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Early experience with topical meloxicam and lidocaine combination for the treatment of vulvodynia.

Introduction

Vulvodynia, defined as a chronic idiopathic vulvar pain, remains a condition of mystery for urologists. Currently, no standardized subtypes of vulvodynia exist, but it is often described as local or generalized and primary (onset prior to sexual activity) or secondary (acquired) (1) with provoked vulvodynia (PVD) being distinguished from spontaneous vulvodynia. (2)

Few modalities of treatment have been empirically validated. Treatments with some proven efficacy are individual or group cognitive behavioural therapy (CBT), (3,4) pelvic floor physical therapy (5-7), and vestibulectomy. (8,9) Medical management of vulvodynia presents a conspicuous gap in empirically validated recommendations. (10) Various medical therapies, including topical (e.g., lidocaine gel or cream, comolyn cream) and systemic agents (e.g., amitriptyline, calcium citrate, desipramine, gabapentin, paroxetine, venlaxafine), have been studied in small trials and case reports. (11) However, large-scale controlled trials have yet to identify an effective and safe drug management strategy for vulvodynia.

Topical agents have been gaining favour for chronic pain syndromes due to their higher local bioavailability and fewer systemic side effects, leading to greater patient adherence. (12) Numerous case series and small RCTs suggest clinical value of various local agents for vulvodynia, including topical capsaicin, (13,14) Botox injections, (15-17) interferon injections, (18-20) topical estrogen, (21) and local anesthetics (e.g., lidocaine).

Peripheral sensitization of nociceptors has been demonstrated as a possible mechanism of vulvodynia. (23) Such is the rationale for the use of local anesthetics, such as lidocaine, which work by blocking sodium channels in neurons, thereby increasing the threshold for depolarization. (24) The lidocaine 5% patch has been used to effectively treat various neuropathic pain conditions. (25-27) A prospective RCT found that lidocaine and CBT significantly improved vestibular pain thresholds, quality of life scores, and sexual functioning at 12-month follow-up. (22)

Inflammation is one of the key processes involved in vulvodynia. (28) Case series using combination lidocaine plus methylprednisolone (29) or betamethasone (30,31) showed promising results. However, because of a lack of high power studies for the efficacy of topical steroids and a significant side effect profile, the use of steroids is currently not recommended to treat vulvodynia. (10)

NSAID-mediated analgesia is achieved by inhibition of COX-2 enzymes, thereby inhibiting prostaglandin production. (32) Meloxicam is a selective COX-2 inhibitor with low molecular mass and high tissue tolerability, (33) and as a result meloxicam has a high intrinsic activity combined with a low ulcerogenic potential it has a therapeutic index lower than piroxicam, diclofenac and indomethacin. (34-36)

Bacchav and Patravale (37) created a topical formulation of meloxicam demonstrating physicochemical stability, excellent in vivo skin penetration, and a lack of skin irritation using the Draize test. The mechanism of the topical delivery of NSAIDs is still unclear but it is believed that local accumulation of the drug in target tissues could occur either by direct penetration or via redistribution through systemic circulation. (38,39) It has been shown that local, targeted. subcutaneous NSAID delivery might be possible and effective through topical delivery. (39)

We postulate that the topically applied combination meloxicam and lidocaine would synergistically reduce nociceptive thresholds in patients diagnosed with vulvodynia, resulting in symptom amelioration.

Methods

Patients

The Queen's University Pelvic/Bladder Pain Clinic evaluates patients presenting with interstitial cystitis, bladder pain syndrome and other urological pelvic pain problems using a standardized protocol. (40) Approximately 17% of patients assessed also complain of or are diagnosed with vulvodynia. Our standard clinic approach has been to prescribe lidocaine cream locally and amitriptyline systematically, but this has led to unsatisfactory results in many patients. Based on rationale outlined in the Introduction section, we offered vulvodynia patients who have failed our standard treatment protocol a compounded combination lidocaine/meloxicam topical gel.

Intervention

Combination lidocaine 5% and meloxicam 0.3% was formulated (Chief Pharmacy, Calgary, Alberta, Canada) and provided to patients in 50 cc labeled jars. Patients were instructed to use 5 cc applied to vulvar area BID.

Assessments

All patients underwent standardized evaluation which included focused history and physical examination (including pelvic examination with Q-tip test for vulvodynia), Interstitial Cystitis Symptom Index (ICSI) and Interstitial Cystitis Problem Index (ICPI), Pain scoring (Likert) for various pain generators including vulvar pain was noted. Patients were assessed one week later with ICSI and ICPI, pain evaluation and subjective global assessment (SGA). SGA was a 6 point questionnaire in which the patients described their symptoms as Markedly worse, Moderately worse, Mildly worse, No change, Mildly better, Moderately better and Markedly better. Responders were defined as patients who indicated that their general symptoms were moderately or markedly better following the intervention.

Analysis

The response in terms of pain score and SGA in this early experience observational study were analyzed descriptively. Since this was not a clinical trial, no effort was made to power this analysis of pilot data based on first experience with this local combination intervention.

Results

Eight of the ten patients offered the topical therapy applied it at least once. Seven of the eight treated patients had failed our standard vulvodynia intervention and the remaining patient had no previous treatment for vulvodynia. Of the eight participants, six had a subjective improvement in their symptoms with the use of the combination gel (Table 1). A pain score reduction between 1 and 4 were reported one week after starting the use of the topical agent. The other two participants saw a worsening of their symptoms, but they reported no change in their pain scores (see Table 1). The most common side effects reported were burning and stinging.

Discussion

Most of the participants had tried recommended therapies for vulvodynia and experienced no improvement. The majority reported moderate improvement of their symptoms after a one-week trial of topical lidocaine 5% and meloxicam 0.3% combination agent. No systemic side effects were reported, corroborating the current evidence that topical agents have fewer systemic side effects. (12) Two participants discontinued use due to local adverse effects such as burning and itching. These local side effects were likely attributable to the lidocaine (41,42) rather than the meloxicam. (41)

In theory, the mechanism by which meloxicam exerts its analgesic effect is via selective COX-2 inhibition as demonstrated in studies of systemic administration. (43) Meloxicam may have an additional or alternate mechanism of action when applied topically, such as inhibition of NMDA receptor hyperalgesia as observed with topical application of diclofenac. (44,45) If true, the combination of meloxicam and lidocaine may work synergistically on the nociceptive threshold to produce an analgesic effect.

Conclusion

The results from this early experience are promising for a potentially effective topical treatment for vulvodynia. A properly designed randomized placebo-controlled trial is the next step to demonstrate efficacy and characterize any adverse effects.

References

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Figures and Tables
Table 1. Early experience data

ID   Age   Symptom    Associated conditions         Previous
           duration                                 treatment(s) for
           (yrs)                                    vulvodynia

1    23     4         IBS, anxiety, urethral pain   Lidocaine cream,
                                                    amitriptyline
2    20     1         Anxiety, depression,          Physiotherapy,
                      endometriosis, persistent     lidocaine cream
                      pelvic pain
3    43     8         IBS, urethral pain,           Amitriptyline, anti-
                      endometriosis,                histamine
                      dyspareunia, chronic yeast
                      infection
4    72    19         Dyspareunia, IBS,             Tramacet,
                      depression, fibromyalgia,     physiotherapy,
                      vaginal atrophy               lyrica, premarin
5    69     2         IBS, dyspareunia, urethral    Amitriptyline
                      pain
6    45     2         Dyspareunia, chonic           None
                      constipation, anxiety

7    54    10         Vaginal atrophy, urethral     Lidocaine cream,
                      pain                          premarin,
                                                    amitriptyline
8    35     1         Traumatic birth               Physiotherapy,
                                                    lidocaine cream,
                                                    PF

ID    ICSI/ICPI      Pain    Pain      Subjective   Reported
      pre vs. post   score   score 1   global       side effects
                     prior   week      assessment
                             post

1     Pre: 14/13;    6       5         Mildly       Stinging (*)
      Post: 14/13                      improved
2     Pre: 3/4;     10      10         Moderately   Stinging,
      Post: 3/4                        worse        burning
3     Pre: 15/16;    8       4         Moderately   Stinging (*),
      Post 19/16                       improved     burning (*)
4     Pre: 11/4;     9       6         Moderately   Itching (*)
      Post: NC                         improved
5     Pre: NC;       7       4         Moderately   Numbness (*)
      Post: NC                         improved
6     Pre: 17/13;    8       8         Moderately   Stinging,
      Post: NC                         worse        burning, labia
                                                    swelling
7     Pre: 14/13;    8       6         Mildly       Itching (*)
      Post: NC                         improved
8     Pre: 14/11;    8       6         Mildly       No issues
      Post: 11/10                      improved

(*) Side effects only experienced during first few applications and
resolved by one week assessment. NC: not completed.


Rufina Kim, BSc (1); Kerri-Lynn Kelly, RN (1); Merle Olsen, PhD (2,3); J. Curtis Nickel, MD, FRCSC (1)

(1) Department of Urology, Queen's University, Kingston, ON; (2) Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB; (3) VP Research, Chief Medical, Calgary, AB; Canada

Cite as: Can Urol Assoc J 2018 April 6; Epub ahead of print.

Published online April 6, 2018

http://dx.doi.org/10.5489/cuaj.4976

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Title Annotation:CUAJ - Original Research
Author:Kim, Rufina; Kelly, Kerri-Lynn; Olsen, Merle; Nickel, J. Curtis
Publication:Canadian Urological Association Journal (CUAJ)
Article Type:Report
Date:Aug 1, 2018
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