Questions and Findings

In this study we addressed the long-term therapeutic effects of TLA and its potential covariates. In our previous study, we reported an 80% success rate with TLA in treating vulvodynia [32]. In the present survey, we delved into potential factors that could influence the therapeutic success of TLA, following these patients for another 5–13 years after the end of therapy. All previous therapy responders remained symptom-free. This observational prospective study involved a reasonably large, homogeneous group of patients with vulvodynia and chronic vulvar pain (secondary vulvodynia).

Variables identified as distinct between responders and non-responders become candidates for factors impeding therapeutic efficacy and may even serve as potential risk factors for the onset of vulvodynia. What accounts for the lack of response in the remaining 20% of patients, despite the majority experiencing complete remission for years? Why do some individuals develop vulvodynia while others do not?

Cofactors of Therapeutic Success in Vulvodynia

We used a very strict definition of “response”, namely, improvement to NAS ≤ 4 within a maximum of 12 TLA sessions. It is therefore important to note that patients assigned to the non-responder group also experienced an improvement to their complaints. This improvement occurred later than in the responder group, but was also significant (p = 0.03), with a median NAS reduction of 2.25 (range 0–3.5), in contrast to responders, with a median reduction of pain of NAS 7.4 [32]. In the evaluation presented here, we have addressed possible influencing factors for non-response, as discussed in the following sections.

Body Mass Index

We observed a significantly lower BMI in the non-responder group, but no correlation with age. Because the responders with an average BMI of 23.6 kg/m2 were still normal-weighted, obesity cannot be a factor. We have no clear-cut explanation of this phenomenon. We may speculate that patients with severe chronic pain may lose weight due to their impaired quality of life. A more mechanical aspect would be the assumption that in low-weight individuals with vulvodynia a mechanical irritation of the pelvic floor may play a role in maintaining vulvar pain. However, there is no scientific data for these assumptions. The phenomenon still needs further evaluation.

Type of Vulvodynia

According to the ISSVD definition of 2003, if an initial trigger of vulvodynia is identified, it is labeled secondary vulvodynia [3], and according to the 2015 nomenclature, it is labeled chronic vulvar pain [1]. Associated factors include genital herpes, lichen sclerosus, or gynecological and obstetrical scars, which, taken together, affect 20% of patients with vulvodynia. Nevertheless, there was no discernible difference in therapeutic success between patients with primary and secondary vulvodynia. All non-responders suffered from the spontaneous (continuous) type of vulvodynia, in contrast to 75% of the responder group. Although not significant (p = 0.09), the spontaneous type seems to be more difficult to treat. This observation needs further evaluation.

Lichen Sclerosus

Lichen sclerosus occurs more frequently in non-responders (p = 0.116). It would be challenging to consider lichen sclerosus as a predictive factor indicating non-response to TLA. However, taking into consideration the limited number of lichen sclerosus patients (3 out of 9), and the fact that successful TLA was also observed in these patients [38], we postulate that lichen may not be the cause, but associated with and/or potentially aggravate vulvar pain.

Pelvic Floor Dysfunction

Pelvic floor dysfunction is assumed to be a major risk factor of vulvodynia [14]. Based on our observations, there is no elevated rate of weak or missing pelvic innervation within our sample. Most of the patients have a normal pelvic tone (N = 22). However, as data on 23 patients are missing, we do not have sufficient pelvic floor assessment data to be able to calculate a difference between the two groups. This will be subject to further evaluations.

Psycho-Drug Intake and Psychotherapy

In women with known psychological factors, especially those undergoing treatment (medication or psychotherapy) before the onset of therapy, we saw a lower success rate (p = 0.177). The rate of patients with the co-factor of depression was relatively high. Paquet et al. [39], Iglesias-Rios et al. [40], and Dagostin Ferraz et al. [12] also observed a correlation with anxiety and depression. It is impossible to differentiate whether this depression is a primary depression in which higher rates of vulvodynia are observed, or if the depression occurred as a sequela caused by chronic pain. One suicide was documented in our sample, attributed to severe pain of vulvodynia. In contrast, from the two patients in the non-responder group who became symptom-free in the meantime (i.e., became responders), we know neither of them suffered from depression. Both observations support the view of depression and psychosocial disturbances as sequelae of vulvodynia, but not primary factors.

Previous Traumata

Previous traumata were reported more frequently (p = 0.10) in the medical history of non-responders. The term “trauma” in our patients consists of a group of very different entities, such as previous traumatic gynecological surgery, traumatic delivery, pain experience, or traumatic psychosocial experience, but see also the results of Iglesias-Rios [40]. Thus, previous traumata are a serious burden impairing therapy success. They should be clarified before the onset of therapy and addressed by early parallel trauma therapy within the multimodal therapy concept.

Cystitis Before and During Therapy

In the group of non-responders suffering from previous recurrent cystitis, more women developed a cystitis during the therapy phase (p = 0.058). Assuming that all events of cystitis were treated with antibiotics by the physician in charge, the question arises: Was the inferior therapy success iatrogenic, e.g., due to a disturbance of the microbiomes of the gut and genital system, with a subsequent reduction of the immune competence? As we do not have data on the kind of therapy prescribed by the urologists, we cannot clarify this question.

In contrast, none of the patients in the responder group previously suffering from recurrent cystitis observed cystitis during therapy. This may have several reasons. The anti-inflammatory effects of LA [41, 42] may have prevented an inflammation of the urogenital tract, or the shared neurological pathways of the vulvar and bladder region may have been simultaneously de-sensitized in cases of a sterile cystalgia, frequently labeled interstitial cystitis. It is a challenge to investigate a potential protective or therapeutic effect of TLA on recurrent cystitis, or cystalgia, accompanying vulvodynia.

Altogether, the rate of previous recurrent cystitis in the patients' medical history was relatively high (23 out of 39; 59.0%; 6 records missing). Connections between vulvodynia and interstitial cystitis have been described [43]. We may speculate on this coincidence as two forms of neurogenic inflammation or hyper-sensitization of the nerves involved. Both conditions show evidence of a genetic predisposition [10, 44]. Future studies should focus more on this important association.

Vulvodynia as a Genital Neuralgia

The long-term success of TLA in vulvodynia described in the present study supports the hypothesis that a substantial number of patients with vulvodynia suffer from pudendal neuralgia [32, 45]. The ISSVD 2015 classification of vulvodynia divides it into different subgroups. This nomenclature does not provide an explanation of the causes, but identifies primary (idiopathic) and secondary forms (associated with previous events), which are then called chronic vulvar pain. We did not see a difference between the success rates in these two groups. Therefore, we hypothesize that an important denominator of vulvodynia is the peripheral sensitization of nerves, independent from its cause. This concurs with other researchers describing vulvodynia as pudendal neuralgia [21, 45,46,47]. Pelvic floor dysfunction [13] according to our findings may be a sequela, not a cause of the neurogenic disorder.

We hypothesize that repeated analgesia of the nerves involved is a major key to reducing this form of neuralgia, independent of its original etiology. LAs address a multitude of receptors, such as Gq-proteins [41], N-methyl-d-aspartate (NMDA) receptor [48], transient receptor potential (TRP) channel [49], and other ion channels. Therefore, LA infiltration of the nerves seems to be more than just a blockade of the nerve conduction, but also a “reset” of neural function and pain memory using the pleiotropic properties of LAs.

The long-term effects of TLA may be based on reset mechanisms in the periphery, such as peripheral de-sensitization and/or reduction of neurogenic inflammation of the pudendal nerve’s target region [46, 47]). Our data describe possible cofactors which may impact the treatment success of vulvodynia.

The treatment modalities described in our survey suggest that vulvodynia is a pain syndrome affecting several nerves of the pelvic region [27, 31, 32], comparable to chronic regional pain syndrome (CRPS) in the extremities [50]. Repeated infiltrations of different neural structures improved the therapeutic success compared to pudendal injection alone, probably reducing peripheral and/or central sensitization on different levels of the genital region.

Until recently vulvodynia has been considered a sexual and/or psychological disorder. We analyzed a high number of potential covariates of therapeutic success. Some of the covariates found in our survey may support this view. A psychological or post-traumatic burden is correlated with an impaired therapeutic outcome. However, we cannot distinguish between psychological factors as a cause, or a sequela of vulvodynia.

For most cases of vulvodynia and its therapeutic success with TLA, however, the disease may be explained by the theory of a silent, neurogenic inflammation [47, 51, 52] and/or a neuralgia, based on a peripheral sensitization, being potentiated or followed by psychosocial factors.

Limitations and StrengthsLoss of Follow-up and Deaths

Thirty-two of 36 patients of the responder group (88.9%) and four patients of the non-responder-group (44%) were available for the follow-up. One patient in the responder group and one patient in the non-responder group had passed away. The first patient died years later for multimorbidity, and the second patient, from the non-responder group, committed suicide in 2020, claiming in her farewell letter that she could no longer stand the pain. We deeply regret that we were not able to alleviate her complaints. This is a serious reminder to all who claim that the pain and suffering from vulvodynia must be simply borne until the symptoms mitigate spontaneously. Suicidality is known to be high amongst patients with vulvodynia [12]. We face the challenge of doing everything we can to support these patients who suffer such misery. TLA is one of these options.

We followed a prospective design including all consecutive cases of vulvodynia treated in the respective period, thus avoiding drop-out failures. A long-term observation of up to 13 years after therapy has not yet been published.

As we lost follow-up contact with four of the nine non-responders (44.4%) and four of the 36 responders (11.1%), a selection bias in the analysis of long-term results cannot be ruled out. Missing data could have introduced bias. Even if we assume that all individuals without information on their long-term follow-up were non-responders, we still have a long-term success rate of 34 out of 43 patients (79.1%). This portion of patients reporting symptom-free status after a median of 95 months (7.9 years) supports the hypothesis that TLA is a highly effective therapy for a large group of patients with vulvodynia and chronic vulvar pain (as defined by the ISSVD). For these patients, the question of disease cure can be postulated.

Placebo Control and the Spontaneous Remission Rate

In complex interventions such as acupuncture, manual therapy, or TLA, creating a control arm is a major challenge. The difficulty of control arms in observational research with complex interventions has been widely discussed, and not yet sufficiently resolved [53]. According to placebo research studies, the placebo effect [54, 55] counts for an average of 20% of therapeutic success [55]. Taking this into account, we still observed an effect far beyond just placebo, lasting several years after previously unsuccessful multimodal therapy.

In 2024, the authors of a review on the spontaneous remission rate of vulvodynia [56] cited the work of Reed et al. [57] who reported on a follow-up period of 2 years (median 19.2 months). In that study, 12.5% of patients received therapy (endocrine, antifungal, topical steroids, cream, or moisturizers); none received pain therapy, antidepressants, or anticonvulsants. In that study, 50.6% of patients showed remission. In our first evaluation in 2022 [32], we demonstrated an 80% response rate after an average of 21 months of follow-up. The long-term remission rate remained at approximately 80% after a median of 7–8 years. All of the patients in the former responder group remained symptom-free.

TLA being used as an add-on therapy can take credit for subsequent therapeutic success, as none of the ongoing or previous therapy has been altered in the protocol, and success was achieved only after the introduction of TLA into the therapeutic concept.

For ethical reasons, an untreated control arm cannot be undertaken. However, our waiting time may serve as a hint for the spontaneous cure rate within a certain period. Patients did not report a spontaneous remission of symptoms during the waiting period of 1–6 months before onset of therapy, whereas 68% of patients reported being symptom-free within the first 1–6 months of the therapy period [32].

Taking all of these observations into consideration, TLA seems to be superior to a “wait and see” regime. While treating patients with TLA over 5 years of multimodal therapy efforts showed no change in the patient’s symptoms, the onset of TLA produced therapeutic success within the first 6 months of treatment in 80% of patients, and a continual remission of symptoms over the next 5–13 years.

TLA in Multimodal Pain Therapy

Vulvodynia is a chronic condition that was considered difficult to treat until now [1]. In previous reports, even after 5 years of multimodal therapy, two thirds of patients were not symptom-free [9]. A multitude of therapeutic approaches have been proposed: antibacterial, antifungal, analgesics (e.g., opiates), anticonvulsives (pregabalin) [58], antidepressants, and surgical excision [4, 7, 8], all with limited success. Vestibulectomy seems to have only short-term success [4]. In a retrospective study, long-term satisfaction was reported to slowly decrease after 2–3 years [7]. In addition, this operation is debilitating, and non-reversible. The ISSVD therefore advocates not only focusing on the primary site of pain but also taking a more holistic approach [59]. Based on the results of our investigations, we suggest integrating TLA into therapeutic regimens. The application of local anesthetics for therapeutic means in previous studies were based on difficult and expensive techniques [23, 25, 29, 60]. The novel yet simplistic TLA approach for pudendal therapy based on the nerve region or dermatome affected is applicable without elaborate tools, and easy-to-learn for gynecologists and other physicians [35]. TLA is a low-risk, low-cost, and effective therapy with little discomfort and no known long-term adverse effects.

Sample Size and Monocenter Setting

Although the study sample of 45 patients in a monocentric setting is relatively small, to our knowledge it is the largest sample of therapeutic use of LA in vulvodynia published so far. Previous studies reported on 32 patients [26], or five patients [30]. Relevant comorbidities, such as herpes simplex virus (HSV), and lichen sclerosus, as well as the subgroups of primary and secondary vulvodynia are represented in this cohort. Nevertheless, due to the limited number of patients and associated cofactors, we can report on trends, but not on significant differences between the two groups. Thus, our results can be only suggestive rather than definitive. Nevertheless, these data allow an estimation of potential risk factors and covariates for future studies.

Strengths of the Study

The long duration of follow-up and the high rate of patients in follow-up are strengths of this study. The study shows a high congruence of results with the previous evaluation of therapeutic success in the first publication, pointing to a strong and persistent long-term effect of TLA. The results are meaningful for these severely suffering patients.