pressure at rest. Guaderrama et al. suggested that the vaginal high-pressure zone is related to the contraction of the pelvic floor musculature, but they did not indicate which particular muscles were involved [16]. In 2007, Jung et al. assessed the shape and characteristics of the vaginal high-pressure zone described by Guaderrama et al. In nine asymptomatic women, they performed ultrasound imaging of a compliant fluid-filled bag that had been placed in the vaginal high-pressure zone. When the bag volume was increased, the vaginal high-pressure zone opened with lateral vaginal wall extension first, followed by anteroposterior vaginal wall extension. Based on these observations, Jung et al. concluded that the puborectalis muscle was responsible for the vaginal high-pressure zone [2]. In 2010, Raizada et al. performed a study on 16 asymptomatic women, using a side-hole infusion manometry technique to measure contact pressure at point locations. Ultrasound and magnetic resonance imaging revealed a vaginal high-pressure zone in the distal part of the vagina [8]. The anal canal, vaginal canal, and urethra have a common embryological origin. During the fourth to seventh week of embryological development, the cloaca becomes separated by the urorectal septum into the urogenital sinus ventrally (which develops into the urethra and vaginal canal) and into the anorectal canal dorsally [17,18]. Based on this knowledge, we hypothesized that the vaginal canal has a canalicular sphincter mechanism, analogous to the anal canal and urethra. This active mechanism in the vaginal canal could contribute to the sexual response and might explain why, in genito- pelvic pain/penetration disorder, vaginal penetration is difficult or even impossible. The purpose of this study was to detect the presence of a canalicular vaginal sphincter Voluntary vaginal contractions and autonomic vaginal reflexes | 111
mechanism by measuring intra-vaginal pressure at different levels of the vaginal canal during voluntary pelvic floor contractions and during induced reflexive contractions.
METHODS Participants The study was conducted on 16 asymptomatic nulliparous women at the Department of Obstetrics and Gynaecology and Sexology and the Department of Surgery, Anorectal Physiology Laboratory of the University Medical Center in Groningen, the Netherlands. In the period from June 2012 to January 2013, 21 women without pelvic floor trauma and sexual dysfunction were recruited by an advertisement sent by e-mail to the medical 6 students at the medical school at the University of Groningen. Interested candidates received a written letter with information about the study. Prior to participation, all the subjects signed an informed consent form and completed a general demographic and medical questionnaire to provide insight into their characteristics and to confirm the absence of sexual dysfunction and pelvic floor trauma. Participants received a small financial compensation for their participation. Inclusion criteria were (i) asymptomatic; (ii) nulliparous; (iii) aged between 18 and 45 years; (iv) able to read and understand the Dutch language; and (v) prepared to give signed informed consent. Exclusion criteria were (i) (current and past) pregnancy; (ii) a history of pelvic floor trauma and/or surgery; and (iii) sexual dysfunction.
Manometry Catheter, Data Recording, and Data Analysis To measure intravaginal pressure and vaginal contractions at different levels in the vaginal canal, a high-resolution solid-state (Boston-type) circumferential catheter (Unisensor K12981, Attikon, Switzerland) was used with an outer diameter of 12F (= 4 mm). Boston-type sensors do have small balloons around the catheter with one microtip transducer inside. Therefore, they measure the mean surrounding pressure at their location. These are absolute pressures. This catheter measured the mean pressure at intervals of 8 mm over a total length of 6.8 cm into the vaginal canal. The sample frequency of the measuring equipment is 50 Hz. The color scheme as used in Figure 1 is a simple transformation of the measured pressures in mm Hg. The lowest pressures (0 mm Hg) is dark blue, while the highest pressure 180 mm Hg is presented as purple as can be seen on the left side of the figure (Figure 1). Another catheter (Unisensor K14204) with an outer diameter of 14F (= 4.7 mm), equipped with two microtip sensors alone, was connected to a vaginal balloon that was inflated 112 | CHAPTER 6
with water at 37°C during the vaginal filling test while recording the pressure inside the balloon. This catheter was placed anteriorly to the earlier mentioned Boston-type catheter. The pressures measured inside this vaginal balloon were corrected for the resistance of the balloon itself as every balloon does not have a linear resistance [19]. Therefore, real absolute vaginal pressures were obtained. The data were recorded and analyzed with the high-resolution manometry equipment version 8.23 (Medical Measurement Systems, Enschede, The Netherlands).
Test Procedure Two tests were performed by a female nurse-practitioner, under the supervision of a surgeon with extensive experience with intracorporal pressure measurements and a gynecologist/sexologist, under nonerotic circumstances. The method of instruction was standardized. First, the “voluntary vaginal contraction test” was conducted in the left lateral recumbent position. During this test, the circumferential catheter, carefully fixed to the buttocks of the participant, was placed into the vaginal canal. Then the basal vaginal pressure was measured, followed by the maximum pressure during maximal voluntary pelvic floor contraction. This contraction pressure was recorded three times; the highest value was used for analysis. Second, the “vaginal filling test” was performed in the left lateral recumbent position and in the sitting position, to evaluate whether the outcomes were position dependent. With the circumferential catheter still in situ, a collapsed balloon connected to a second catheter was placed into the vaginal canal. When the patient was completely relaxed, the balloon was inflated very slowly (0.5 mL/second) with water at 37°C. During inflation, the pressure in the vaginal balloon (corrected for the pressure of the balloon itself), the pressure on different levels in the vagina canal, and the volume of water inflated into the balloon were recorded. The women were instructed to retain the balloon for as long as possible. The test was stopped when the patient had reached the limit of tolerance. Then the balloon was emptied completely. Subsequently, the test was repeated in sitting position. The study was approved by the Medical Ethical Board of the University Medical Centre in Groningen. Voluntary vaginal contractions and autonomic vaginal reflexes | 113
Statistical Analysis The data were analyzed with SPSS for Windows, version 20.0 (IBM SPSS Statistics, IBM Corporation, Armonk, NY, USA). Nonparametric tests were used, because the distribution of (some of) the data was not symmetrical. Consequently, median and range (minimum and maximum) values are given. The Wilcoxon paired data rank test was used to compare differences between the parameters in the study group. A P value of <0.05 was considered to be statistically significant.
RESULTS Study Population 6 Originally, 21 women were recruited for the study. Five subject measurements were excluded because of technical problems with pressure recording. Ultimately, 16 nulliparous subjects completed the study and had evaluable data. They did not report any adverse side effects. Mean age of the subjects was 23 years (standard deviation [SD] 3.5; range 20–32). Mean weight was 68 kg (SD 4.7; range 61–76) and mean height was 172 cm (SD 5.2 range; 163– 180). All the participants had a high education level: 87.5% university and 12.5% higher education. The majority of the women in the study population were students (87.5%) (Table 1). One woman had attention deficit hyperactivity disorder for which she was receiving methylphenidate; none of the other women were using medication. Fifty percent of the women had a heterosexual relationship. None of the women reported homosexual orientation. Ten women were sexually active (62.5%), whereas six women were not sexually active (37.5%). The majority of the women (56%) were using an oral contraceptive; three women (19%) had an intrauterine device and one woman was using condoms for contraception (6%). Three women (19%) were not using any contraceptives at all. Two out of the 16 participants had contracted a sexually transmitted disease in the past (chlamydia and human papillomavirus, respectively). None of the women in the study reported sexual abuse. None of the women had pelvic floor trauma or surgery and none reported sexual dysfunction. 114 | CHAPTER 6
TABLE 1 | Demographic and medical characteristics of the study population
Study population (N = 16)
Mean (SD) or n %
Age (years) 23 (SD 3.5) Weight (kg) 68 (SD 4.7) Height (cm) 172 (SD 5.2) Highest education University 14 87.5 Higher education 2 12.5 Student Yes 14 87.5 No 2 12.5 Diseases ADHD 1 6 No diseases 15 94 Use of medication Methylphenidate 1 6 No 15 94 Relationship Heterosexual 8 50 Homosexual 0 0 No relationship 8 50 Sexually active Yes 10 62.5 No 6 37.5 Use of contraceptive Condoms 1 6 Oral contraceptive 9 56 Intrauterine device 3 19 No 3 19 Sexual transmitted infections in the past Yes 2 12.5 No 14 87.5 Sexual abuse Yes 0 0 No 16 100 Pelvic floor trauma/operations Yes 0 0 No 16 100 Dyspareunia and sexual dysfunction Yes 0 0 No 16 100 ADHD = attention deficit hyperactivity disorder; SD = standard deviation Voluntary vaginal contractions and autonomic vaginal reflexes | 115
Voluntary Vaginal Contraction Measurements in the Left Lateral Recumbent Position Deep and Superficial Median deep vaginal basal pressure was 5 mm Hg (range 0–30); median deep vaginal maximum squeeze pressure was 45 mm Hg (range 10–110). Median superficial vaginal basal pressure was 15 mm Hg (range 5–35); median superficial vaginal maximum squeeze pressure was 65 mm Hg (range 15–115) (Table 2).
TABLE 2 | Voluntary and reflexive contractions in the left lateral recumbent position
Voluntary vaginal Reflexive vaginal contraction in left lateral contraction in left lateral 6 recumbent position (n = 16) recumbent position (n = 12) Wilcoxon median range median range rank test Basal vaginal pressure 5 0-30 0.006 15 0-30 (mmHg)
Deep Maximum vaginal 45 10-110 0.006 173 90-225 pressure (mmHg) Wilcoxon median range median range rank test Basal vaginal pressure 15 5-35 0.032 25 0-105 (mmHg) Maximum vaginal 65 15-115 0.015 145 30-225
Superficial pressure (mmHg)
P < 0.05 = significant
Reflexive Vaginal Contraction Measurements in the Left Lateral Recumbent Position Deep Median vaginal basal pressure was 15 mm Hg (range 0–30). Median starting point of reflexive contraction after balloon filling was 53 mL (range 20–95), with a local vaginal pressure of 25 mm Hg (range 10–40). Median maximum reflexive contraction after balloon filling was 175 mL (range 90–340), with a local vaginal pressure of 173 mm Hg (range 90–225). Median local vaginal contraction duration was 307 seconds (range 172– 555). Median maximum vaginal balloon pressure was 50 mm Hg (range 5–90), and the maximum length of the local vaginal high-pressure zone was 3 cm (range 2–4) (Tables 2 and 3). 116 | CHAPTER 6
TABLE 3 | Reflexive contractions in the left lateral recumbent position and in sitting position
Reflexive vaginal Reflexive vaginal contraction in left contraction in sitting lateral recumbent position (n = 16) position (n = 12) Wilcoxon median range median range rank test Basal vaginal pressure (mmHg) 15 0-30 NS 18 5-60 Starting point reflexive contraction: 53 20-95 NS 68 10-135 after balloon filling (ml) Starting point reflexive contraction: 25 10-40 NS 30 10-85 local vaginal pressure (mmHg) Maximum reflexive contraction: 175 90-340 NS 160 75-315 after balloon filling (ml) Maximum reflexive contraction: 173 90-225 NS 165 60-460 Deep local vaginal pressure (mmHg) Maximum local vaginal contraction 307 172-555 NS 305 100-525 duration (s) Maximum vaginal balloon pressure 50 5-90 NS 45 5-100 (mmHg) Maximum length of local vaginal 3 2-4 NS 2.6 2-4 high pressure zone (cm) Wilcoxon median range median range rank test Basal vaginal pressure (mmHg) 25 0-105 NS 30 5-115 Starting point reflexive contraction: 90 30-225 NS 78 5-150 after balloon filling (ml) Starting point reflexive contraction: 35 15-55 NS 38 15-91 local vaginal pressure (mmHg) Maximum reflexive contraction: 153 30-275 NS 135 75-310 after balloon filling (ml) Maximum reflexive contraction: 145 30-225 NS 160 25-455 Superficial local vaginal pressure (mmHg) Maximum local vaginal contraction 155 70-640 NS 240 70-420 duration (s) Maximum length of local vaginal 1.5 2-3 NS 2.2 2-3 high pressure zone (cm) P < 0.05 = significant NS = not significant Voluntary vaginal contractions and autonomic vaginal reflexes | 117
Superficial Median vaginal basal pressure was 25 mm Hg (range 0–105). Median starting point of reflexive contraction after balloon filling was 90 mL (range 30–225), with a local vaginal pressure of 35 mm Hg (range 15–55). Median maximum reflexive contraction after balloon filling was 153 mL (range 30–275), with a local vaginal pressure of 145 mm Hg (range 30–225). Median local vaginal contraction duration was 155 seconds (range 70–640), and the maximum length of the local vaginal high-pressure zone was 1.5 cm (range 2–3) (Tables 2 and 3).
Reflexive Vaginal Contraction Measurements in the Sitting Position Deep 6 Median vaginal basal pressure was 18 mm Hg (range 5–60). Median starting point of reflexive contraction after balloon filling was 68 mL (range 10–135), with a local vaginal pressure of 30 mm Hg (range 10–85). Median maximum reflexive contraction after balloon filling was 160 mL (range 75–315), with a local vaginal pressure of 165 mm Hg (range 60–460). Median local vaginal contraction duration was 305 seconds (range 100–525). Median maximum vaginal balloon pressure was 45 mm Hg (range 5–100), and the maximum length of the local vaginal high-pressure zone was 2.6 cm (range 2–4) (Table 3; Figure 1).
Superficial Median vaginal basal pressure was 30 mm Hg (range 5–115). Median starting point of reflexive contraction after balloon filling was 78 mL (range 5–150), with a local vaginal pressure of 38 mm Hg (range 15–91). Median maximum reflexive contraction after balloon filling was 135 mL (range 75–310), with a local vaginal pressure of 160 mm Hg (range 25–455). Median local vaginal contraction duration was 240 seconds (range 70–420), and the maximum length of the local vaginal high-pressure zone was 2.2 cm (range 2–3) (Table 3; Figure 1). There were no significant differences between the measurements obtained in the left lateral recumbent position and the sitting position (Table 3). 118 | CHAPTER 6
Pressure transducers position in relation to the most superficial pressure sensor (cm)
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0.0 Deep | 1 Figure vaginal vaginal balloon in the sitting position of one asymptomatic, woman. nulliparous On the left side, color translation can be seen of the measured local vaginal pressures. Blue means atmospheric pressure (outside the vagina); red means high-pressure recording. On of contraction the can been horizontal seen. axis, The right vertical the axis shows duration the position of the pressure transducers superficial and deep The (black stripes) recording. pressure in atmospheric the of location the relation from calculated be can to canal the vaginal the in position The most sensor. superficial pressure During superficial). and (deep lines horizontal black with marked are zones high-pressure the of Borders figure. the in indicated are zones high-pressure zone high-pressure the superficial why explains a This little canal. moved bitvaginal up inside catheter the recording balloon filling, pressure the local canal. vaginal outside the displaced partly was Voluntary vaginal contractions and autonomic vaginal reflexes | 119
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Pressure (mmHg) Pressure (mmHg) 2 lateral recumbent position: low, gradually decreasing and fluctuating pressures with a relatively short duration (less than 1.5 minutes). (B) Reflexive short (less duration than 1.5Reflexive (B) minutes). relatively with a and fluctuating pressures decreasing gradually position: low, recumbent lateral
A B contractions in the sitting position: much higher, gradually increasing pressures of much longer duration (up to 6+ minutes). to (up duration much longer of pressures increasing gradually in the sitting position: much higher, contractions left left Figure 120 | CHAPTER 6
DISCUSSION
Voluntary contractions and reflexive contractions were measured with the voluntary vaginal contraction test and the vaginal filling test, respectively. Voluntary contractions were characterized by low (decreasing) and fluctuating pressures (“cogwheel phenomenon”) of short duration (less than 1.5 minutes). In contrast, reflexive contractions were characterized by much higher (increasing) pressures of much longer duration (even longer than 6 minutes) (Figure 2). Strikingly, the basal pressure, maximum pressure, and duration of the reflexive contractions significantly exceeded the pressures and duration of the voluntary contractions. These high vaginal pressures were registered with low pressures in the vaginal balloon (Table 3). Obviously, low intravaginal pressure provokes contractions of the vagina and/or surrounding muscles. This implies a (autonomic) reflexive process. There were no significant differences between the reflexive measurements obtained in left lateral recumbent position and those obtained in the sitting position. Apparently, the reflexive contractions were not position dependent. This study revealed that 15 out of the 16 women had two separate vaginal high- pressure zones: a deep high-pressure zone (median length 2.6 cm) and a superficial high-pressure zone (median length 2.2 cm). Even a very low pressure in the balloon resulted in powerful reflexive contractions in these two areas of the vaginal canal. In one woman, no superficial vaginal high-pressure zone was measured and this could not be attributed to technical failure. Her medical history did not account for this observation. A possible explanation is anatomical variation, for example, absent or defective receptors/reflex in this area. Based on our findings, we hypothesize that the deep high-pressure zone represents the “deep vaginal sphincter,” i.e., puborectalis muscle contraction, mediated by the vagino-puborectalis reflex [20]. We further postulate that the superficial vaginal high- pressure zone represents the “superficial vaginal sphincter,” i.e., bulbocavernosus muscle contraction, mediated by the superficial vagino-bulbocavernosus reflex. In a study of Shafik, both the vagino-puborectalis reflex and vagino-bulbocavernosus reflex were absent upon distension of the anesthetized vagina, which implies that afferent receptors are locatedsome where deep and superficial in the vaginal canal [21]. At present, the pathophysiology of female sexual pain disorders, renamed in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition as genito- pelvic pain/penetration disorder, is not fully understood [22]. We theorize that the canalicular vaginal sphincter mechanism identified in this study could play a substantial role in female sexual (dys)functioning. In 1995, Shafik suggested that during vigorous Voluntary vaginal contractions and autonomic vaginal reflexes | 121
penile thrusting, the vagina distends and two genito-pelvic reflexes might be triggered: the vagino-bulbocavernosus reflex and the vagino-puborectalis reflex [20]. It has also been suggested that during orgasmic arousal or because of penile thrusting, simultaneous contraction of the puborectalis muscle and the bulbocavernosus muscle narrows the vaginal tube and the vaginal introitus. At the same time, the contractions of the pubococcygeus muscle and iliococcygeus muscle (owing to their lateral pull directions) contribute to the tenting effect [20,23]. Masters andJohnson have assumed that orgasms come about by stimulation of various genital areas that have the same feeling quality [24]. Others distinguish two or even three different types of orgasmic feelings: clitoral/vulvar, vaginal (vaginal wall), and uterine/cervical [25]. More frequent vaginal orgasm is associated with experiencing greater excitement from deep vaginal 6 stimulation [26]. Brody et al. found that current sensitivity and responsiveness of the cervix are associated with greater vaginal orgasm consistency, which might be due to (at least in part) the differentneurophysiological projections of those regions in comparison with other genital areas. Whether these “specific neurophysiological projections” also might be involved in our voluntary and reflexive contractions, as response to intra- vaginal stimulation, is obvious, but needs confirmation by research focusing on these voluntary contractions and autonomic reflexes under erotic conditions. When we apply our results to genito-pelvic pain/penetration disorders, our hypothesis is that in lifelong vaginismus, autonomic reflexive contractions in the bulbocavernosus muscles occur. We also postulate that in the initial stages of dyspareunia, voluntary contractions in the puborectalis muscle and bulbocavernosus muscle occur (as a defense mechanism) [27]. It is reported that the pelvic floor is indirectly innervated by the limbic system [28]. Therefore, it is reasonable that the pelvic floor muscles respond to emotional stimuli and/or states, such as anxiety [29]. In a study of Broens et al., they proved that a comparable anal-external sphincter continence reflex is started by stimulation of anal submucosal receptors [30]. Most likely this superficial vaginal reflex will be triggered on the same way. Long-lasting contractions of the vagina may induce mucosal injury followed by an overreaction of the autonomic reflexive contractions of these muscles, which makes it impossible to differentiatevaginis mus from dyspareunia on the basis of clinical examination. Our study has a number of limitations. Prior to the tests, no manual examination of the pelvic floor muscles on the asymptomatic women was performed. Although all participants reported no sexually or pelvic floor complaints, theoretically it might have been possible that some women were not able to contract and relax their pelvic floor muscles adequately. However, the median basal pressures measured in these women 122 | CHAPTER 6
were 25 mm Hg. This makes it unlikely that these women had an overactive pelvic floor. Moreover, this would not have affected the outcome of the study because voluntary contractions were compared with reflexive contractions within the same woman. In 1 woman out of 16 women, no super ficially high pressure zone could be detected. Because of a low number of participants, we cannot predict the prevalence of this anatomical/ physiological variant. A significant next step would be to investigate intravaginal pressures and the vaginal reflex profile in women with lifelong vaginismus and dyspareunia. Detailed knowledge of the intravaginal pressures and vaginal contractions in these two patient groups may help to identify the specific pathogenesis of these severely distressing conditions. In addition, it would also be interesting to investigate the role of different emotional stimuli (e.g., disgust) on pelvic floor muscle contractions in healthy subjects and women with genito-pelvic pain/penetration disorder
CONCLUSION
The two high-pressure zones found in this study, as a result of voluntary contractions and, even more pronounced, as a result of reflexive contractions on intravaginal stimulation, support the hypothesis that the vaginal canal has an active and passive canalicular sphincter mechanism. Further investigation of this sphincter mechanism is required to identify its role in the sexual response and the genito-pelvic pain/penetration disorder.
ACKNOWLEDGMENTS
We would like to thank O.J. Pras for her assistance in the Anorectal Physiology Laboratory and J. Abma-Hill for editing the English. Furthermore, we would like to thank C. Borg and J.R. Georgiadis for their comments on our manuscript. Voluntary vaginal contractions and autonomic vaginal reflexes | 123
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23. Park K, Goldstein I, Andry C, Siroky MB, 28. Blok BF, Sturms LM, Holstege G. A PET Krane RJ, Azadzoi KM. Vasculogenic female study on cortical and subcortical control of sexual dysfunction: The hemodynamic pelvic floor musculature in women. J Comp basis for vaginal engorgement insufficiency Neurol 1997;389:535–44. and clitoral erectile insufficiency. Int J Impot 29. Both S, van Lunsen R, Weijenborg P, Res 1997;9:27–37. Laan E. A new device for simultaneous 24. Masters WH, Johnson VE. Human sexual measurement of pelvic floor muscle response. Boston: Little, Brown & Co; 1966. activity and vaginal blood flow: A test in a 25. Komisaruk BR, Whipple M. Functional MRI nonclinical sample. J Sex Med 2012;9:2888– of the brain during orgasm in women. Annu 902. Rev Sex Res 2005;16:62–86. 30. Broens PM, Penninckx FM, Ochoa JB. Fecal 26. Brody S, Klapilova K, Krejcˇová L. More continence revisited: The anal external frequent vaginal orgasm is associated sphincter continence reflex. Dis Colon with experiencing greater excitement Rectum 2013;56:1273–81. from deep vaginal stimulation. J Sex Med 2013;10:1730–6. 27. van der Velde J, Laan E, Everaerd W. Vaginismus, a component of a general defensive reaction. an investigation of pelvic floor muscle activity during exposure to emotion-inducing film excerpts in women with and without vaginismus. Int Urogynecol J Pelvic Floor Dysfunct 2001;12:328–31. CHAPTER 7 The Distinct Impact of Voluntary and Autonomic Pelvic Floor Muscles on Genito-Pelvic Pain/ Penetration Disorder
Symen K. Spoelstra Willibrord C. M. Weijmar Schultz Elke D. Reissing Charmaine Borg Paul M.A. Broens
Submitted for publication. 126 | CHAPTER 7
ABSTRACT
While the debate on diagnostic distinction continues, the DSM-5 combined dyspareunia and vaginismus into the genito-pelvic pain/penetration disorder. Recent research into the pathophysiology of dyspareunia and vaginismus has focused mainly on general pelvic floor pathology, the experience of pain, and cognitive-affective factors, while ignoring female genito-pelvic reflexes. It has not been taken into account that the vaginal canal, with its surrounding musculature, is an active canal capable of genito- pelvic reflexes, and that several of these reflexes might be triggered separately and/or simultaneously during sexual activity. We hypothesize that vaginal reflexive contractions play a substantial role in the pathogenesis of genito-pelvic pain/penetration disorder and postulate the genito-pelvic reflex hypothesis, i.e. in acute dyspareunia, primarily voluntary contractions or inadequate relaxation of the pelvic floor muscles predominate to guard against the pain due to vaginal trauma/infection and/or stress/anxiety. In chronic dyspareunia, these voluntary contractions induce increasingly (sub)mucosal vaginal damage: contact- and pain receptors become more sensitive. The increased sensitivity of the contact receptors induces powerful autonomic reflexive contractions. These autonomic contractions provoke vulvar pain, which causes overreactive pelvic floor muscles. In lifelong vaginismus, autonomic reflexive contractions of the pelvic floor muscles predominate the entire disease process. The genito-pelvic reflex hypothesis in GPPPD | 127
INTRODUCTION
Vaginismus and dyspareunia are characterized by persistent and recurrent problems with vaginal penetration. In vaginismus, the key symptom is the inability to allow vaginal penetration; in dyspareunia, the central issue is pain during sexual intercourse.(1) Although accurate figures are lacking, the prevalence of vaginismus is approximately 0.5-1%,(2) while the prevalence of dyspareunia is believed to range from 12% to 21%.(3) Over the past 15 years, there has been ongoing debate about whether vaginismus can be differentiated categorically or on a dimension of severity from dyspareunia/provoked vestibulodynia(PVD).(4) Discussions continue owing to the lack of valid and reliable diagnostic criteria for vaginismus and the notion that dyspareunia and vaginismus share many similarities. To a greater or lesser extent, these similarities are the presence of i) vulvar pain during (attempts to) vaginal penetration, ii) pelvic floor overreactivity, iii) fear 7 and/or anxiety and iiii) sexual, psychological and relational distress.(5) In a recent functional MRI study, sexually asymptomatic women and women with either vaginismus or dyspareunia were exposed to penile-vaginal penetration stimuli and stimuli that elicited disgust. Similarities and overlap in brain activity were found between the three groups of women.(6) Although group differences in subjective sexual arousal were observed in one study,(7) Cherner & Reissing(8) did not find any difference in physiological genital arousal after exposure to erotic film excerpts between women with lifelong vaginismus and dyspareunia. Notwithstanding the existing evidence of similarities, recent research that focused in particular on lifelong vaginismus in comparison with dyspareunia, has uncovered a number of specific differences between the two disorders. These differences could have clinical implications. Compared to women with dyspareunia, women with lifelong vaginismus were found to experience less subjective sexual arousal and show more negative reactions to sexual stimuli, which included fear of pain and fear of losing control of one’s body during vaginal penetration.(8-9) One study reported stronger subjective disgust and heightened facial expressions of disgust towards sexual stimuli (measured by the facial levator labia superior muscle as a unique physiological marker of disgust) in women with lifelong vaginismus.(9) Perhaps not surprisingly, avoidance behaviour has been reported as a substantial differentiator between women with vaginismus and dyspareunia.(10) In women with vaginismus, it is possible that negative cognitions, emotions and a propensity for disgust induce them to avoid vaginal penetration and sexual behaviour in general. In contrast, women with dyspareunia are more likely to continue having sexual intercourse, despite the discomfort and/or pain, albeit with reduced frequency.(8-12) 128 | CHAPTER 7
Although the DSM-5 has combined the two disorders into the genito-pelvic pain/ penetration disorder (GPPPD), the debate on diagnostic distinction continues.(13) Starting with the 1980 edition of the DSM, vaginismus was defined by a singular diagnostic criterion: recurrent or persistent involuntary spasm of the musculature of the outer third of the vagina that interferes with sexual intercourse.(14) In the DSM-5 “vaginal spasm” was removed in favour of “marked tension or tightening of the pelvic floor muscles during attempted vaginal penetration”.(13) The justification for this change was that vaginal spasm in previous iterations of the DSM had never been demonstrated as reliable or valid diagnostic criterion. However, it is questioned whether the rather vague notion of pelvic muscle tension or tightening in the current DSM-5 is an improvement. In our opinion, the original spasm criterion should be reconsidered and re-examined in terms of genito-pelvic reflexes. In this paper, we propose the genito-pelvic reflex hypothesis, which offers a new perspective on our understanding of vaginal penetration problems that interfere with sexual intercourse.
Anal canal The idea for the genito-pelvic reflex hypothesis finds its origin in anorectal research. In 1985, Preston and colleagues described “paradoxical” reflexive contractions in the anal canal, which they named ”anismus”, in a group of constipated patients during attempted defecation.(15) Anismus, recently renamed dyssynergic defecation, refers to failure of normal relaxation of the pelvic floor muscles during (attempted) defecation, i.e. unconscious voluntary external anal sphincter contraction occurs instead of relaxation. Interestingly, Preston drew already analogies between dyssynergic defecation and vaginismus in the 1990s. His theory was that in women with vaginismus, paradoxical reflexive contractions occur probably in the pubococcygeal muscle.(16-18) In a study of Broens et al. it was demonstrated that an autonomic anal-external sphincter continence reflex can be solicited by stimulation of anal submucosal receptors. In the anorectum, overreaction of this anal-external sphincter continence reflex increased the basal anal sphincter pressure.(19) After anal injection of botulinum toxin this high anal basal pressure normalised.(20) Also an autonomic reflex of the puborectalis muscle has been found: the puborectal continence reflex. Autonomic reflexes are “involuntary” and occur unconsciously. This puborectalis reflex appears to be triggered by stretching of the puborectalis muscle and can cause a long-lasting contraction of the puborectalis muscle.(21) The genito-pelvic reflex hypothesis in GPPPD | 129
Vaginal canal The anal canal, the vaginal canal and the urethra have a common embryological origin. Based on this knowledge, Broens et al. recently theorized that the vaginal canal has a sort of canalicular sphincter (reflex) mechanism, analogous to the anal canal and urethra, and that this mechanism could be involved in GPPPD.(22) Intravaginal pressures and vaginal contractions in asymptomatic women were evaluated, using high resolution solid state circumferential catheters. In response to intravaginal stimulation, the vaginal canal was found to have deep and superficial high pressure zones. These zones were generated by voluntary contractions and (very strong) reflexive contractions. Even a very low pressure in the balloon triggered autonomic reflexive contractions in these two zones that by far exceeded the pressure and duration of maximal voluntary contractions. The authors suggests that it’s possible that autonomic reflexive contractions are 7 involved in the pathogenesis of vaginismus and dyspareunia. They theorized that the deep high-pressure zone represents a “deep vaginal sphincter,” i.e., puborectalis muscle contraction, mediated by the vagino-puborectalis reflex. They further postulated that the superficial vaginal high-pressure zone represents a “superficial vaginal sphincter”, i.e., bulbocavernosus muscle contraction, mediated by the superficial vagino- bulbocavernosus reflex.(22) The bulbocavernosus muscle, ischiocavernosus muscle, anal and urethral sphincters, and, possibly, also the puborectalis muscle, i.e. muscles that derive from the embryonic cloaca, are regulated by motoneurons in a special sacral motor neuronal pool termed Onuf’s nucleus.(23-25) Onuf motoneurons have been suggested to be of a combined somatic and autonomic type.(26)
Pathogenesis; peripheral and central sensitization Minor vaginal submucosal damage could induce release of inflammatory mediators and neurogenic inflammation resulting in a reduction in the thresholds of nociceptors (peripheral sensitization). However, the pathogenesis of PVD cannot be exclusively ascribed to peripheral neurogenic inflammation. Neuronal inflammation may also be the effect of changes at central level.(27) A prevailing theory for PVD is the neuromatrix theory, suggesting that chronic pain can be the result of alterations in the widely distributed neural network, including the brain. It is believed that injury, pathology and even chronic stress can modulate this matrix.(28) According to this theory, somatic sensory input is only one component of the neuromatrix. Consequently, vulvar pain in PVD might be due to modifications in the neural network, in the absence of a physical cause. In summary, neurogenic inflammation and the accompanying pain are chronic sequels to central- 130 | CHAPTER 7
and peripheral sensitization, which results from the bidirectional influence of peripheral input and the nervous system.(1)
GENITO-PELVIC REFLEX HYPOTHESIS IN GPPPD
According to our genito-pelvic reflex hypothesis, in dyspareunia, women inadequately relax or contract their pelvic floor muscles (PFM), while continuing vaginal penetration despite pain. Primarily, in acute dyspareunia, voluntary pelvic floor muscle contractions or inadequate relaxation occurs to guard against pain due to vaginal trauma/infection and/or stress/anxiety. In chronic dyspareunia, these PFM contractions induce increasingly (sub)mucosal damage: contact- and pain receptors become more sensitive. This increased sensitivity of the contact receptors induces powerful autonomic reflexive contractions. These powerful autonomic reflexive contractions provoke vulvar pain, which causes overreactive PFM. In contrast to the voluntary system, the autonomic system is not triggered by pain and its contractions are more powerful than the voluntary contractions.(22) Vulvar (sub)mucosal damage activates both the voluntary and autonomic system and this occurs simultaneously, suggesting that these systems are connected. However, in essence these systems are not coupled. Therefore, the willingness to relax PFM does not affect the autonomic circle. In contrast to women with dyspareunia, women with lifelong vaginismus are struggling with powerful autonomic reflexive contractions which dominate the entire disease process, which causes these women’s inability to allow vaginal penetration. (see figure 1:Genito-Pelvic Reflex Hypothesis in GPPPD).
GPPPD and pelvic floor muscles Several pelvic floor study’s support our hypothesis. Shafik and colleagues (2002) reported that in women with vaginismus, the basal EMG activity in the levator ani, puborectal and bulbocavernosus muscles was significantly higher than in control women.(29) Frasson performed a neurophysiological study and observed involuntary muscular activity in the levator ani, external anal sphincter and the bulbocavernosus muscle in women with vaginismus as well in patients with dyspareunia. He concluded that the “bulbocavernosus muscle reflex” was “hyperexcitable” in women with vaginismus. (30) In 2010, Gentilcore-Saulnier and her colleagues used surface EMG and a probe to measure superficial bulbocavernosus activity and deep pelvic floor activity respectively. Compared to a control group, the women with dyspareunia showed significantly higher contractility at rest in the superficial as well as deep layers.(31) The genito-pelvic reflex hypothesis in GPPPD | 131
Vaginal trauma/infection and/or stress/anxiety
Voluntary PFM contractions Voluntary system or inadequate relaxation to guard against pain
Damage vaginal (sub)mucosa: Autonomic system Contact-receptors become more sensitive
Pain-receptors become 7 more sensitive
Provoked vestibulodynia
Overreactive PFM
Powerful autonomic reflexive contractions
Lifelong vaginismus
Figure 1 | Genito-Pelvic Reflex Hypothesis in GPPPD. Primarily, in acute dyspareunia, voluntary pelvic floor muscle (PFM) contractions or inadequate relaxation occurs to guard against pain due to vaginal trauma/infection and/or stress/anxiety. In chronic dyspareunia, these PFM contractions induce increasingly (sub)mucosal damage: contact- and pain receptors become more sensitive. This increased sensitivity of the contact receptors induces powerful autonomic reflexive contractions. These powerful autonomic reflexive contractions provoke vulvar pain, which causes overreactive PFM. In contrast to the voluntary system, the autonomic system is not triggered by pain and its contractions are more powerful than the voluntary contractions. Vulvar (sub)mucosal damage activates both the voluntary- and autonomic system and this occurs simultaneously, suggesting that these systems are connected. However, in essence these systems are not coupled. Therefore, the willingness to relax PFM does not affect the autonomic circle. In contrast to women with dyspareunia, women with lifelong vaginismus are struggling with powerful autonomic reflexive contractions which dominate the entire disease process, and causes these women’s inability to allow vaginal penetration. 132 | CHAPTER 7
Our hypothesis finds also support in a recent review study of Thibault-Gagnon and Morin (2015), in which they describe active (contractile) and passive (viscoelastic) components of pelvic floor muscle tone in women with provoked vestibulodynia. Based on their review they suggest that pelvic floor muscle overreactivity may have a predominant influence on the pelvic floor muscle contractile capacities in women with PVD.(32) A recent study of Lahaie et al. (2015) found that vaginal muscle tension was significantly greater in a group of women with vaginismus compared to women suffering from dyspareunia/PVD.(33) Similar to other muscle groups, the pelvic floor musculature is indirectly innervated by the limbic system.(34) Therefore, it is very likely that the puborectal and bulbocavernosus muscles are reactive to emotional stimuli and states, such as stress, anxiety, fear or disgust. Both and her colleagues measured pelvic floor muscle activity and genital sexual arousal in sexually healthy women without pelvic floor dysfunction using a vaginal photoplethysmograph with built-in-surface electromyography. The results of their study were that vaginal pulse amplitude (VPA) increased in response to sexual film footage and EMG values were significantly higher in response to anxiety-evoking film footage. Higher EMG values in response to the anxiety film footage were associated with lower VPA”.(35)
GPPPD and treatment modalities The genito-pelvic reflex hypothesis gains further support when prevailing treatment modalities are taken into account. It is generally believed that GPPPD should be treated according to a multidimensional approach. Main components of this approach are: psychological interventions, pelvic floor physiotherapy and vestibulectomy. In case of therapy-resistance, transcutaneous electrical nerve stimulation (TENS) and botulinum toxin are sometimes added.(36) Ideally, treatment interventions target both the voluntary and autonomic system. Some studies have been published on botulinum toxin-A treatment for pelvic floor overreactivity in women with dyspareunia and vaginismus.(37-40) Botulinum toxin is a potent neurotoxin produced by the bacterium Clostrium botulinum, a Gram-positive spore-forming organism. When injected for therapeutic purposes, it binds to peripheral nerve receptors and prevents the release of acetylcholine into the synaptic cleft, which leads to muscle paralysis.(41) In a recent study, multiple injections of botulinum toxin type A in women with pelvic floor muscle overreactivity provided significant relief from dyspareunia.(42) In a study by Ghazizadeh with 24 women with vaginismus, botulinum toxin A was injected into the puborectalis muscle at three sites bilaterally. At 1 week post- The genito-pelvic reflex hypothesis in GPPPD | 133
treatment, the symptoms of vaginismus had diminished or disappeared completely in 23 (95%) of the women; 18 (75%) were able to have pain-free intercourse after one injection, while four (16.7%) experienced mild pain during intercourse. At one-year follow-up, no symptom recurrence was reported.(43) TENS is suggested to have two mechanism for relieving pain: 1) inhibition of pain signals by stimulating non-nociceptive afferent neurons and 2) by supraspinal inhibition.(44) In a study of Vallinga et al. addition of transcutaneous electrical nerve stimulation (TENS) to a multidimensional approach reduced the level of vulvar pain and the need for vestibulectomy in women with PVD.(44) In vestibulectomy, an invasive and irreversible surgical technique, presumably pain receptors and/or pro-inflammatory molecules are removed. Success rates are reported, ranging from 61-94%.(45) Pelvic floor physiotherapy targets also the proposed hypothesis.(5) Pelvic floor muscle exercises consist of voluntary contraction as well as relaxation, in order to reduce the 7 resting tone, guarding reactions, and overreactivity of the pelvic floor muscles. Outcome studies reported successful treatment results in women with dyspareunia.(46-47) Only one retrospective outcome study is available on physiotherapy in women with vaginismus. While intercourse was reported to be possible at the end of therapy, the duration of treatment was significantly longer than that for dyspareunia.(48) Ter Kuile et al. demonstrated that therapist-aided exposure to fear eliciting vaginal penetration objects was an effective treatment for lifelong vaginismus. The therapists facilitated the women to perform vaginal penetration exercises (i.e., with a finger and/ or dilatator) in order to overcome avoidance behaviour and fear. Nearly all the women reported successful intercourse following treatment.(49) This supports that problematic sexual intercourse in women with lifelong vaginismus can be defeated without any form of ‘invasive’ intervention.
CONCLUSIONS AND RECOMMENDATIONS
Although it has never been investigated systematically, vaginal spasm has been abandoned in the new DSM-combined diagnosis and replaced by an exceedingly vague criterion that potentially applies to vaginismus as well as dyspareunia: “Marked tensing or tightening of the pelvic floor muscles during attempted vaginal intercourse/penetration”. In this paper we postulate that systematic investigation of deep- and superficial vaginal pelvic- and perineal muscle (reflex)activity is long overdue and essential to help clarify the role of pelvic pathology in vaginismus and dyspareunia. 134 | CHAPTER 7
A first step to test the genito-pelvic reflex hypothesis would be to measure vaginal reflexive contractions in sexually asymptomatic women under different conditions: at neutral-baseline, in response to negative emotions (e.g., disgust and threat) and most importantly, during exposure to erotic stimuli and disorder-specific stimuli (e.g., penile- vaginal penetration). Modern neurophysiological techniques are suitable to analyse and describe the components of the reflex arc. Ideally, a histological approach should be used to detect the exact anatomical locations of the (intra)vaginal receptors. In order to confirm the autonomic character of the reflexes, tests need to be replicated in different study groups under different circumstances, e.g., in asymptomatic women, under superficial and spinal anaesthesia, and in women with spinal cord (19)lesions. Vaginal reflexive contraction tests should also be applied to clinical populations, in particular to women with vaginismus and dyspareunia. It is of major importance to evaluate further the role of different emotional stimuli on pelvic floor muscle contractions in healthy subjects and in women with vaginismus and dyspareunia to pursue the hypothesis of a clear link with the limbic system/pelvic musculature. More knowledge on genito-pelvic reflexes is urgently required to invigorate the scientific interest in PVD and lifelong vaginismus. Research focussing on the underlying pathophysiology of female sexual pain disorders will contribute to solve the diagnostic dilemma, and will provide more insight into the pathogenesis in order to develop differential and improved management protocols for women with these distressing disorders. The genito-pelvic reflex hypothesis in GPPPD | 135
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PART III Reflection
CHAPTER 8 “Throwing the Baby Out with the Bathwater’’: The Demise of Vaginismus in Favor of Genito-Pelvic Pain/Penetration Disorder
Elke D. Reissing Charmaine Borg Symen K. Spoelstra Moniek M. ter Kuile Stephanie Both Peter J. de Jong Jacques J. D. M. van Lankveld Reinhilde J. Melles Philomeen Th. M. Weijenborg Willibrord C. M. Weijmar Schultz
Charmaine Borg and Symen K. Spoelsta are both second author.
Arch Sex Behav 2014;43(7):1209-13
Throwing the baby out with the bathwater | 143
COMMENTARY ON THE DSM-5 DIAGNOSIS GENITO-PELVIC PAIN/PENETRATION DISORDER
Over the past 15 years, there has been ongoing debate about whether vaginismus can be differentiated from dyspareunia categorically, dimensionally, or not at all (Reissing, Binik, & Khalife´, 1999). Despite the fact that the debate on diagnostic distinction continues, a significant change was made in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; American Psychiatric Association, 2013). The diagnosis of Genito-Pelvic Pain/Penetration Disorder (GPPPD) was introduced to replace the hitherto separate diagnoses of Dyspareunia and Vaginismus, previously under the subcategory of sexual pain disorders (DSM-IV-TR; American Psychiatric Association, 2000). Binik (2005a) argued that the sexual pain disorders were the only pain conditions that were classified according to the activity they interfered with and argued for their removal from the classification of sexual dysfunctions. This was received with broad skepticism from clinicians and researchers alike (Binik,2005b). The introduction of GPPPD may 8 represent an apparent compromise. The diagnostic criteria for this new category have focused on symptomatology related to pain during sexual activity and/or pain with (anticipated) vaginal penetration. The multidimensional diagnosis of GPPPD is clearly more in line with the outcomes of scientific research and clinical practice than the original categorical classification in DSM-IV-TR as outlined elegantly by Binik’s (2010a, 2010b) summary of the literature. However, GPPPD fails to capture the complexity of sexual difficulties in women who have never been able to experience intercourse (for the purpose of this commentary referred to by the previous diagnostic label of lifelong vaginismus). In our opinion, we run the risk that the baby (lifelong vaginismus) is thrown out with the bathwater (sexual pain disorders). By summarizing different aspects of lifelong vaginismus based on the results of recent studies, we will underscore this and offer a temporary solution to assist clinicians and researchers to mediate the omission of lifelong vaginismus from the DSM-5. Vaginismus was first mentioned as a sexual/reproductive problem by the Italian physician Trotula of Salerno in the eleventh century: ‘‘On the tightening of the vulva so that even a woman who has been seduced may appear a virgin’’ (1940; p. 37). The diagnostic term ‘‘vaginismus’’ was coined by the English gynecologist, J. Marion Sims, in 1861. Even in the first description of vaginismus, the confusion between pelvic floor tension and hypersensitivity/pain is remarkable: ‘‘…by the term Vaginismus I propose to designate an involuntary spasmodic closure of the vagina… (Sims, 1861, p. 362). The slightest touch with a feather or with a camel-hair pencil at the reduplication of the 144 | CHAPTER 8
hymeneal band produced as severe suffering as if she were cut with a knife’’ (p. 361). Vaginismus was first introduced to the DSM classification of sexual dysfunction in 1980 with its sole diagnostic criterion of vaginal spasm interfering with sexual intercourse (American Psychiatric Association, 1980). Despite lack of empirical validation of the diagnostic criterion and associated factors, few changes followed since its first inclusion in the DSM (Reissing, Binik, Khalife´, Cohen,& Amsel, 2004). Starting in the mid-1990s, research focusing on dyspareunia flourished with the attention on vulvodynia as a main cause for (superficial) dyspareunia in pre-menopausal women (e.g., Meana & Binik, 1994; Weijmar Schultz et al., 2005). Increasingly researchers struggled to categorically define dyspareunia and vaginismus and research findings pointed towards significant overlap of the two disorders (e.g., Binik, Bergeron, & Khalife´, 2007; Borg et al., 2014; de Kruiff et al., 2000; Engman et al., 2004; Har-Toov, Militscher, Lessing, Abramov, & Chen, 2001; ter Kuile et al., 2005). However, despite this overlap, evidence has emerged over the past few years to suggest that there are potential differences in etiology, clinical presentation, and treatment. The process of determining the diagnostic distinction is complex because of difficulties in determining whether symptomatology overlapped due to actual dimensional differences, poor differentiation of study groups, lack of valid and distinct diagnostic criteria, or some combination thereof. Nevertheless, the accumulated evidence of overlapping symptomatology and paucity of information on categorical differences at the time of the development of the DSM-5 criteria resulted in the inferred inclusion of lifelong vaginismus under the collective diagnosis of GPPPD (Binik, 2010b). For researchers and clinicians who work with women with the complaint of impossible intercourse despite desire and attempts to have intercourse, it should be clear that the diagnosis of lifelong vaginismus can no longer be made on the basis of DSM-5. The current diagnosis focuses on ‘‘difficulties…(with) vaginal penetration during intercourse’’ (American Psychiatric Association, 2013, p. 437) but does not provide for the inability to experience intercourse. In the new DSM-5, women with lifelong vaginismus fall into a diagnostic void. A significant number of these women, especially in countries other than North America and Europe, will indicate reasons other than pain or fear of pain impeding their ability to experience intercourse (e.g., Badran et al., 2006; Dogan, 2009; Michetti et al., 2013; Nabil Mhiri et al., 2013; Yasan & Akdeniz, 2009). In the diagnostic features of GPPPD, it is mentioned that ‘‘In other cases, this marked fear does not appear to be closely related to the experience of pain, but nonetheless leads to avoidance of intercourse and vaginal penetration situations’’ (American Psychiatric Association, 2013, p. 438). However, these diagnostic features are not typically a part of the communication Throwing the baby out with the bathwater | 145
of diagnoses and not part of diagnostic and inclusion criteria used for clinical practice (e.g., choice of treatment) and research. Consequently, reasons other than pain- related are not adequately captured by the diagnostic dimensions of ‘‘vulvo-vaginal or pelvic pain (…)’’ and ‘‘fear and anxiety about vulvo-vaginal or genital pain (…)’’ (American Psychiatric Association, 2013, p. 437). Finally, the notion of ‘‘marked tensing or tightening of the pelvic floor muscles (…)’’(p. 437) is hardly an improvement over the vagueness of ‘‘… involuntary spasm of the musculature of the outer third of the vagina (…)’’ of the DSM-IV- TR (American Psychiatric Association, 2000, p. 556). Women report low proprioception of their pelvic floor muscle function and reports of gynaecologists’ evaluation are not reliable (Reissing et al., 2004). Pelvic floor physical therapists are well-trained to perform such evaluations; however, they are not typically charged with the diagnosis of women with GPPPD. In addition, for many women with lifelong vaginismus, such an examination would provoke too much anxiety to be carried out. While arguably an improvement in capturing the scientific and clinical portrait of women who experience pain with sexual activity, GPPPD is clinically not useful for women who have never been able to experience 8 intercourse. Even more considerable is the deleterious impact on research. Not being able to differentiate women, at least descriptively (as in Female Orgasmic Disorder: ‘‘never experienced orgasm under any situation’’; American Psychiatric Association, 2013, p. 430), prematurely obliterates research efforts to highlight the characteristics of potential dimensional differences and/or to clarify categorical differences. Currently, the accumulated body of research with women unable to experience intercourse is still relatively modest. There are some indications, however, that women with lifelong vaginismus can be distinguished from women with dyspareunia by the degree of catastrophic or fearful penetration cognitions (Borg, Peters, Weijmar Schultz, & de Jong, 2012; Cherner & Reissing, 2013b; Klaassen & ter Kuile, 2009; Reissing, 2012), marked avoidance behavior (de Kruiff et al., 2000; Reissing et al., 2004), disgust of sexual intercourse (Borg & de Jong, 2010, Borg et al.,2011; de Jong, van Overveld, Weijmar Schultz, Peters, & Bu- walda, 2009; Reissing, 2012), and disgust for stimuli contaminated with sexual byproducts (van Overveld et al., 2013). In addition, better treatment outcome in lifelong vaginismus is associated with a reduction in fear and avoidance behavior (Melles et al., 2014; ter Kuile et al., 2009, 2013), far more so than other treatment approaches (Melnik, Hawton, & McGuire, 2012). Treatment paradigms focusing on pain (e.g., Landry, Bergeron, Dupuis, & Desrochers, 2008; Masheb, Kerns, Lozano, Minkin, & Richman, 2009; Spoelstra, Dijkstra, van Driel, & Weijmar Schultz, 2011) have never been evaluated in women who are unable to experience intercourse. It is, however, noteworthy that in treatment studies using an exposure paradigm successfully, the interventions are based 146 | CHAPTER 8
on countering fear and avoidance behavior (ter Kuile & Reissing, 2014; ter Kuile et al., 2009, 2013). While pain may have been one fear about penetration, it does not appear to be pivotal during or after treatment. Rather, it appears that behavioral avoidance keeps women from confronting and disconfirming their penetration-related fears and maladaptive expectations (pain, disgust, injury, etc.; ter Kuile & Reissing, 2014). Women with lifelong vaginismus report significantly more negative cognitions related to vaginal penetration (e.g., Klaassen & ter Kuile, 2009; Reissing, 2012; ter Kuile et al., 2009) and have higher pain catastrophizing cognitions when compared to both women without sexual pain and to women with dyspareunia (Borg et al., 2012; Klaassen & ter Kuile, 2009). In experimental conditions, women with vaginismus demonstrated enhanced levels of fear towards sexual penetration stimuli compared to women with dyspareunia (Borg et al., 2010). Consistent with the view that catastrophic appraisal of anticipated vaginal penetration may promote hypervigilance to pain and avoidance behavior, women with vaginismus also scored higher on harm avoidance (Borg et al., 2012). The finding that these women were inclined towards higher levels of harm avoidance is in line with behavioral evidence indicating that women with vaginismus, compared to women with dyspareunia, display significantly stronger defensive reactions during gynecological and pelvic floor examinations despite no significant differences in reports of pain (Reissing et al., 2004). In addition, they displayed notably more avoidant behaviors and were less likely to have had gynecological examinations or use tampons and were less likely to attempt vaginal intercourse (Cherner & Reissing, 2013b; de Kruiff et al., 2000). Thus, both pain catastrophizing cognitions and trait harm avoidance could jointly contribute to strengthen the link between sexual cues and (anticipation of) pain (or a negative experience) by eliciting further negative processes and reactions as summarized in the fear avoidance model of vaginismus (Reissing, 2009; ter Kuile, Both, & van Lankveld, 2010; ter Kuile & Reissing, 2014). In addition to fear of pain, pain catastrophizing cognitions, and harm avoidance, disgust and fear of contamination in women with lifelong vaginismus have offered insights into potential differences between dyspareunia and vaginismus (Borg et al., 2010; Cherner & Reissing, 2013a; de Jong et al., 2009, 2013; Reissing, 2012). Various body parts and body products that are directly involved in sex differ in their contamination sensitivity and disgust potency (Rozin, Nemerhoff, Horowitz, Gordon, & Voet, 1995). In addition, disgust is highly associated with avoidant tendencies and defensive reflexes that may help to protect and to avoid (the anticipated) contamination (Yartz & Hawk, 2002). In this reasoning, the prospect of mere physical contact with the vulva and/or the anticipation of penetration by the partner’s penis may elicit flinching or protective muscle contractions Throwing the baby out with the bathwater | 147
given the high risk of contamination associated with penetration (de Jong et al., 2009; Rozin et al., 1995; van der Velde & Everaerd, 2001). As a consequence, it seemed reasonable to assume that the more automatically activated associations in memory that lead to the more spontaneous type of behavior (e.g., flinching and defensive reactions) are most relevant in vaginismus. Although for women with vaginismus sexual penetration stimuli indeed automatically elicited associations with disgust (in a single-target implicit association task), similar automatic sex-disgust associations were also evident in women with dyspareunia (Borg et al., 2010). Yet, underscoring the potential importance of reflexive disgust response in vaginismus, women with vaginismus responded with increased levator activity in response to erotic stimulation (Borg et al., 2010). Conceivably, the increased facial levator activity could indicate that women with vaginismus respond with a more intense, general muscular (disgust-induced) defensive response (Shafik & El Sibai, 2002). Consistent with this, previous research has demonstrated that women with vaginismus (but not dyspareunia) score high on disgust propensity (de Jong et al., 2009) and self-report significantly more 8 causal attributions for their vaginal penetration difficulties as related to disgust (Reissing, 2012). It appears that in women with vaginismus, in contrast to those with dyspareunia, the validation process does not give rise to a correction of the initial (penetration-disgust) association (Borg et al., 2010, 2014). Recent research on pelvic floor muscle activity might shed light on the physiological processes underlying the penetration-disgust or potential penetration-anxiety association and why some women are able to experience intercourse despite anticipation and experience of pain while others are not. Ironically, this research is also suggesting a return to a variation of the much maligned vaginal spasm criterion for lifelong vaginismus (Spoelstra, Weijmar Schultz, Reissing, Borg & Broens, 2014). The vagina is equipped with genito-pelvic reflexes and during sexual arousal and/or intercourse, several of these reflexes can be triggered. In addition, the pelvic floor musculature, along with other muscle groups, is indirectly innervated by the limbic system and may be highly reactive to emotional states (Blok, Sturms, & Holstege, 1997; Spoelstra et al., 2014; van der Velde, Laan, & Everaerd, 2001). Therefore, it seems reasonable to assume that pelvic floor muscles (puborectalis and bulbocavernosus muscles) are highly reactive to emotional stimuli and emotional states, such as anxiety, fear, and disgust. In fact, Both, van Lunsen, Weijenborg, and Laan (2012), using the‘‘combi-probe’’(evaluating vaginal pulse amplitude and pelvic floor activity concurrently), reported increased pelvic floor activity in response to fear stimuli in women. Another study was carried out to determine the presence of vaginal sphincter mechanisms through the assessment of intra-vaginal 148 | CHAPTER 8
pressures during voluntary and induced reflexive pelvic floor contractions by filling an intra-vaginal balloon gradually (Broens, Spoelstra, & Weijmar Schultz, 2014). Intra- vaginal pressures and contractions were measured at superficial and deeper levels of the vaginal canal using high resolution, solid state circumferential catheters. Even a very low pressure in the vaginal balloon provoked autonomic reflex contractions of two areas in the vagina, by far exceeding the pressure and duration of voluntary contractions. Summarizing the recent work on vaginal muscle activity, some have hypothesized that autonomic genito-pelvic reflexes occur in reaction to emotional stimuli (e.g., disgust, anxiety, fear) and specific states (e.g., sexual arousal) in women with GPPPD (Spoelstra et al., 2014). Specifically in lifelong vaginismus, autonomic, non-voluntary (paradoxal) reflex contractions of the bulbocavernosus muscle may occur. Clearly, these investigations are in their early phase, but are innovative and promising. Further, this line of research highlights the risks of ignoring potentially critical differences between women who are unable to experience intercourse versus women who experience pain during sexual activity. In summary, the GPPPD is an empirically based and clinically useful improvement for the diagnosis of pain experienced with sexual activity (in women). However, we believe that the baby is thrown out with the bathwater and GPPPD taxa fall short of demonstrating clinical utility in women who have never been able to experience intercourse. Further, GPPPD does not accurately capture the symptomatology of lifelong vaginismus and suffers of an occidental bias which is noteworthy as greater prevalence rates of vaginismus are observed in non-Western countries (e.g., Michetti et al., 2013). Perhaps most disconcerting is the obstructive effect of the umbrella diagnosis of GPPPD on research. Eliminating even the possibility to denote that vaginal penetration was never possible as a ‘‘specifier’’ associated with the DSM-5 diagnosis (as in Female Orgasmic Disorder) severely curtails the ability of researchers to use formal diagnostic criteria to describe their study groups. In conclusion, we would like to propose two ways by which the omission of lifelong vaginismus in the DSM-5 can be mitigated. First, we suggest the addition of an ad hoc specifier to the GPPPD, indicating that ‘‘vaginal intercourse has never been possible.’’ This allows researchers and clinicians to use the umbrella diagnosis of GPPPD and its diagnostic criteria as they may apply, while being able to identify the subgroup of women suffering lifelong vaginismus. Second, while the diagnostic features outline that avoidance of vaginal penetration can be the result of fear that is not closely related to the experience of pain and has a phobic quality, avoidance is not per se part of the Throwing the baby out with the bathwater | 149
diagnostic criteria. More research is necessary to understand the nature and causes of the substantive avoidance noted in the majority of women with lifelong vaginismus. In the meantime, we suggest that researchers and clinicians alike pay close attention to whether marked avoidance behavior related to vaginal penetration is present and report this in their diagnostic decision and/or inclusion criteria. With these provisional steps we expect that women who have never been able to experience intercourse and/or show significant avoidance can receive a diagnosis that will guide decisions on appropriate treatment interventions and that research investigating lifelong vaginismus will not be hindered but rather, flourish.
8 150 | CHAPTER 8
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41. Spoelstra, S. K., Dijkstra, J. R., van Driel, M. F., 48. Trotula of Salerno. (1940). The diseases & Weijmar Schultz, W.C. M. (2011). Long-term of women (W. Mason-Hohl, Trans.).Los results of an individualized, multifaceted, Angeles: The Ward Ritchie Press. and multidisciplinary therapeutic approach 49. van der Velde, J., & Everaerd, W. (2001). The to provoked vestibulodynia. Journal of relationship between involuntary pelvic Sexual Medicine, 8, 489–496. floor muscle activity, muscle awareness 42. Spoelstra S.K., Weijmar Schultz W.C.M., and experienced threat in women with and Reissing E.R., Borg C., Broens P.M.A. without vaginismus. Behaviour Research (2014). The distinct impact of voluntary and Therapy, 39, 395–408. and autonomic pelvic floor muscles on 50. van der Velde, J., Laan, E., & Everaerd, genito-pelvic/pain penetration disorder. W. (2001). Vaginismus, a component of a Manuscript submitted for publication. general defensive reaction: An investigation 43. ter Kuile, M. M., Both, S., & Van Lankveld, J. J. of pelvic floor muscle activity during D. M. (2010). Cognitive behavioral therapy for exposure to emotion-inducing film excerpts sexual dysfunctions in women. Psychiatric in women with and without vaginismus. Clinic of North America, 33, 595–610. International Urogynecology Journal of 44. ter Kuile, M. M., Bulte, I., Weijenborg, P. T. Pelvic Floor Dysfunction, 12, 328–331. M., Beekman, A., Melles, R., & Onghena, P. 51. van Overveld, M., de Jong, P. J., Peters, M. (2009). Therapist-aided exposure for women L., van Lankveld, J. J. D. M., Melles, R., & with lifelong vaginismus: A replicated ter Kuile, M. M. (2013). The Sexual Disgust single-case design. Journal of Consulting Questionnaire: A psychometric study and and Clinical Psychology, 77, 149–159. a first exploration in patients with sexual 45. ter Kuile, M. M., Melles R. J., de Groot, H. dysfunctions. Journal of Sexual Medicine, E., Tuijnman-Raasveld, & van Lankveld, J. 10, 396–407. J. D. M. (2013). Therapist-aided exposure 52. Weijmar Schultz, W. C. M., Basson, R., Binik, for women \with lifelong vaginismus: A Y., Eschenbach, D., Wesselmann, U., & van randomized waiting-list control trial of Lankveld, J. J. D. M. (2005). Women’s sexual efficacy. Journal of Consulting and Clinical pain and its management. Journal of Sexual Psychology, 81, 1127–1136. Medicine, 2, 301–316. 46. ter Kuile, M. M., & Reissing, E. D. (2014). 53. Yartz, A. R., & Hawk, L. W. (2002). Addressing Lifelong vaginismus. In Y.M. Binik & K. Hall the specificity of affective startle modulation: (Eds.), Principles and practice of sex therapy Fear versus disgust. Biological Psychology, (5th ed., pp. 177–192). New York: Guilford 59, 55–68. Press. 54. Yasan, A., & Akdeniz, N. (2009). Treatment 47. ter Kuile, M. M., van Lankveld, J. J. D. M., Vliet of lifelong vaginismus in traditional Islamic Vlieland, C. V., Willekes, C., & Weijenborg, P. couples: A prospective study. Journal of T.M. (2005). Vulvar vestibulitis syndrome: An Sexual Medicine, 6, 1054–1061. important factor in the evaluation of lifelong vaginismus? Journal of Psychosomatic Obstetrics and Gynecology, 26, 245–249. PART VI Conclusion
CHAPTER 9 Summarizing discussion and future perspectives
Summarizing discussion and future perspectives | 157
In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) the female sexual pain disorders vaginismus and dyspareunia have been merged into the genito-pelvic pain/penetration disorder (GPPPD).(1) The principal reason behind this merging is that in clinical practice it always has been difficult to make a categorical distinction between dyspareunia and vaginismus. Generally, these two female sexual pain disorders are considered to lie on a phenotypical continuum. Nevertheless, a growing body of evidence has emerged over the past few years to suggest that lifelong vaginismus and dyspareunia are indeed two separate entities.(2-3) In this thesis we approach this paradox from different perspectives. Provoked vestibuldodynia (PVD) is the most frequent cause of chronic superficial dyspareunia in premenopausal women.(4) Until now, there is no plausible Dutch translation for this condition. The pain in PVD is provoked specifically by touch, pressure and vaginal penetration.(5) Its aetiology is multifactorial and its pathophysiology is yet unknown. PVD often leads to sexual, psychological and/or relational problems.(6-7) The subject of this thesis is the pathophysiology and clinical management of PVD. The way this subject is investigated can best be described as rooted in the Psychosomatic 9 Obstetrics & Gynaecology tradition. In the literature on Psychiatry and Psychotherapy this approach is described as the ‘scientist practitioner-model’. Where scientist refers to the process of fundamental reflection by doing research, the term practitioner refers to ‘on-the-job-experience’. One of the main characteristics of this tradition is ‘building the bridge from two sides’ to connect theory with clinical practice. The main purpose of using this approach in this thesis is twofold: 1) to evaluate the clinical treatment of PVD, and 2) to gain more insight into the pathophysiology of vaginismus and dyspareunia. Although formulated as two separate questions, these questions are highly interrelated by a mechanism known as clinical reasoning. Clinical management of PVD is based on clinical reasoning, represented by the aetiology-diagnosis-treatment trias. The rationale for this entire research project, the ‘raison d’etre’, lies in the fact that in PVD the explanation model on which diagnosis and treatment are (supposedly) grounded, is incomplete. In PVD there is no clear (linear causal) relationship between pathology and complaints. In order to be able to understand the underlying mechanisms, as a clinician one has to rely on careful and detailed chronological history taking. Subsequently, it often becomes clear that PVD symptoms in the beginning show up as normal psychophysiological protective functions. After a while, however, they seem to transform into ‘inappropriate’ symptoms: complaints. The link between the owner, the patient, and their protective function somewhere gets lost underway. This means that, in contrast to ‘normal’ 158 | CHAPTER 9
pathology (sic), primarily, the ‘cause’ of PVD symptoms probably does not lie in the phenomenon itself, but in its contextual (in)appropriateness, i.e. the (mis)match between action and reaction. A central question is why normal adaptation, with regard to perception and/or (sexual) behaviour, does not take place under seemingly normal circumstances. To understand why and how normal psychophysiological reactions have become too extreme, too prolonged, and/or too intense, PVD symptoms should always be put into a biopsychosocial perspective. From this perspective, different treatments can be initiated. In such a case, this is referred to as a multidimensional approach. This thesis starts with chapter 1, which describes the symptoms, aetiology, pathogenesis, differential diagnosis and treatment of PVD based on the case history of a young woman with PVD. Arguments are put forward why a biopsychosocial approach is required. Pain and fear of pain are key elements in PVD. Both of these elements are normal psychophysiological protective functions that are appropriate in situations of real or threatened danger. However, in PVD, they overshoot their purpose and become too extreme, too prolonged, and/or too intense. Apparently, there are often concealed and subconscious reasons for such a reaction. In this case, we are dealing with functional complaints, and consequently a bio- medical explanation model does not adequately fit the bill. The most important element in the treatment is ultimately to break the vicious circle of pain and fear. However, even after successful treatment - as this thesis will demonstrate - when resuming sexual intercourse, caution is warranted while having intercourse. To provide some insight into the clinical management of PVD, we firstly discuss the results of our treatment studies.
PART I: TREATMENT
The pharmacotherapy of PVD consists mainly of local application of anaesthetic or fatty ointments. In addition, antidepressants(8) and anticonvulsants are sometimes prescribed. Anticonvulsants are known to relieve pain in neuropathic pain conditions. (9) As discussed in chapter 2, based on the assumption that in PVD the pain has a neuropathic character, anticonvulsants (gabapentin, lamotrigine and carbamazepine) have occasionally been prescribed for the treatment of vulvodynia. Eight relevant studies on gabapentin and lamotrigine in vulvodynia were found; two case reports, three retrospective studies, two non-randomized studies and one open- label pilot trial. Seven out of these eight studies focused on the efficacy of gabapentin, while one study focused on lamotrigine. It is remarkable that we did not find any studies Summarizing discussion and future perspectives | 159
on the use of carbamazepine in the treatment of vulvodynia. Success rates with gabapentin to reduce vulvar pain ranged from 50 to 82%. In the lamotrigine study ‘substantial’ pain relief’ was reported and satisfaction with symptom relief was 82%. These results seem promising, but the studies have several methodological weaknesses. Assessment of the quality of these studies with the Oxford Centre for Evidence Based Medicine levels of Evidence revealed insufficient convincing evidence to support the use of these anticonvulsants. However, their prescription based on the clinical expertise of the gynaecologist should not be eliminated altogether. The results of some of the reviewed studies suggest that anticonvulsants were beneficial in symptom relief in at least some of the women with vulvodynia. Of course, patient care should be as evidence-based as possible, but not at the expense of a patient-based comprehensive approach. It is essential to combine clinical expertise with the needs of each individual patient. This is particularly important in case of treatment for therapy-resistant disorders such as PVD. However, to get a more definitive answer to the efficacy of anticonvulsants pharmacotherapy for the treatment of vulvodynia prospective studies are needed with a double-blind, randomized controlled design. 9
Although a one-dimensional approach, as anticonvulsant mono-pharmacotherapy is preferable to assess the therapeutic outcome of one specific intervention, it is also limited in its scope and impact. This is especially the case in PVD because its burden goes far beyond the experience of pain during intercourse. The majority of treatment studies on PVD used a one-dimensional approach and based their treatment success exclusively on the degree of persistent coital vulvar pain. This approach seems too limited. Including other criteria in the evaluation, such as sexual functioning and sexual related psychological stress, will increase the number of treatment goals. Subsequently, a multidimensional approach is required. PVD should be considered as a heterogeneous, multisystemic and multifactorial disorder and has to be treated accordingly. As identified in chapter 3 the efficacy of the multidimensional treatment approach to PVD in our medical centre was examined retrospectively in 64 women. The treatment resulted in long-term vulvar pain reduction in 81% of the women (mean follow-up 5 years). Eighty percent had resumed intercourse after treatment and 80% would recommend a similar treatment approach to other women with PVD. Although pain reduction was reported in 81%, only 8% of the patients reported complete painless sexual intercourse, i.e. 92% of the women still mentioned pain while having intercourse. Not surprisingly, compared to a matched Dutch norm group, sexual functioning scores in our study group were significantly lower and scores for sexually related personal distress significantly 160 | CHAPTER 9
higher. It was striking that there were no significant differences in relational sexual satisfaction. These women and their partners were able to adjust somehow to the circumstances, at least in terms of relational sexual satisfaction, despite the continuing (although less intense) vestibular pain. Apparently this made the treatment in the eyes of patients worthwhile, explaining the women’s positive advice to fellow sufferers to undergo such a treatment as well. In literature, it appears that PVD is not necessarily associated with general relationship maladjustment of the woman and her partner. (10) It is also suggested that facilitative male partner responses will improve sexual functioning, whereas solicitous and negative responses may be detrimental for sexual functioning. Therefore psychological interventions that target partner responses may promote sexual rehabilitation.(11-12) The data obtained, support our hypothesis that a multifaceted approach to PVD can lead to substantial improvements in vulvar pain and the resumption of intercourse. However, caution with intercourse is still warranted and even after treatment, intercourse continues to be a hypersensitive act in the majority of cases. It is essential to discuss this prior to treatment, preferably together with the partner. Not only the symptoms but also the treatment goals and results should be considered in the context of the mutual interaction in general and specifically while making love. At intake and prior to treatment realistic information should be given about the outcome of treatment, and patient education should also include possible changes in the couples’ sexual repertoire. Because of the retrospective design, lack of pre-treatment measurements and the absence of a control group, the outcome of this study should be considered as ‘preliminary’. However, given the scarcity of research in the multidimensional approach these results may provide useful information for future prospective research efforts.
Before 2009 in our medical centre, vestibulectomy was the end-of-the-line treatment for otherwise therapy-resistant women. Success rates of vestibulectomy (in the short- term) in the literature varied from 61-94%, but 9% of the women reported increased pain at long-term follow-up.(13) From a medical perspective, high impact surgery is an ultima refuge, because it is irreversible and invasive. We therefore searched for a less intrusive treatment for PVD than vestibulectomy, to enhance the therapeutic power of our multidimensional approach. Transcutaneous electrical nerve stimulation (TENS) has positive effects in chronic pain conditions and is non-invasive. As PVD is considered to be a chronic pain disorder, TENS might be a less radically therapeutic option than vestibulectomy for women with therapy-resistant vulvodynia. The therapeutic effect of TENS is most likely achieved by Summarizing discussion and future perspectives | 161
inhibition of pain signals by stimulation of non-nociceptive afferent neurons (gate-control theory)(14) and by supraspinal inhibition.(15-17) As PVD is considered to be a chronic pain disorder, we introduced TENS as an additional treatment intervention for women with otherwise therapy-resistant PVD. We opted to apply TENS in a domiciliary protocol after giving the women comprehensive instruction, because this setting is patient-friendly, most likely cost-effective and the women are expected to be more relaxed in their home environment. The disadvantage of this domiciliary procedure is the impossibility to determine the exact compliance rate. In line with what was discussed in chapter 4 our feasibility study showed that the addition of self-administered TENS to multidimensional treatment significantly reduced the level of vulvar pain and considerably reduced the need for vestibulectomy. The beneficial effect on vulvar pain remained stable in the long-term (mean follow-up 10.1 months). Sexual functioning and sexual related personal stress improved significantly after administration of TENS as well. Whereas previously 23% of our serious treatment-resistant patient population ultimately underwent vestibulectomy(18), after the introduction of TENS this percentage fell to 4%. These results not only support the hypothesis that domiciliary 9 TENS constitutes a feasible and beneficial addition to a multidimensional treatment for therapy-resistant PVD, but also that PVD can be considered a chronic pain syndrome. Researchers should realize that, placing the electrodes by the women herself could promote familiarity with the genital area, a non-intentional form of desensitisation, which in itself might have been therapeutic. In this study there was no control group. In future studies a transient sham TENS device could be used.(19)
PART II: PATHOPHYSIOLOGY
The second part of this thesis concerns the pathophysiology of provoked vestibulodynia. Although psychological ‘inappropriateness’ may be the key factor in understanding PVD, it is also interesting to study which physiological phenomena are involved, especially those which are considered to be ‘involuntary’. The female reproductive system includes an active and responsive genital tract that shows involuntary activity that might be triggered by sexual arousal, genital stimulation and/or orgasm.(20-21) In this thesis, we explore whether reflex muscle activity (‘genito-pelvic reflexes’) might be an important constituent of the (dys)functional female sexual response. First, in chapter 5 we reviewed fifteen female genito-pelvic reflexes and their presumed sexual implications. At present, the literature on genito-pelvic reflexes and their sexual implications is very limited. It is speculated that these reflexes might be involved in the 162 | CHAPTER 9
sexual response; clitoral erection, milking semen from the male urethra during sexual intercourse, the tenting effect, sperm-ovum transport and possibly also in GPPPD. In several studies, it was also suggested that female genito-pelvic reflexes might play a role in preventing the leakage of faeces, flatus and urine during sexual intercourse. However, the majority of studies on genito-pelvic reflexes have many methodological shortcomings. In addition, most of the studies are performed by the same research group and studies about the suggested sexual implications are not replicated by other groups. Therefore, the proposed sexual implications of the genito-pelvic reflexes reported in these studies have to be considered speculative. More neurophysiological and sexological research is needed to confirm the presumed sexual implications of the genito-pelvic reflexes. We recommend that all the available studies are replicated according to current neurophysiological standards. More detailed information is required about the reflex arc, i.e. the receptors, afferent and efferent limbs, the integrative centre and effector(s). In addition, it would be worthwhile to investigate the brain areas involved in different genito-pelvic reflexes and to perform histological research in order to detect intravaginal receptors and their exact locations.
The anal, urethral and vaginal canals have a common embryonic origin. The vaginal canal is mainly considered as a canal for the passive passage of the penis, foetus, sperm and menses. Recent findings, however, suggest an active-responsive canal with pressure gradients.(20-22) Therefore, we evaluated whether the vaginal canal has its own sphincter-type mechanism in analogy with the anal- and urethral canals. To shed more light on pelvic- and perineal contractions, in the study exposed in chapter 6, we performed intravaginal pressure measurements in 16 asymptomatic nulli-para women, using high solid-state circumferential catheters. In fifteen out of the sixteen women, two high-pressure zones were found, which indicates a deep and superficial contraction mechanism. These zones were generated by voluntary contractions and reflexive contractions. The pressures and the duration of the autonomic reflexive contractions significantly exceeded the pressures and duration of the voluntary contractions. The two high-pressures zones, as a result of voluntary contractions and, even more pronounced, as a result of reflexive contractions on intravaginal stimulation support our hypothesis that the vagina could have a sphincter-type mechanism. There were no significant differences between the reflexive measurements obtained in the left lateral recumbent to that in the sitting position. The preliminary data presented in this study will have to be validated in future studies. Summarizing discussion and future perspectives | 163
Based on our findings in chapter 6, and also supported by findings from previous studies by others (23-24), we postulate the genito-pelvic reflex hypothesis in chapter 7. Until now, the role of genito-pelvic reflexes is almost ignored in sexual pain disorders. Our hypothesis is that vaginal contractions play an important role in the pathophysiology of the GPPPD. According to our genito-pelvic reflex hypothesis, in acute dyspareunia, women inadequately relax or contract their pelvic floor muscles (PFM), while continuing vaginal penetration despite pain. Voluntary pelvic floor muscle contractions or inadequate relaxation occurs to guard against pain due to vaginal trauma/infection and/or stress/ anxiety. In chronic dyspareunia, these PFM contractions induce increasingly (sub) mucosal damage: contact- and pain receptors become more sensitive. This increased sensitivity of the contact receptors induces powerful autonomic reflexive contractions. These powerful autonomic reflexive contractions provoke vulvar pain, which causes overreactive PFM. In contrast to the voluntary system, the autonomic system is not triggered by pain and its contractions are more powerful than the voluntary contractions. Vulvar (sub)mucosal damage activates both the voluntary- and autonomic system and this occurs simultaneously, suggesting that these systems are connected. However, in 9 essence these systems are not coupled. Therefore, the willingness to relax PFM does not affect the autonomic circle. In contrast to women with chronic dyspareunia/PVD, women with lifelong vaginismus are struggling with powerful autonomic reflexive contractions that dominate the entire disease process. This causes these women’s inability to allow vaginal penetration. More research is needed to test this genito-pelvic reflex hypothesis. A first step could be to measure vaginal reflexive contractions in sexually asymptomatic women under different conditions: at neutral-baseline, in response to negative emotions (e.g. disgust and threat) and most importantly, during exposure to erotic stimuli and disorder-specific stimuli (e.g. penile-vaginal penetration). Neurophysiological techniques are suitable means to analyse and describe the components of the reflex arc. Additionally, a histological approach is needed to detect the exact anatomical locations of the vaginal/vulvar receptors. In order to confirm the autonomic character of the reflexes, tests need to be replicated in different study groups under different circumstances, e.g. in asymptomatic women 1) under superficial anaesthesia and 2) under spinal anaesthesia and 3) in women with spinal cord lesions. In future research vaginal reflexive contraction tests should also be applied to clinical populations, in particular to women with lifelong vaginismus and chronic dyspareunia/PVD. Moreover, it is of major importance to evaluate the roles of different emotional stimuli on pelvic floor muscle contractions in healthy subjects and in women with vaginismus and dyspareunia to pursue the hypothesis of a link with the limbic system. 164 | CHAPTER 9
PART III: REFLECTION
In chapter 8 we comment on the merging of vaginismus and dyspareunia into genito- pelvic pain/penetration disorder (GPPPD). This complicates the continuation of research on differences between lifelong vaginismus and dyspareunia/PVD. To be able to identify lifelong vaginismus within the GPPPD classification our proposal is to add an ad hoc specifier to the GPPPD to indicate that “vaginal intercourse has never been possible”. There are study results that show that women with vaginismus on levels of anxiety and avoidance behavior can be distinguished from women with dyspareunia.(25) Fear of pain can lead to avoidance behaviour. Fear, however, does not immediately have to be a result of pain. Avoidance of vaginal penetration can be the result of fear that is not directly related to the experience of pain and has a more phobic character. Despite these two different forms of avoidance, avoidance is not a separate diagnostic criterion for GPPPD, while women with vaginismus precisely seem to distinguish from women with dyspareunia in their form of avoidance. In addition, better treatment outcome in lifelong vaginismus is associated with a reduction in fear and avoidance behavior, far more so than other treatment approaches.(26) With the introduction of GPPPD it is and still remains unclear whether it concerns a woman with a genital pain problem or a penetration phobia. Our second proposal is to state this contextual information explicitly in the diagnosis and/or inclusion criteria of scientific research. Summarizing discussion and future perspectives | 165
REFERENCES 13. Bergeron S, Binik YM, Khalife S, Pagidas K, 1. American Psychiatric Association. (2013). Glazer HI, Meana M, Amsel RA. A randomized Diagnostic and statistical manual of mental comparison of group cognitive behavioral disorders (5th ed.) Arlington, VA: Author therapy, surface electromyographic 2. Cherner RA, Reissing ED. A comparative biofeedback, and vestibulectomy in the study of sexual function, behavior, treatment of dyspareunia resulting from and cognitions of women with lifelong vulvar vestibulitis. Pain 2001;91:297–306. vaginismus. Arch Sex Behav 2013;42:1605- 14. Melzack R, Wall PD. Painmechanisms:A new 1614. theory.Science 1965;150:971–9. 3. Borg C, de Jong PJ, Weijmar Schultz WCM. 15. Sluka KA, Walsh D. Transcutaneous Vaginismus and dyspareunia: automatic vs. electrical nerve stimulation: Basic science deliberate disgust responsivity. J Sex Med mechanisms and clinical effectiveness. J 2010;7:2149-2157. Pain 2003;4:109–21. 4. Meana M, Binik YM, Khalife S, Cohen D. 16. Liebano RE, Rakel B, Vance CG, Walsh Dyspareunia: Sexual dysfunction or pain DM, Sluka KA. An investigation of the syndrome? J Nerv Ment Dis 1997;185:561–9 development of analgesic tolerance to 5. Friedrich J. Vulvar vestibulitis syndrome. J TENS in humans. Pain 2011;152:335–42. Reprod Med 1987;32:110–4. 17. Melzack R, Wall P. Transcutaneous electrical 6. Ponte M, Klemperer E, Sahay A, Chren MM. nerve stimulation. In: Houston MJ, ed. Effects of vulvodynia on quality of life. J Am Handbook of pain management. 1st edition. Acad Dermatol 2009;60:70–6. London: Elsevier limited; 2003:464–70. 7. Arnold LD, Bachmann GA, Rosen R, Kelly S, 18. Spoelstra, SK, Dijkstra, JR, van Driel, MF, & 9 Rhoads GG. Vulvodynia: Characteristics and Weijmar Schultz, WCM. Long-term results associations with comorbidities and quality of an individualized, multifaceted, and of life. Obstet Gynecol 2006;107: 617–24. multidisciplinary therapeutic approach 8. Leo RJ, Dewani S. A systematic review of the to provoked vestibulodynia. J Sex Med utility of antidepressant pharmacotherapy 2011;8:489–496. in the treatment of vulvodynia pain. J Sex 19. Rakel B, et al. A new transient sham device Med 2013;10:2498-2505. allows for investigator blinding while 9. Ben-David B, Friedman M. Gabapentin delivering a true placebo treatment. J Pain therapy for vulvodynia. Anesth Analg 2010;11:230-238. 1999;89:1459–60 20. Levin RJ. Do women gain anything from 10. Smith KB, Pukall CF. A systematic review coitus apart from pregnancy? Changes in of relationship adjustment and sexual the human female genital tract activated by satisfaction among women with provoked coitus. J Sex Marit Ther 2003;29:59-69. vestibulodynia. J Sex Res 2011;48:166-91. 21. Ringrose CA. Pelvic reflex phenomena- 11. Rosen NO, Bergeron S, Sadikaj G, Glowacka incidence and significance. J Reprod Fertil M, Delisle I, Baxter ML. Impact of male 1966;12:161-165. partner responses on sexual function in 22. Broens PMA, Spoelstra SK, Weijmar Schultz women with vulvodynia and their partners: WCM. Dynamic clinical measurements a dyadic daily experience study.Health of voluntary vaginal contractions and Psychol 2014;33:823-31. autonomic vaginal reflexes. J Sex Med 12. Rosen NO, Bergeron S, Sadikaj G, Glowacka 2014;11:2966-2975. M, Baxter ML, Delisle I. Relationship 23. Shafik A, El-Sibai O. Study of the pelvic satisfaction moderates the associations floor muscles in vaginismus: a concept of between male partner responses and pathogenesis. Eur J Obstet Gynecol Reprod depression in women with vulvodynia: Biol 2002;105:67-70. a dyadic daily experience study. Pain 2014;155:1374-83. 166 | CHAPTER 9
24. Lahaie MA, Amsel R, Khalifé S, Boyer S, 26. Ter Kuile MM, Melles R, de Groot HE, Faaborg-Andersen M, Binik YM. Can fear, Tuijnman-Raasveld CC, van Lankveld JJ. pain, and muscle tension discriminate Therapist-aided exposure for women with vaginismus from dyspareunia/Provoked lifelong vaginismus: a randomized waiting- vestibulodynia? Implications for the new list control trial of efficacy. J Consult Clin DSM-5 diagnosis of genito-pelvic pain/ Psychol. 2013;81:1127-1136. penetration disorder. Arch Sex Behav. 2015;6-1547-1550. 25. Reissing ED, Binik YM, Khalife S, Cohen D, Amsel R. Vaginal spasm, pain, and behavior: an empirical investigation of the diagnosis of vaginismus. Arch Sex Behav 2004;33:5-17. CHAPTER 10 Nederlandse samenvatting
Nederlandse samenvatting | 169
In de vijfde editie van de Diagnostic and Statistical Manual of Mental Disorders (DSM-5) zijn de seksuele pijnstoornissen vaginisme en dyspareunie bij elkaar gevoegd onder de noemer genito-pelvienepijn/penetratiestoornis (GPPPS).(1) De reden voor deze samenvoeging is dat in de klinische praktijk vaginisme en dyspareunie als ziektecategorieën moeilijk te onderscheiden zijn. De algemene overtuiging is dat deze seksuele pijnstoornissen op een fenotypisch continuüm liggen. Er komen de laatste jaren echter steeds meer aanwijzingen die erop duiden dat primair vaginisme en dyspareunie toch twee verschillende entiteiten zijn.(2-3) In dit proefschrift benaderen we deze vermeende tegenstrijdigheid vanuit verschillende perspectieven. De meest voorkomende oorzaak van chronische oppervlakkige dyspareunie bij premenopauzale vrouwen is provoked vestibulodynia (PVD).(4) Tot op heden bestaat er geen goede Nederlandse vertaling voor deze aandoening. Het is kenmerkend voor PVD dat vulvaire pijn wordt uitgelokt door aanraking, druk en vaginale penetratie.(5) De etiologie van deze aandoening is multifactorieel en de pathofysiologie is vooralsnog onbekend. PVD leidt niet zelden tot seksuele, psychische en relatieproblemen.(6-7) De onderwerpen van dit proefschrift zijn de pathofysiologie en de behandeling van PVD. Deze onderwerpen worden onderzocht in de traditie van de Psychosomatische Obstetrie en Gynaecologie. In de psychiatrische en psychotherapeutische literatuur 10 wordt deze benadering omschreven als het ‘scientist practitioner model’. Daar waar wetenschappers refereren naar het proces van fundamentele reflectie door het verrichten van onderzoek, verwijst de term practitioner naar ‘on the job experience’. Eén van de hoofdeigenschappen van deze traditie is ‘building the bridge from two sides’, om op deze wijze theorie met klinische praktijk te verbinden. Het hoofddoel van het gebruik van een dergelijke benadering in dit proefschrift is tweeledig: 1) evalueren van de behandeling van PVD, en 2) meer inzicht verkrijgen in de pathofysiologie van vaginisme en dyspareunie. Hoewel geformuleerd als twee aparte doelstellingen, zijn zij nauw verweven met het proces van klinisch redeneren in de vorm van de trias: etiologie-diagnose-behandeling. De rationale voor dit gehele onderzoeksproject, de ‘raison d’etre’, ligt verscholen in het feit dat bij PVD het verklaringsmodel waarop diagnostiek en behandeling zijn gestoeld niet compleet is. Er is bij PVD immers geen duidelijke (lineaire causale) relatie tussen de pathologie en de klachten. Om de onderliggende mechanismen te begrijpen moet een clinicus varen op een zorgvuldige en gedetailleerde chronologische anamnese. Het wordt dan vaak duidelijk dat PVD symptomen zich in de beginfase als normale psychofysiologische beschermende functies presenteren. Echter, na verloop van tijd transformeren deze functies naar ‘ongepaste’ symptomen, in casu: klachten. De 170 | CHAPTER 10
beschermde functie wordt hiermee de klacht. Dit betekent dat, in tegenstelling tot bij ‘normale’ pathologie (sic), de primaire ‘oorzaak’ van PVD symptomen waarschijnlijk niet in het fenomeen zelf is gelegen, maar in haar contextuele (on)gepastheid, d.w.z. de (mis) match tussen actie en reactie. De centrale vraag is waarom normale adaptatie met betrekking tot perceptie en/of (seksueel) gedrag niet plaatsvindt onder ogenschijnlijk normale omstandigheden. Om te begrijpen waarom en hoe normale psychofysiologische reacties te extreem, te lang en/of te intens zijn, moeten PVD symptomen altijd in een biopsychosociaal perspectief worden geplaatst. Vanuit dit perspectief kunnen verschillende behandelingen worden geïnitieerd en spreken we over een multidimensionale benadering. Dit proefschrift begint in hoofdstuk 1 met de ziektegeschiedenis van een jonge vrouw aan de hand waarvan de epidemiologie, symptomatologie, etiologie en pathogenese, differentiaal diagnose en de behandeling van PVD wordt beschreven. Er worden argumenten aangevoerd waarom bij PVD een biopsychosociale benadering is vereist. PVD wordt namelijk in belangrijke mate gekleurd door pijn en de angst daarvoor. Zowel pijn als angst vormen bij reële bedreiging of gevaar gezonde reacties op een ongezonde situatie. In het geval van PVD lijken deze reacties hun doel voorbij te schieten door te extreem, te lang en/of te intens aanwezig te zijn. Niet zelden is er ook sprake van een klacht achter de klacht. In dat geval spreekt men van functionele klachten en schiet het biomedisch verklaringsmodel tekort. Het belangrijkste element van de behandeling is om de dan eenmaal ontstane vicieuze cirkel van angst en pijn te doorbreken. Maar zelfs na een succesvolle behandeling zal – zo toont dit proefschrift aan - bij hervatting van geslachtsgemeenschap tijdens de coïtus voorzichtigheid geboden blijven. Om inzicht te geven in de behandeling van PVD worden eerst de resultaten van onze behandelstudies besproken.
DEEL 1: BEHANDELING
Farmacologische behandeling van PVD bestaat vooral uit lokale toediening van anestheserende- of vette zalven. Soms worden antidepressiva(8) of anticonvulsiva voorgeschreven (gabapentine, lamotrigine and carbamazepine). Van anticonvulsiva is bekend dat zij ook werkzaam zijn bij neuropatische pijn.(9) Gebaseerd op de aanname dat de pijn bij PVD een neuropathisch karakter heeft, wordt in hoofdstuk 2 de effectiviteit van het gebruik van anticonvulsiva bij vulvodynie onderzocht. Nederlandse samenvatting | 171
Er werden acht relevante studies over gabapentine en latmorigine bij vulvodynie gevonden: twee case reports, drie retropectieve studies, twee non-randomized studies en een open label pilot studie. Zeven van de acht studies gaan over de effectiviteit van gabapentine, terwijl één studie gaat over de effectiviteit van lamotrigine. Het is opvallend dat er geen studies naar de effectiviteit van carbamazepine werden gevonden. De succespercentages van gabapentine om de vulvaire pijn te reduceren variëren van 50-82%. In de lamotrigine studie wordt substantiële vermindering van pijn beschreven en is de tevredenheid over symptoomverlichting 82%. Deze resultaten lijken veelbelovend, maar zonder uitzondering zijn al deze studies methodologisch zwak. Wanneer we de resultaten leggen langs de meetlat van de Oxford Centre for Evidence-Based Medicine – levels of evidence dan is er onvoldoende overtuigend bewijs om anticonvulsiva aan te bevelen voor de behandeling van vulvodynie. Dat betekent echter niet dat in de klinische praktijk in het geheel van het gebruik van deze middelen moet worden afgezien. De resultaten van studies suggereren immers dat het voorschrijven van anticonvulsiva bij enkele vrouwen met vulvodynie wel degelijk tot symptoomverlichting leidt. Natuurlijk moet ons streven zijn om zo evidence-based mogelijk te werken. Echter, zolang daarover nog geen uitsluitsel bestaat zal klinische expertise moeten worden gecombineerd met de behoeften van elke afzonderlijke 10 patiënt, zeker in het geval van therapieresistente aandoeningen zoals PVD. Tegelijkertijd moeten prospectief gecontroleerde studies worden opgezet om meer helderheid te verkrijgen over de effectiviteit van deze middelen.
Hoewel een uni-dimensionale benadering, zoals anticonvulsiva farmacotherapie, de voorkeur geniet bij het vaststellen van de uitkomst van een specifieke interventie, is deze wijze van benadering tegelijkertijd ook beperkt in zijn scope en impact. Dit is met name het geval bij PVD omdat de hierbij optredende klachten veel verder gaat dan alleen het ervaren van pijn tijdens de geslachtsgemeenschap. In de meeste studies naar de effectiviteit van de behandeling van PVD is de benadering unidimensionaal, d.w.z. gericht op één interventie, en meet men het succes van de behandeling vaak uitsluitend af aan de mate van pijnreductie ten tijde van de coïtus. Dit is een heel beperkte benadering. Wie echter kiest voor het betrekken van andere criteria in de evaluatie, zoals seksueel functioneren en seksueel gerelateerde psychische klachten, vergroot daarmee ook vrijwel altijd het aantal behandeldoelen en ook het behandelrepertoire. Omdat PVD bij uitstek een heterogene, multisystemische en multifactoriële aandoening is dient deze stoornis ook multidimensionaal behandeld te worden. 172 | CHAPTER 10
In hoofdstuk 3 wordt verslag gedaan van een onderzoek naar de effectiviteit van de multidimensionale behandeling van PVD. Het onderzoek is in opzet retrospectief en betreft 64 in het Universitair Medisch Centrum in Groningen behandelde vrouwen. 81% van deze vrouwen rapporteert bij een gemiddelde follow-up van 5 jaar een aanzienlijke reductie van de vulvaire pijn en tachtig procent heeft weer geslachtsgemeenschap. Vier op de vijf vrouwen geeft desgevraagd aan een dergelijke behandeling ook aan andere vrouwen te adviseren. Hoewel er bij 81% van de vrouwen sprake was van pijnvermindering, was geslachtsgemeenschap slechts voor 8% geheel pijnloos. De onderzochte groep behandelde vrouwen scoorde, in vergelijking met de op leeftijd gematchte Nederlandse normpopulatie, lager op de kwaliteit van hun seksuele functioneren, terwijl de scores voor seksueel gerelateerde persoonlijke stress significant hoger waren. Opvallend is dat er desondanks geen significant verschil in relationele seksuele tevredenheid is. Deze vrouwen en hun partners zijn kennelijk in staat om zich, ondanks de nog aanwezige vestibulaire pijn, aan te passen, tenminste in termen van relationele seksuele tevredenheid. Daarnaast beoordelen ze de behandeling als de moeite waard, gezien hun positieve advies aan lotgenoten om ook een dergelijke multidimensionale behandeling te ondergaan. Uit de literatuur blijkt dat PVD niet noodzakelijkerwijs geassocieerd is met algemene relationele ontregeling tussen vrouw en partner.(10) Er wordt ook gesuggereerd dat een faciliterende mannelijke partner reactie het seksuele functioneren ten goede komt terwijl onverschillige of negatieve partner reacties dit functioneren negatief kunnen beïnvloeden. Psychologische interventies gericht op de partnerrelatie, ter bevordering van de seksuele rehabilitatie, zijn daarom zinvol.(11-12) De retrospectief verkregen resultaten ondersteunen de hypothese dat de multidimensionale en multidisciplinaire behandeling van PVD weliswaar tot vermindering van vulvaire pijn en tot hervatting van de geslachtsgemeenschap kan leiden, maar ook dat na behandeling voorzichtigheid geboden blijft. Geslachtsgemeenschap blijft voor de meerderheid van deze vrouwen een gevoelige aangelegenheid en het is daarom essentieel om dit voor de behandeling, bij voorkeur samen met de partner, te bespreken. Niet alleen de klachten, maar ook de behandeldoelen en - resultaten dienen te worden bezien in de context van de algemene onderlinge interactie en in de vrij-situatie in het bijzonder. Tijdens het intake gesprek en voor aanvang van de behandeling is het van belang realistische informatie over de behandeluitkomsten te geven. Tijdens de behandeling zal aandacht moeten worden besteed aan de seksuele interactie tussen patiënte en haar partner. Vanwege het retrospectieve design, het gebrek aan metingen vooraf en de afwezigheid van een controle groep, moeten de studieresultaten als preliminair worden beschouwd. Nederlandse samenvatting | 173
Voor 2009 was vestibulectomie in het Universitair Medisch Centrum Groningen de ‘end- of- the-line’ behandeling bij therapieresistente vrouwen met PVD. De succespercentages van vestibulectomie op de korte termijn variëren in de literatuur van 61-94%, terwijl 9% van de vrouwen op langere termijn een toename van de pijn ondervindt.(13) Vanuit medische perspectief is een operatieve interventie een ultimum refugium vanwege het invasieve karakter en de irreversibele gevolgen. We zochten daarom naar een minder ingrijpend alternatief. Daarbij gingen onze gedachten uit naar Transcutane Elektrische Neuro Stimulatie (TENS). Het is bewezen dat TENS positieve effecten op chronische pijncondities heeft. Daarnaast is de methode non-invasief. Als we er vanuit gaan dat PVD een chronische pijnstoornis is zou TENS bij therapieresistente PVD, in vergelijking met een vestibulectomie, wellicht een minder radicale behandeloptie zijn. Het therapeutische effect van TENS komt waarschijnlijk tot stand door remming van pijnsignalen door de stimulatie van niet-nociceptieve afferente neuronen (14) en door supraspinale inhibitie.(15-17) We kozen ervoor om TENS na uitgebreide instructie toe te passen in de thuissituatie. De vrouwen zijn naar verwachting in deze setting meer ontspannen dan in de kliniek en daarnaast is de behandeling in deze setting waarschijnlijk ook kosteneffectiever. Nadeel van de thuissituatie is dat de therapietrouw niet kan worden gecontroleerd. 10 In hoofdstuk 4 worden de resultaten van een longitudinale prospectieve follow-up studie beschreven naar de effectiviteit van TENS in de thuissituatie bij vrouwen met therapieresistente PVD. Resultaten van de studie laten zien dat TENS in de thuissituatie toegevoegde waarde heeft voor de multidimensionale behandeling van vulvaire pijn: de pijn neemt aanzienlijk af en daarmee ook de noodzaak tot vestibulectomie. Het gunstige effect op vulvaire pijn bleef op langere termijn gehandhaafd (gemiddelde follow-up 10.1 maanden). Terwijl voorheen 23% van onze patiëntenpopulatie uiteindelijk een vestibulectomie onderging(18), was dit na introductie van TENS nog slechts bij 4% het geval. Het betreft hier een populatie uit een 3e lijns centrum waardoor er sprake is van een zeer therapieresistente selectie van patiënten. Het seksuele functioneren en de seksueel gerelateerde persoonlijk stress verbeteren na TENS significant. Deze resultaten ondersteunen niet alleen onze hypothese dat TENS in de thuissituatie een effectieve bijdrage levert aan de multidimensionale behandeling van therapieresistente PVD, maar ook dat PVD kan worden beschouwd als een chronisch pijnsyndroom. Door zelf de electroden aan te brengen in de vulvaire regio worden vrouwen meer vertrouwd met hun genitale gebied. Je zou kunnen spreken van een soort niet-intentionele vorm van desensitisatie, wat op zich al therapeutische kan werken. In dit onderzoek is geen gebruik gemaakt van een controle groep. Daarvoor zou in toekomstige studies de 174 | CHAPTER 10
zogenaamde Sham TENS gebruikt kunnen worden.(19) DEEL 2: PATHOFYSIOLOGIE
Het tweede deel van dit proefschrift gaat over de pathofysiologie van PVD. Zoals beschreven in de inleiding is het belangrijk om te realiseren dat normale psychofysiologische beschermende functies na verloop van tijd ‘ongepaste’ symptomen kunnen worden. Het is interessant om te onderzoeken welke fysiologische fenomenen daar mogelijk bij betrokken zijn. We denken dan vooral aan fenomenen die als ‘onvrijwillig’ kunnen worden beschouwd. Het vrouwelijke reproductieve systeem is immers een actief en responsief genitaal kanaal waarin onvrijwillige activiteit kan worden uitgelokt door seksuele opwinding, genitale stimulatie en/of orgasme.(20-21) In het tweede deel van dit proefschrift onderzoeken we de rol die genito-pelviene reflexen spelen bij de (dys)functionele vrouwelijke seksuele respons. In Hoofdstuk 5 wordt een overzicht gegeven van de in de literatuur beschreven vrouwelijke genito-pelviene reflexen en hun vermeende seksuele implicaties zoals zwelling van de clitoris, de voortstuwing van sperma uit de mannelijke urethra tijdens geslachtsgemeenschap, het ‘tenting-effect’, en het sperma-eicel transport. In verscheidene van de in totaal 15 gevonden studies wordt verder gesuggereerd dat vrouwelijke genito-pelviene reflexen tevens een rol zouden spelen bij het verhinderen van defecatie-, flatus- en urine-incontinentie tijdens de geslachtsgemeenschap. De meerderheid van de studies heeft vele methodologische beperkingen. Het valt op dat de meeste van de studies door dezelfde onderzoeksgroep zijn verricht en niet door andere onderzoeksgroepen zijn gerepliceerd. Substantieel bewijs voor een causaal verband tussen de genito-pelviene reflexen en de genoemde seksuele implicaties ontbreekt. Alle beschikbare studies dienen te worden gerepliceerd volgens de moderne neurofysiologische standaard. Meer informatie is nodig over de reflex boog, d.w.z. de betrokken receptoren, de afferente en efferente reflexbogen, het schakelcentrum en de effector(en). Ook is het de moeite waard om te onderzoeken welke hersengebieden betrokken zijn bij de diverse reflexen en om histologisch onderzoek te doen naar intravaginale- en vulvaire receptoren en hun exacte locaties.
Tot op heden wordt de vagina vooral gezien als een kanaal voor passieve passage van penis, foetus, sperma en menses. Maar in toenemende mate rijst het inzicht dat er eerder sprake is van een actief responsief kanaal met drukgradiënten.(20-22) Omdat het anale, urethrale en vaginale kanaal een gemeenschappelijke embryologische origine hebben, rijst in het verlengde hiervan de vraag of het vaginale kanaal, analoog aan het Nederlandse samenvatting | 175
anale- en urethrale kanaal, ook een sfincter mechanisme heeft. Om meer inzicht te krijgen in pelviene- en perineale bekkenbodemspiercontracties, werden bij 16 asymptomatische nullipara-vrouwen intravaginale drukmetingen verricht m.b.v. manometrische katheters. Deze geavanceerde katheters kenmerken zich doordat zij per gemeten locatie en rondom de absolute gemiddelde intravaginale druk registreren. De resultaten hiervan staan in hoofdstuk 6 beschreven. Bij vijftien van de zestien vrouwen blijken er diep en oppervlakkig twee duidelijk van elkaar te onderscheiden gebieden te zijn waar de druk verhoogd is op het moment van vrijwillige contracties en nog in veel hogere mate op het moment van reflectoire contracties. De basale en maximale intravaginale drukken en de duur van de reflectoire contracties overschreden in hoge mate de druk en duur van de vrijwillige contracties. Er waren geen verschillen tussen de waargenomen reflexieve contracties in linker zijligging en in zittende houding. De twee waargenomen gebieden met verhoogde druk onderschrijven de hypothese dat het vaginale kanaal een sfinctermechanisme heeft. Deze preliminaire data moet in toekomstige studies worden gevalideerd.
Gebaseerd op de uitkomsten van de voorgaande studie en bevindingen uit andere studies (23-24), wordt in hoofdstuk 7 de genito-pelviene reflex hypothese gepostuleerd. 10 Tot op heden is de rol van genitopelviene reflexen bij seksuele pijnstoornissen vrijwel genegeerd. Onze hypothese is dat vaginale contracties een belangrijke rol spelen in de pathofysiologie van de GPPPS. Volgens deze hypothese treden bij acute dyspareunie aanvankelijk vrijwillige bekkenbodemcontracties op of is er onvoldoende relaxatie als reactie op de pijn ten gevolge van vaginale trauma/infectie en/of stress/angst. Naarmate de dyspareunie langer bestaat (chronische dyspareunie) induceren deze bekkenbodemcontracties in toenemende mate (sub)mucosale schade: de gevoeligheid van de vulvaire contact- en pijnreceptoren neemt toe. De toegenomen sensitiviteit van de contactreceptoren induceert krachtige autonome reflectoire contracties. Deze autonome reflectoire contracties triggeren op hun beurt weer vulvaire pijn, wat weer tot overactieve bekkenbodemspieren leidt. In tegenstelling tot het vrijwillige systeem, wordt het autonome systeem niet door pijn getriggerd en zijn diens contracties veel krachtiger dan de vrijwillige contracties. Vulvaire (submucosale) schade activeert zowel het vrijwillige als het autonome systeem tegelijkertijd, wat suggereert dat deze systemen verbonden zijn. Echter, in essentie zijn deze systemen niet gekoppeld. Willekeurige aansturing van het autonome systeem is niet mogelijk. In tegenstelling tot de situatie bij vrouwen met chronische dyspareunie/PVD, domineren de krachtige autonome 176 | CHAPTER 10
reflectoire contracties bij vrouwen met primair vaginisme het gehele ziekteproces. Meer onderzoek is nodig om deze hypothese te toetsen. Een eerste stap zou (intra) vaginale reflectoire metingen bij seksueel asymptomatische vrouwen onder verschillende condities kunnen zijn: neutraal, in reactie op negatieve emoties (bijv. walging en bedreiging) en meest belangrijk, tijdens blootstelling aan aandoeningspecifieke erotische stimuli (peniele vaginale penetratie). Neurofysiologische technieken zijn nodig om de verschillend componenten van de reflex boog te beschrijven. Verder is histologisch onderzoek nodig om de exacte anatomische locaties van de vaginale receptoren te bepalen. Om het autonome karakter van de reflexen te bevestigen, moeten de testen in verschillende studies onder verschillende omstandigheden worden uitgevoerd: bijv. bij asymptomatische vrouwen, 1) onder oppervlakkige anesthesie en 2) onder spinale anesthesie en 3) bij vrouwen met ruggenmerg laesies. In toekomstig onderzoek zouden vaginale reflectoire contractie testen ook kunnen worden toegepast bij vrouwen met primair vaginisme en chronische dyspareunie/PVD. Verder is het van wezenlijk belang om de rol van verschillende emotionele stimuli op bekkenbodemcontracties in asymptomatische vrouwen en vrouwen met vaginisme en dyspareunie te onderzoeken, om de hypothese een link met het limbische systeem te geven.
DEEL 3: REFLECTION
In hoofdstuk 8 plaatsen we een aantal kritische opmerkingen bij het samenvoegen van vaginisme en dyspareunie onder de noemer genito-pelvienepijn/penetratiestoornis (GPPPS). Door het GPPPS-paradigma kan de diagnose primair vaginisme niet meer worden gesteld. Dit compliceert het onderzoek naar de verschillen tussen primair vaginisme en dyspareunie/PVD. Om primair vaginisme toch een plaats binnen de GPPPS classificatie te geven is ons voorstel om een ad hoc-specificatie toe te voegen die aangeeft dat vaginale geslachtsgemeenschap nog nooit mogelijk is geweest. Er zijn studies die laten zien dat vrouwen met vaginisme zich voor wat betreft angst niveau en vermijdingsgedrag onderscheiden van vrouwen met dyspareunie.(25) Angst voor pijn kan tot vermijdingsgedrag leiden. Angst hoeft echter niet direct een resultaat van pijn te zijn maar angst kan ook fobisch van aard zijn. Ondanks dat vrouwen met vaginisme zich in vermijdingsgedrag onderscheiden van vrouwen met dyspareunie, is vermijdingsgedrag niet een separaat criterium voor de diagnose GPPPS. Goede behandeluitkomsten bij primair vaginisme zijn geassocieerd met een vermindering van pijn en vermijding.(26) Met de komst van de GPPPS is en blijft het derhalve onduidelijk of er sprake is van vermijdingsgedrag in het kader van een Nederlandse samenvatting | 177
vaginaal pijnprobleem of in het kader van een penetratiefobie. Ons tweede voorstel is dan ook om bij het stellen van de diagnose en/of het opstellen van inclusie criteria ten behoeve van wetenschappelijk onderzoek dit gegeven expliciet te vermelden.
10 178 | CHAPTER 10
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PART V Appendices
LIST OF A ABBREVIATIONS
List of abbreviations | 185
PVD Provoked vestibulodynia GPPPD Genito-pelvic pain/penetration disorder NMDA N-Methyl-D-Aspartate receptor antagonists NRV Dutch relationship questionnaire FSFI Female Sexual Function Index FSDS Female Sexual Distress Scale DSM Diagnostic and Statistical Manual of Mental Disorders TENS Transcutaneous Electrical Nerve Stimulation ICM Ischiocavernosus muscle BCM Bulbocavernosus muscle EMG Electromyography VPA Vaginal Pulse Amplitude PFM Pelvic floor muscles GPPPS Genito-pelvienepijn/penetratiestoornis GABA Gamma-aminobutyric acid VAS Visual Analogue Scale MPQ-DLV McGill Pain Questionnaire-Dutch Language Version
A
CO-AUTHORS B AND THEIR AFFILIATIONS
Co-authors and their affiliations | 189
From the Department of psychosomatic Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Willibrord C. M. Weijmar Schultz, MD, PhD Marleen S. Vallinga, MD
From the Wenckebach Institute, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands H.B.M. van de Wiel, PhD
From the Department of Clinical Psychology and Experimental Psychopathology, University of Groningen, Groningen, the Netherlands Charmaine Borg, PhD P.J. De Jong, PhD
From the Department of Obstetrics and Gynecology, Isala Clinics, Zwolle, the Netherlands Jeroen R. Dijkstra, MD
From the department of Urology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Mels F. van Driel, MD, PhD
From Private floor physiotherapy practice Pelvicum, Groningen, the Netherlands B Inge L.M. Hemel
From the Department of Obstetrics and Gynecology, Nij Smellinghe Hospital, Drachten, The Netherlands Esther R. Nijhuis, MD, PhD
From the Department of Neuroscience, section Anatomy, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Janniko R. Georgiadis, PhD
From the Department of Surgery, Anorectal Physiology Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Paul M.A. Broens, MD, PhD 190 | CO-AUTHORS AND THEIR AFFILIATIONS
From the School of Psychology, University of Ottawa, Canada Elke D. Reissing, PhD
From the Outpatient Clinic of Psychosomatic Gynecology and Sexology, Department of Gynecology, Leiden University Medical Centre, Leiden, The Netherlands M. M. ter Kuile, PhD S. Both, PhD P. Th. M. Weijenborg, MD, PhD
From the Faculty of Psychology and Educational Sciences, Open University, Heerlen, The Netherlands J. J. D. M. van Lankveld, PhD DANKWOORD
From the department of Psychiatry and Psychology, Maastricht University Medical ACKNOWLEDGEMENTS Centre, Maastricht, The Netherlands R. J. Melles, MSc CURRICULUM D VITAE
Curriculum Vitae | 201
Symen Kornelis Spoelstra was born in Leeuwarden, the Netherlands, on November 21st 1979. After finishing grammar school, he studied economics. Upon successful completion of this study, he studied medicine at the University of Groningen, the Netherlands, where he obtained his MD in 2012. During his medical training, he started working on a PhD research project in the field of genito-pelvic pain/penetration disorder, formerly known as female sexual pain disorders, at the Department of Psychosomatic Obstetrics and Gynaecology of the University Medical Centre in Groningen. Over the years, he presented published work at national and international congresses. In addition, he gave lectures to medical students at the Medical Faculty of the University of Groningen, he provides support to medical students writing scientific research theses and assisted individuals with their personal (professional) development. He also followed specialized courses in Sexual Medicine in Groningen, Amsterdam and Oxford, UK. In 2013 he started working as a psychiatry resident at the mental health care organization Lentis in Groningen.
D
PUBLICATION E OVERVIEW
Publication overview | 205
RELATING TO HIS THESIS
Symen K. Spoelstra, Harry B.M. Van de Wiel. A woman with coital pain: new perspectives on provoked vestibulodynia. Accepted for publication as a chapter in the book “Bio-Psycho-Social-Obstetrics and Gynecology, a Competency Oriented Approach”
Symen K. Spoelstra, Charmaine Borg, Willibrord C.M. Weijmar Schultz. Anticonvulsant pharmacotherapy in generalized and localized vulvodynia; a critical review of the literature J Psychosom Obstet Gyneacol 2013;34(3):133-138
Symen K. Spoelstra, Jeroen R. Dijkstra, Mels F. van Driel, Wilibrord C.M. Weijmar Schultz. Long-term results of an individualized, multifaceted and multidisciplinary therapeutic approach to provoked vestibulodynia J Sex Med 2011;8(2):489-496
Marleen S. Vallinga, Symen K. Spoelstra, Inge L.M. Hemel, Harry B.M. van de Wiel, Willibrord C.M. Weijmar Schultz. Transcutaneous electric nerve stimulation as an additional treatment for women suffering from therapy-resistant provoked vestibulodynia: a feasibility study J Sex Med 2015;12(1):228-237
Symen K. Spoelstra, Esther R. Nijhuis, Willibrord C.M. Weijmar Schultz. Janniko R. Georgiadis. Female genito-pelvic reflexes and their sexual implications: a systematic review. Submitted for publication
Paul M.A. Broens, Symen K. Spoelstra, Willibrord Weijmar Schultz. Dynamic clinical measurements of voluntary vaginal contractions and autonomic vaginal reflexesJ Sex Med 2014;11(12):2966-2975
Symen K. Spoelstra, Willibrord C.M. Weijmar Schultz, Elke D. Reissing, Charmaine Borg, E Paul M.A. Broens. The distinct impact of voluntary- and autonomic pelvic floor muscles on genito-pelvic pain/penetration disorder Submitted for publication
Elke D. Reissing, Charmaine Borg, Symen K. Spoelstra, Moniek M. ter Kuile, Stephanie Both, Peter J. de Jong, Jacques J. D. M. van Lankveld, Reinhilde J. Melles, Philomeen Th. M. Weijenborg, Willibrord C. M. Weijmar Schultz. Throwing the baby out with the bathwater: the demise of vaginismus in favor of genito- pelvic pain/penetration disorder Arch Sex Behav 2014;43(7):1209-13 206 | PUBLICATION OVERVIEW
OTHER
Spoelstra SK, Baas C, Knegtering R. Antipsychotica bij therapieresistente schizofrenie. Tijdschrift van psychiatrie 2016;15:611.
Baas C, Spoelstra SK, Knegtering R. De ontwikkeling van nieuwe antipsychotica: maken nieuwe aangrijpingspunten de verwachtingen waar? Tijdschrift van psychiatrie 2016;3:243.
Knegtering R, Spoelstra SK, Baas C, Van Es, F. Lurasidon een nieuwe optie bij de behandeling van psychosen en bipolaire depressie. GGzet wetenschappelijk 2015;19:15-23.
Spoelstra SK, Baas C, Knegtering R. Lurasidon in de behandeling van depressieve episoden bij een bipolaire 1 stoornis. Tijdschrift van psychiatrie 2014;12:827.
Borg C, Georgiadis JR, Renken RJ, Spoelstra SK, Weijmar Schultz W, de Jong PJ. Brain processing of visual stimuli representing sexual penetration versus core and animal- reminder disgust in women with lifelong vaginismus. PLoS One. 2014 Jan 22;9(1):e84882
Madelief Mollers, Karin Lubbers, Symen K. Spoelstra, Willibrord CM Weijmar- Schultz, Toos Daemen, Tjalke A Westra, Marianne AB van der Sande, Hans W Nijman, Hester E de Melker and Adriana Tami. Equity in human papilloma virus vaccination uptake?: sexual behaviour, knowledge and demographics in a cross-sectional study in (un)vaccinated girls in the Netherlands. BMC Public Health 2014, 14:288 doi:10.1186/1471-2458-14-288
Spoelstra SK, Waldinger MD, Nijhuis ER, Weijmar Schultz WCM. A woman with restless genital syndrome: a difficult-to-treat condition. Ned Tijdschr Geneeskd. 2013;157(16):A5805.