Follow us on :


Take a look at the Recent articles

Transmucosal delivery of macromolecules using vaginal electroporation to treat vestibulodynia: A pilot study

Filippo MURINA

Lower Genital Tract Disease Unit, V. Buzzi Hospital–University of Milan, Milan, Italy

E-mail : aa

Raffaele FELICE

Lower Genital Tract Disease Unit, V. Buzzi Hospital–University of Milan, Milan, Italy

Stefania DI FRANCESCO

Lower Genital Tract Disease Unit, V. Buzzi Hospital–University of Milan, Milan, Italy

Silvia ONEDA

Lower Genital Tract Disease Unit, V. Buzzi Hospital–University of Milan, Milan, Italy

DOI: 10.15761/COGRM.1000196

Article
Article Info
Author Info
Figures & Data

Abstract

Background: Provoked vestibulodynia (VBD), is characterized by burning and cutting pain localized to the vulvar vestibule in response to light touch.

Objective: To assess the effectiveness of the electroporation (EP), applied through the vaginal probe  using a mix of two drugs: amitriptyline + lidocaine in patients with a diagnosis of VBD.

Method: 17 patients with the diagnosis of VBD received a weekly  vaginal EP  for a total of eight sessions using the following  mixture of drugs: amitriptyline at a dose of 60mg and lidocaine at a dose of  40 mg, all dissolved in a conductive gel. Visual analogue scale (VAS), Marinoff score for dyspareunia, and current perception threshold obtained from the vulvar  vestibule were assessed at baseline and at the end of treatment.

Results: The VAS was reduced from a baseline of 7.4 (1.2) to a 6.3 post therapy (1.8), and despite the variation not apparently of  large extent was actually statistically significant (p 0.05). Dyspareunia also  reduced , from baseline of 2.3 (1.0) to a post- therapy of 1.8 (1.1)  without statistical significance. There were no relevant side effects that prompted discontinuation of treatment.

Conclusions: Based on what aforementioned vaginal EP can be defined as an promising technique in the management of VBD. Although further studies are needed to define the number and frequency of sessions required, as well as the mix of drugs to be used.

Key words

 vulvodynia, transcutaneous electrical nerve stimulation, electroporation, vestibulodynia, transdermal delivery

Introduction

Vulvodynia is a common multifactorial, heterogeneous, and chronic gynecological disorder that affects a large number of women worldwide. It is estimated that the prevalence rate of vulvodynia is 16% in women aged 18 to 64 years, resulting in constant demand for medical care [1]. The predominant form of vulvodynia, provoked vestibulodynia (VBD), is characterized by burning and

cutting pain localized to the vulvar vestibule in response to light touch [2]. Etiology for vulvodynia has yet to be established, yet several theories exist.  Numerous factors have been proposed and a relevant role appears to be that of a dysfunctional state of the somatosensory system, with a peripheral and central neural sensitization [2].

Vulvodynia may result from peripheral sensitization in the skin, central sensitization in the spinal cord, or both of them. An inflammatory process in the vulvar skin could release a cascade of cytokines that sensitize the nociceptors  resulting in a physical increase in the number of nerves. Furthermore the local sensory pain nerves could become progressively more sensitized, and develop abnormal neuro-secretion with ulterior pain deterioration or persistence [2-3]

There is no standard treatment of the disease, and few randomized controlled trials have been performed [4]. The recommendations are in favor of a multi-dimensional approach, focusing on the management of pain and restoration of proper  pelvic floor function. Medical therapy (topical or oral) is a mainstay of the management of VBD [5].  Amitriptyline is  a tricyclic antidepressant that effectively treats many conditions of chronic neuropathic pain [6].  It modulates the pain by acting on the central inhibition of neuronal reuptake of neurotransmitters and  inhibition of sodium channels. Although oral administration of amitriptyline is the gold standard for the treatment of neuropathic pain and it is often used in the VBD, the systemic side effects such as postural hypotension, sedation, anticholinergic effects  limit the attainment of therapeutic doses.

The long-term use of topical lidocaine has been suggested as a specific therapy for VBD, with the rationale that the regular application of lidocaine interrupts the pain signals and reduces the  pain amplification [7]. The  use of local anesthetics in the long term can cause itching or sensitization , with severe reaction and contact dermatitis , especially with products such as benzocaine [8]. Transcutaneous electrical nerve stimulation (TENS ) with biphasic currents of frequencies between 2 and 100 Hz and a pulse duration of 50-100 microsec, has been widely used with a  high efficacy (75%) as compared to the placebo  in the treatment of VBD [9].

Electoporation (EP) is the transitory structural perturbation of lipid bilayer membranes due to the application of high voltage pulses.  Its topical application has been shown to increase the transdermal delivery of drugs with different order of magnitude [10]. In addition, the  EP expands the range of drugs ( macromolecules, lipophilic or hydrophilic , charged or neutral molecules ) that can be delivered  transdermally [11].

The aim of our study was to evaluate the effectiveness of the EP applied through the vaginal probe , using a mix of two drugs: amitriptyline + lidocaine in patients with a diagnosis of VBD. The presumption  is  to reach the area of clinical interest with a higher concentration of active ingredients, reaching higher concentration than systemic administration but with fewer side effects.

Material and methods

A total of 17 patients were enrolled. All had diagnosis of VBD due to the coexistence of the following conditions: a history of chronic  vulval pain elicited by stimulation or attempted intercourse and a positive cotton-swab test, that is tenderness at palpation of the vestibular  area with a cotton tip applicator and   the absence of any clinically detectable manifestation. Exclusion criteria were pregnancy, cardiac pacemakers, vaginal infections and neurological disorders.

The patients completed a questionnaire regarding their vulvovaginal situation, general health, demographic characteristics, and some questions about psychosexual factors.

Subsequently, each patient  underwent a gynecological examination and  evaluation of vulvovaginal symptoms with details concerning:

-Visual-analogue scale of pain (VAS) graduated from 0 to 10 (0 = no pain, 10 = maximum pain)

-Dyspareunia-graded by Marinof score (0 = absent, 1 = mild, 2 =  intense pain with reduced frequency of intercourse, 3 = penetration almost impossible).

Patients were  also subjected to a sensory electrodiagnostic evaluation of the vestibular nerve conduction  by measuring the minimum threshold of perception of a sensory input on the vestibular mucosa (CPT). The CPT values were measured using the Neurometer CPT/C electro diagnostic neurostimulator (Neurotron, Inc., Baltimore,MD), which emits alternating sinusoid waveform current stimuli at frequencies of 2,000 Hz (specific for large, myelinated AA fibers), 250 Hz (specific for AC fibers) and 5 Hz (specific for C fibers), at intensity levels from 0.001 to 9.99 mA.

Each woman included in the study received a weekly  vaginal EP  for a total of eight sessions through a plastic vaginal probe  (Bluemoon-Italy) with two transversal metal rings as electrodes connected to a unit calibrated for the  EP (Bluemoon-Italy).

The new probe has been designed with a slot for a 2.5 ml syringe,  in which  the product to be conveyed in the vestibular mucosa was placed. In the disposable syringe we inserted following  mixture of drugs: amitriptyline at a dose of 60mg and lidocaine at a dose of  40 mg, all dissolved in a conductive gel. The  EP unit was set with the following parameters of TENS, in agreement with previous studies that have used the technique in the treatment of VBD [9]:

- Phase I: 100 Hz - 50 ms- pulse duration for a  duration of 15 min.

- Phase II: 5 Hz - 100 ms-pulse duration for a duration of 15 min.

The patients were re-evaluated at the end of treatment both from symptomatic point of view (VAS and Marinof  score of dyspareunia), and  objectively through re-evaluation of the CPT.

Results

All  the recruited patients   completed the treatment protocol , and none were lost during follow-up . The characteristics of the patients studied are summarized in Table 1. The main age of the patients was 32,5 years (20-48 years). Eighty-eight percent of the patients were nulliparous (15/17). If we consider the mean duration of the symptoms was 27,5 months (6-80 months).

Table 1. Characteristics of the study population.

Age, mean (range) y

32.5 (20-48)

Nulliparous, n (%)

15/17 (88)

Duration of symptoms, mean (range), mo

27.5 (6-80)

VAS, mean (SD)

7.4 (1.2)

Marinoff dyspareunia scale, mean (SD)

2.3 (1.0)

VAS: Visual Analogue Scale

The VAS was reduced from a baseline of 7.4 (1.2) to a 6.3 post therapy (1.8) , and despite the variation not apparently of  large extent was actually statistically significant (p 0.05). Dyspareunia also  reduced , from baseline of 2.3 (1.0) to a post- therapy of 1.8 (1.1)  without statistical significance (Table 2) .

Table 2. Post treatment scores of VAS and Marinoff dyspareunia scale.

n. 17 Patients

p

VAS, mean (SD)

6.3 (1.8)

0.05

Marinoff dyspareunia scale, mean (SD)

1.8 (1.1)

NS

VAS: Visual Analogue Scale

Table 3 summarizes the values of the CPT baseline and post-therapy.

Table 3. Results of CPT measurement (100 = 1.0 mA) at 3 selected stimulation frequencies before and after therapy.

N. 17 patients

2,000 Hz

(Aβ fibers)

250 Hz

(Aδ fibers)

5 Hz

(C fibers)

Basal

 

442,2

 

201,5

 

90,8

 

After therapy

 

523,4

 

253,3

 

120,2

 

Difference, %

15,5

 

20,4

 

24,4

 

Data are expressed as means (Hz = cycles per second). CPT: Current Perception Threshold

Most changes involved the subpopulation of nociceptive C fibers with 24.4 % reduction in sensitivity. In the group of Aß and Aδ fibers, the reduction rate was respectively 15.5% and 20.4 %. There were no relevant side effects that prompted discontinuation of treatment, a post- treatment mild transient stinging was seen in about 7% of cases , and transient sedation in 10 % of patients.

Discussion

In VBD, aunanimous  pathophysiological data  is the proliferation of nerve endings in the vestibular mucosa , which is considered a non-specific reaction of previous mucosal triggers , such as infection, trauma, and hormonal factors. Another factor observed in women with this disease is the dysfunction of the pelvic floor muscles, contracted around the distal part of the vagina, probably as a reaction to persistent pain. Amitriptilina is the most widely used oral medication, although its real usefulness in the treatment of VBD is not clear. The doses commonly used vary ( 30-100 mg )  as can vary the percentage of the response, ranging between 30-60 % .This mainly derives from the difficulty in achieving an optimal therapeutic threshold resulting in high number of drop-outs due to  the  occurrence of side effects.

The lidocaine, a local anesthetic, has been used topically as well as in local infiltration of the pudendal nerve with the aim of reducing the ectopic neuronal activity, responsible for allodynia and hyperalgesia, peculiar elements of neuropathic  pain syndromes as well as that  of the VBD. A multimodal approach towards the VBD is considered to be optimal, and from this point of view association of  TENS  with the use of drugs may prove to be a winning strategy.

The EP allows to combine the  electrical stimulation to the transmucosal transport of macromolecules even in high concentrations, which are then  focused at the site of pain elicitation, vaginal vestibule, thus reducing the incidence of side effects.

Our results suggest the effectiveness of the technique. The doses of  amitriptyline and lidocaine that we used  used were high and no patient had to discontinue the treatment for the occurrence of side effects. The synergistic effect of TENS further contributed to the " reset" of the previously altered nociceptive system.

The demonstration of the absorption and action of drugs as a result of channeling through vaginal EP, is  confirmed  by CPT values. A 20 % average reduction of the sensitivity of vestibular nerve fibres proves the effect of the combination of TENS with that of drugs in the management of the dysfunction in the pain perception system, proper to the VBD.

A mild  improvement of the symptoms may be due  to the reduced frequency (1 appl./Week) and a relatively low number of EP vaginal sessions.

In fact , previous studies on TENS led to brilliant results  with an average of approximately 20 sessions.  Moreover, the patients recruited had already been treated  with limited or transient efficacy, leading to define them as "difficult".

Based on what aforementioned vaginal EP can be defined as an  effective and promising technique in the management of VBD. Although further studies are needed to define the number and frequency of sessions required, as well as the mix of drugs to be used . It may further lead  the foundation for the use of the technique in other vulvovaginal problems that require the use of drugs locally .

References

  1. Polpeta NC, Giraldo PC, Teatin Juliato CR, Gomes Do Amaral RL, Moreno Linhares I, et al. (2012) Clinical and therapeutic aspects of vulvodynia: the importance of physicaltherapy. Minerva Ginecol 64: 437-445. [Crossref]
  2. Ventolini G (2013) Vulvar pain: Anatomic and recent pathophysiologic considerations. Clin Anat 26: 130-133. [Crossref]
  3. Tympanidis P, Terenghi G, Dowd P (2003) Increased innervation of the vulval vestibule in patients with vulvodynia. Br J Dermatol 148: 1021-1027. [Crossref]
  4. Haefner HK , Collins ME, Davis GD, Edwards L, Foster DC, et al. (2005) The vulvodynia guideline. J Low Genit Tract Dis 9: 40-51. [Crossref]
  5. Groysman V (2010) Vulvodynia: new concepts and review of the literature. Dermatol Clin 28: 681-696. [Crossref]
  6. Reed BD, Caron AM, Gorenflo DW, Haefner HK (2006) Treatment of vulvodynia with tricyclic antidepressants: efficacy and associated factors. J Low Genit Tract Dis 10: 245-251. [Crossref]
  7. Dede M, Yenen MC, Yilmaz A, Baser I (2006) Successful treatment of persistent vulvodynia with submucous infiltration of betamethasone and lidocaine. Eur J Obstet Gynecol Reprod Biol 124: 258-259. [Crossref]
  8. Zolnoun DA, Hartmann KE, Steege JF (2003) Overnight 5% lidocaine ointment for treatment of vulvar vestibulitis. Obstet Gynecol 02: 84-87. [Crossref]
  9. Murina F, Bianco V, Radici G, Felice R, Di Martino, et al. (2008) Transcutaneous electrical nerve stimulation to treat vestibulodynia: a randomized controlled trail. BJOG 115: 1165-1170. [Crossref]
  10. Denet AR, Vanbever R, Préat V (2004) Skin electroporation for transdermal and topical delivery. Adv Drug Deliv Rev 56: 659-674. [Crossref]
  11. Lombry C, Dujardin N, Préat V (2000) Transdermal Drug Delivery of Macromolecules Using Skin Electroporation. Pharm Res 17: 32-37. [Crossref]

Editorial Information

Editor-in-Chief

Article Type

Research Article

Publication history

Received: October 02, 2017
Accepted: October 16, 2017
Published: October 19, 2017

Copyright

©2017 Murina F. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Murina F, Felice R, Francesco SD, Oneda S (2017) Transmucosal delivery of macromolecules using vaginal electroporation to treat vestibulodynia: A pilot study. Clin Obstet Gynecol Reprod Med 3 doi: 10.15761/COGRM.1000196

Corresponding author

Filippo Murina

V. Buzzi Hospital, Via Castelvetro 32-Milano, Italy

Table 1. Characteristics of the study population.

Age, mean (range) y

32.5 (20-48)

Nulliparous, n (%)

15/17 (88)

Duration of symptoms, mean (range), mo

27.5 (6-80)

VAS, mean (SD)

7.4 (1.2)

Marinoff dyspareunia scale, mean (SD)

2.3 (1.0)

VAS: Visual Analogue Scale

Table 2. Post treatment scores of VAS and Marinoff dyspareunia scale.

n. 17 Patients

p

VAS, mean (SD)

6.3 (1.8)

0.05

Marinoff dyspareunia scale, mean (SD)

1.8 (1.1)

NS

VAS: Visual Analogue Scale

Table 3. Results of CPT measurement (100 = 1.0 mA) at 3 selected stimulation frequencies before and after therapy.

N. 17 patients

2,000 Hz

(Aβ fibers)

250 Hz

(Aδ fibers)

5 Hz

(C fibers)

Basal

 

442,2

 

201,5

 

90,8

 

After therapy

 

523,4

 

253,3

 

120,2

 

Difference, %

15,5

 

20,4

 

24,4

 

Data are expressed as means (Hz = cycles per second). CPT: Current Perception Threshold