Advances in the therapeutic approach of pudendal neuralgia: a systematic review.

CONTEXT
Although pudendal neuralgia (PN) has received growing interest over the last few years, diagnosis remains difficult, and many different therapeutic approaches can be considered.


OBJECTIVES
This article aims to provide an overview of the possible treatments of PN and investigate their efficacies.


METHODS
Utilizing PubMed and ScienceDirect databases, a systematic review was carried out and allowed identification of studies involving patients with PN, as defined by Nantes criteria, and their associated treatments. Relevant data were manually reported.


RESULTS
Twenty-eight articles were selected, totaling 1,013 patients (mean age, 49 years) and six different types of interventions. Clinical outcomes, most frequently quantified utilizing the Visual Analog Scale (VAS), vary greatly with both the therapy and time after intervention (from 100 to <10%). However, neither peri nor postoperative serious complications (grade > II of Clavien-Dindo classification) are reported. Although surgery seems to provide a higher proportion of long-term benefits, identifying the most efficient therapeutic approach is made impossible by the multitude of outcome measurements and follow-up frequencies. It should also be noted that literature is sparse regarding randomized controlled trials with long-term follow-up.


CONCLUSIONS
Although there are a number of modalities utilized for the treatment of PN, there are no current recommendations based on treatment efficacies. This seems to be largely in part caused by the lack of standardization in outcome quantification. Future research in this field should focus on prospective cohort studies with high levels of evidence, aimed at assessing the long-term, if not permanent, benefits of available therapies.

Pudendal neuralgia (PN, also called Alcock canal syndrome, pudendal nerve compression, or pudendal nerve entrapment) emerges as a result of compression within the pudendal canal, also known as Alcock canal [1]. The pudendal canal is formed by the fascia of the obturator internus muscle. The first well-known symptom of this rare pathology is pain, mainly in the perineal region. Labat et al. [2] have summarized the different forms of pain originated by PN: burning, sensations of torsion or squeezing, electrical shocks of varying intensities, and/or sensitivity disorders. The disease is recognized by the French Social Security System and managed in its severe forms when severe deterioration of the living conditions of patients is reported [3]. The French Association for Pudendal Neuralgia (Association d'Information sur la Névralgie Pudendale et les Douleurs Pelvi-Périnéales) mentions that maintaining a professional activity is often compromised [4], and Beco, in a 2015 interview [5], mentions three patients who committed suicide due to pain.

Anatomy of the pudendal nerve
Arising from the second, third, and fourth sacral nerves, the pudendal nerve is an assembly of sensory, motor, and autonomic fibers. It follows a curved trajectory out of the pelvis through the greater sciatic foramen and between the piriformis and ischiococcygeus muscles. After a short gluteal path, the pudendal nerve spans dorsally around the sciatic spine, or generally around the distal insertion of the sacrospinous ligament [1,6]. Its three different branches are the rectal nerve (innervating the external anal sphincter), the dorsal nerve of the clitoris in females and of the penis in males, and the perineal nerve innervating the scrotum, labia majora, part of the muscles elevating the anus, the ischio and bulbocavernosus muscles as well as the bulb of the penis ( Figure 1). Consequently, the role of the pudendal nerve is essential in the erection process and in both urinary and fecal continence [1].

A brief history of pudendal neuralgia
Zuelzer first described PN in 1915, but it was not until 1987 that Amarenco et al. [7] investigated perineal paralysis due to compression in Alcock's canal in cyclists. However, there are several reasons why the prevalence of PN is rarely reported in the literature. First and foremost, health professionals lack training in treating PN, making diagnosis difficult. Second, the painful body area very often prevents patients from seeking medical attention: it is worth mentioning that "pudendal" comes from a Latin word meaning, "to be ashamed." As a result, the International Pudendal Neuropathy Foundation estimates that the prevalence of PN may be around 1/100,000 of the world's population (age: 50-70 years old; 2/3 females) [8]. In France, according to the Orphanet database [9], the prevalence of PN is estimated at 1/6,000.
No accurate etiology has been established yet. However, PN is often reported to arise from one or several of the following: -Intensive practice of cycling or horseback riding (although less reported), leading to compression of the pudendal nerve -Pelvic or orthopedic surgery -Nerve stretching during childbirth -Anomalies in the sacroiliac joint -Prolonged sitting position, generally in professional activities Several studies [10][11][12][13] enumerate these factors as triggers of PN. Cycling, and to a lesser extent horse riding [14], have been reported as the most common causes of PN. Both of these activities involve prolonged sitting with cyclic shocks, compressing the pudendal nerve at two possible locations: between the sacrotuberous and sacrospinous ligaments, or at the pudendal canal level ( Figure 2). It has been reported that 7-8% of cyclists suffer from PN with long-distance practice [15]. The main reason is that repeated impacts generate high perineal pressure, resulting in indirect compression of the pudendal nerve, thus increasing friction in Alcock's canal [16]. Anatomically speaking, tissues are compressed between the saddle and pubic symphysis, as well as between the saddle and ischial tuberosities [17].

Diagnosis of pudendal neuralgia
The diagnosis of PN is complex because it may easily be confused with gynecological disorders in females, or urological symptoms in males [18,19]. Moreover, the very intimate location of this pathology often prevents patients from taking action. To date, the diagnosis of PN, as defined by Labat et al. [20] and commonly referred to as "Nantes criteria," is still based on five clinical criteria: -Pain in the pudendal nerve territory -Increased pain while sitting -Pain does not awaken patient from sleep -Pain with no objective sensory impairment -Pain relieved by anesthetic pudendal block Once the first four criteria are met, a positive anesthetic pudendal block (fifth and final criterion) ascertains a diagnosis of PN. Other characteristic symptoms of neuropathic pain, such as allodynia, hyperpathia, or sympathalgia, may also appear.
Exclusion criteria include purely coccygeal, gluteal, pubic, or hypogastric pain, exclusively paroxysmal pain, painful defecation, and pruritus where objective sensitivity impairments observed by imaging may explain the pain [2]. In the end, positive local anesthetic blocks at the contact of the pudendal nerve remain the most efficient protocol in the diagnosis of PN [21].

Treatments
The therapeutic approach to PN is generally composed of four steps. Antiepileptics or antidepressants (e.g., pregabalin) are generally prescribed, followed by local muscle relaxers, such as opium or diazepam [8]. If ineffective, infiltrations coupled with local anesthetics and corticoids may be prescribed, targeting the distal insertion of the sacrospinous ligament in the sciatic notch and the fascia of the obturator internus in Alcock's canal [22]. The effectiveness of this intervention has been reported in the literature [8,23]. In the case of pelvic pain associated with hypertonia, physiotherapy is advised [8]. If all of the previously mentioned treatments prove ineffective, surgery may be considered as a last resort [24,25], as long as PN has been present for more than 1 year [26,27]. Finally, it is worth mentioning that few literature reviews are available regarding PN. To the best of the authors' knowledge, only two systematic reviews have been published in this matter: one about drug-resistant PN by Tricard et al. [28] and the other on uncertain diagnoses of PN by Indraccolo et al. [29].
The review presented herein aims at analyzing the different therapeutic protocols tested and offered to patients suffering from PN and assessing their respective efficacies.

Source
In February 2021, EP and SM conducted the review that delivered an initial set of 1,345 articles published between 1949 and 2021. The main strategy adopted consisted of carrying out an exhaustive analysis of the scientific literature, based on the PubMed and ScienceDirect databases. The following keywords were employed to create a methodological search filter: "Alcock syndrome," "Pudendal neuralgia," "Pudendal nerve compression," "Urogenital disorders," and "Pudendal nerve entrapment." A complementary strategy was aimed at obtaining additional information by examining and combining bibliographic references cited in the relevant articles obtained earlier.
Other studies related to the topic of interest were therefore made available. In an attempt to increase the probability of finding further information, the table of contents listed in a number of medical journals as well as online documents from the AINP Association (French Association for the Information on Pudendal Neuralgia, approved by the Ministry of Health) were investigated.
EP, GP, F. Beaumont, F. Bogard, and SM reviewed the results of this initial search. Disagreements that were not resolved through discussion were arbitrated by MK.

Inclusion criteria
In this literature review, scientific papers and bibliographic studies about the various treatments of PN were selected. In view of the constant advances in medicine, only articles published after the year 2000 were included to ensure that results are correlated to current treatments. Although most articles are written in English and published in international journals, papers from French journals were also included to broaden the spectrum of knowledge in this rare disease.

Exclusion criteria
Papers mentioning perineal pain unrelated to PN were discarded. In addition, being that this is a literature review and not a study involving patient enrollment (randomized controlled, single or double blind, etc.) aimed at gathering statistically significant data, the exclusion criteria may match those selected in published statistical studies. However, being that PN is a rare disease, most works are case studies in which exclusion criteria are not explicitly defined.

Fields of interest
All selected articles were reviewed, and several sets of data were extracted. In a first step, the effectiveness of the investigated treatment, in terms of pain reduction, was recorded. The value generally consists of a Visual Analog Scale (VAS) score, even though several studies utilize different names for equivalent quantification. The second outcome of interest was the complications, as defined by the Clavien-Dindo classification [30]. This five-scale classification system aims at reporting the negative events after surgery in a simple and reproducible way, contrary to the subjective "minor" or "major" designations.

Results
Utilizing the criteria described in Section "Methods", a set of 95 articles was built from PubMed and ScienceDirect.
Seven articles published prior to the year 2000 were discarded. Thirty-two other articles were found to not be PN-specific and subsequently discarded. Twenty-five articles only described the anatomy of the pudendal nerve or did not mention the efficacy of the treatment, so they were also discarded. Finally, three articles were not included because they reported procedures applied on animals or cadavers.
Once all of these filters and criteria were taken into account, a total of 28 articles were selected, encompassing 1,013 patients who were diagnosed with PN and treated. Figure 3 presents the synopsis of the selection protocol, which was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [31].
Six different types of therapies are presented in the selected articles: transgluteal and laparoscopic decompressions, pudendal infiltration, radiofrequency, osteopathic manipulation, and nerve stimulator implantation. The most frequently utilized methods of objectification rely on the VAS, consisting in an 11-point value scale in which the score ranges from 0 (no pain) to 10 (unbearable pain), and a self-completed questionnaire on the patient's quality of life (QoL, SF-36). Table 1 summarizes data about the selected articles, such as the authors' names, the study population, the treatment type, the assessment method and its duration, and the remarkable results. Of all treatments adopted in the frame of PN, the most cited treatments are based on local infiltration targeted to the pudendal nerve and pudendal nerve decompression through surgery (including radiofrequency). A number of   complementary and/or novel treatments, such as the use of electrical stimulators or osteopathic manipulative treatment (OMT), have also been reported.

Outcomes
The outcomes reported by the selected articles are presented in Table 2. Even though most of them rely on VAS scores, the effectiveness indicators vary significantly from one study to another: treatment may be considered successful if VAS decreases by a given value or a given percentage. In some studies, the effectiveness threshold is not specified. Other studies utilize pain or QoL questionnaires to evaluate the treatment outcome, making quantification difficult. Case studies were not included in Table 2, since no treatment outcome assessment (in terms of percentage of the involved cohort) can be established.

Complications
As seen in Table 3, eight studies report complications. Two of them [21,32] required surgery (grade III of the Clavien-Dindo classification [30]), and all others were ranked grade II or below.

Discussion
Overall level of scientific evidence

Outcome of available therapeutic approaches
Raw examination of the included studies shows that surgery, with no preferential site, seems to be the most efficient therapeutic approach: pain is significantly relieved [36][37][38][39], sometimes even completely [32,40]. In all articles dedicated to this type of treatment, the patients' QoL is reported as considerably improved, ensuring a return to optimal social life and overall health status. The most striking benefit of surgery is the duration of pain improvement, which varies from long-term (commonly 4 years) to permanent. Moreover, no serious postoperative complication was reported in any of the studies. In some cases, a second surgical intervention is required several months later to achieve complete recovery [21]. Many articles report patients treated by medication at the onset of pain in the pudendal nerve territory [34,[41][42][43][44][45], although the efficacy of the medication decreases after a few months [34]. Being that PN is a debilitating disease, prescribing antidepressants and anxiolytics makes it easier for patients to accept their pathology, but it has no effect on pain intensity. As mentioned by Tricard et al. [28], pharmacological treatments cannot be considered a sustainable solution for the treatment of PN.
Infiltration has a reported short-term efficacy [34,[46][47][48][49][50], while effects up to 1 year are observed in only a very small proportion of patients [51]. As expected in this type of treatment, it appears that infiltrations must be repeated to bring relief to patients, and their effect is only temporary. However, in cases of acute pain, it constitutes a good compromise due to much easier planning than surgery and the absence of recovery phase. Conversely, the effects of surgery (whether temporary or permanent) are perceived after about a year.
The use of electrical stimulation (transcranial [52], dorsal root ganglion [42]) has yielded satisfactory outcomes, although the reduced size of the cohorts as well as the lack of long-term follow-up make it difficult to evaluate the viability of this type of therapy. In addition, such invasive approaches cannot be used as a first line treatment.
In a 2018 study reporting a prospective, randomized controlled trial of 77 patients, Fang et al. [35] showed that Pulsed RadioFrequency (PRF) is able to significantly reduce pain after 3 months (the mean VAS score decreased by two). However, only the mean VAS score is reported, which explains why the study is not included in Table 2, because no success rate can be extracted. In addition, no follow-up is reported beyond 3 months, which makes it As far as osteopathic medicine is concerned, several works report the effectiveness of OMT on peripheral nerve compression syndromes such as carpal tunnel syndrome [53][54][55][56]. In a 2012 report, the French National Institute of Health and Medical Research (INSERM) mentioned that the effectiveness of osteopathic medicine as a complementary treatment was moderate at best [57]. Nevertheless, it also stated that the literature was sparse and that the methodological limitations of the available studies were too significant for reliable conclusions to be drawn. In the present review, only two case studies-one by Lafave and Sutter [58] and the other by Origo and Tarantino [59]-were found regarding OMT-based approaches to PN. These two studies report a lasting effect on PN, with two different profiles: a male and a female, ages 31 and 40 respectively. It would seem that osteopathic medicine, as a first-intention manual therapy aimed at improving the overall motor function of the patient, can be complementary to surgery with a purpose of long-term, if not permanent, pain relief. However, both studies involve young subjects (<40 years old). Therefore, future research about the outcome of osteopathic medicine should therefore be based on older patients, given that PN mainly affects people between ages 50 and 70.
No article in the literature reports on studies about physiotherapy directly applied to PN, yet the therapy is a possible treatment for muscular hypertonia in PN patients [60]. Physiotherapy may be complementary to osteopathic medicine after a surgical intervention. New treatments that are less invasive than surgery have emerged over the last few years, such as PRF [35,61,62] or laparoscopic decompression [63], and proven their effectiveness in reducing pain and improving the patients' QoL. However, the duration of these effects is limited to an average of 6 weeks.
In this review, the most conspicuous observation to emerge is that the follow-up of crucial variables, such as pain intensity and QoL, is ensured for durations that are far too diverse. In addition, the number of patients in most studies is too low, making the assertion of an optimal treatment of PN uncertain: studies involving larger patient cohorts are required to be able to generalize the effectiveness of a given treatment. The pathology was highlighted only recently, and it remains unaddressed or just lightly addressed in medical education. However, even though the amount of dedicated scientific papers remains very limited, it has been increasing during the last few years, which shows that there is growing interest in PN. Hopefully, the related knowledge will be improved by utilizing studies with higher levels of scientific evidence, such as randomized controlled trials validated by reliable indicators such as the Physiotherapy Evidence Database (PEDro) scale [64]. More reliable conclusions should be able to highlight a relevant therapy.

Comparative efficacies
As mentioned earlier, all nine single case studies [19,36,37,39,41,45,52,58,59], representing 32.1% of the studies selected after review, were not included in Table 2. The prospective, randomized control trial by Fang et al. [35]  Restricting the analysis to only those studies that rely on a significant numerical decrease of the VAS (or equivalent) score, i.e., VAS score decreased by >50% and/or by >3, it clearly appears that infiltration, regardless of the selected site, offers very satisfying immediate results. However, the beneficial effects disappear after 6 months. Radiofrequencybased approaches seem to provide similar results in terms of efficacy and duration, although further studies involving larger cohorts are needed to support this result. A very similar conclusion may be drawn regarding electrical stimulation, with very promising results reported even after 2 years. Minimally invasive procedures, such as laparoscopic decompression, exhibit an excellent outcome [63], but studies are lacking to support this observation. Finally, surgery in the form of transgluteal decompression shows very satisfying outcomes in the long term (up to 4 years).
Finally, it should be mentioned that osteopathic medicine may be utilized as a first-intention and/or complementary treatment, its efficacy being reported in other peripheral nerve compression syndromes. However, further studies are required, as only two single-case studies are detailed in this review.

Limitations
As discussed in the previous section, treatment may be considered successful in many different ways: six studies [38,42,44,47,62,63] utilize mean VAS (or equivalent) score decreases, which makes it impossible to define an effectiveness indicator, while nine studies rely on different variations of the VAS score (e.g., relative variation, decrease by a given value). The remaining three studies utilize very different indicators, such as a complete loss of sensation [46], qualitative estimation of pain relief [50], or overall QoL improvement [61].
Consequently, and contrary to Nantes criteria that are now widespread in the diagnosis of PN, it can reasonably be concluded that there is no consensus regarding the best therapy assessment method and follow-up of patients. The multiplicity of both the result quantification items and the assessment criteria makes it difficult to analyze the clinical outcomes, and this calls for standardized indicators. Given the very recent advances in a number of therapeutic techniques of PN, emphasis should be placed on the establishment of international homogeneous criteria for patient assessment and follow-up. In such a way, all procedures could be compared directly.

Conclusions
In the present systematic review, 28 studies focusing on patients with PN and treated utilizing various approaches were investigated. It has been shown that to date, no actual scientifically robust consensus exists regarding either optimal treatment or follow-up. The scientific evidence level remains too low, due to a limited number of randomized controlled studies in the literature. It appears, however, that among all of the available treatments, surgery offers the best long-term results. Widespread knowledge of the clinical symptoms of PN should allow health professionals to directly diagnose this pathology, ensuring rapid care.
As far as osteopathic physicians are concerned, OMT can be offered to patients in addition to surgery of the pudendal nerve. However, the efficiency of such a combined approach remains to be scientifically validated by future research with a proven level of evidence.
Research funding: None reported. Author contributions: E.P., M.K., and S.M. provided substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; E.P. and S.M. drafted the article or revised it critically for important intellectual content; G.P., F.B., and F.B. gave final approval of the version of the article to be published; and all authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Competing interests: None reported.