Vulvodynia: A Review of the Literature

Abstract

Objective: To evaluate the literature and educate the pharmacy community about the different treatment options for vulvodynia. Data Sources: Searches were performed through MEDLINE (1946-May 2018) using OVID and EBSCOhost, and Excerpta Medica (1974-May 2018) using EMBASE. Search terms included vulvar vestibulitis syndrome, vestibulodynia, vulvodynia, vulvar pain, provoked vulvar vestibulitis, and vulvodynia treatment. References of all relevant articles were then used to find additional applicable articles. Study Selection and Data Extraction: This review includes articles in the English language and human trial literature. Twenty-five trials explored the use of oral and topical medications in the treatment of vulvodynia. Data Synthesis: Vulvodynia is a poorly understood disease with an unknown etiology. Oral tricyclic antidepressants and gabapentin continue to be the most commonly used treatments for vulvodynia pain. This is due to their ease of use and patient preference. Topical treatments that have efficacy data are amitriptyline, gabapentin, lidocaine, baclofen, and hormones. This route of administration avoids systemic adverse effects and interpatient variability that accompanies oral administration. Alternative therapies more commonly used include physiotherapy, psychotherapy, and surgery. Treatment length may vary due to dose titrations and potential changes in medication therapy. Conclusions: Several medication and alternative therapies may be effective in treating vulvodynia. Current studies used wide dosing ranges, making it difficult to standardize therapy. No consistent method of assessing pain was used between studies, as well as a limited number being randomized and placebo controlled. Additional research is needed to increase knowledge and further develop vulvodynia treatments.

Introduction

Vulvodynia was defined in 2003 as “vulvar discomfort, most often described as burning pain without relevant visible findings or a specific, clinically identifiable, neurologic disorder” by the International Society for the Study of Vulvovaginal Disease (ISSVD).¹ The pain can be described as burning, itching, stinging, rawness, or irritation that may be localized to one area or generalized to the entire vulva. It could be triggered by direct touch (inserting a tampon or sexual intercourse), indirectly by walking, or even without provocation.²

It was estimated in 2012 that vulvodynia affects about 8% of women in the United States.³ That estimation increased to 16% in 2014.⁴ However, due to the negative psychological and sexual impact of vulvodynia and the number of patients who do not seek treatment, this number is probably underreported. Historically, lack of evidence during physical examination has led some practitioners to believe this was strictly a psychological problem.⁵ However, vulvodynia has been shown as a multifactorial disorder with no one proven etiology. Some of the suggested etiologies or associated factors have been genetics, inflammation, frequent yeast infections, neuropathic pain, pelvic floor hypertonic dysfunctions, pelvic organ prolapse, hormone imbalances/hormonal contraceptives, high urine oxalates, and psychological disorders.^1,5-7

Many terms have been used to describe vulvar pain. Initially, it was identified as psychosomatic vulvovaginitis, pudendagra or burning vulva syndrome, focal vulvitis, vulvar vestibulitis syndrome, and vestibulodynia. Due to the wide variety of terms, the ISSVD met in 1999, 2001, and 2003 to continue modifications in terminology. The panel initially released terms referring to the pain as either generalized or localized vulvar dysesthesia, which was later expanded to include either provoked or spontaneous vulvar dysesthesia.¹

In 2015, another panel of specialized professional organizations was assembled to update the definition of vulvodynia to match ongoing research. The panel included representatives from the ISSVD, the International Society for the Study of Women’s Sexual Health, and the International Pelvic Pain Society. The updated definition identifies vulvar pain related to a specific disorder or vulvodynia, the latter having potential descriptors used to describe the quality of pain (Table 1). Vulvodynia is a diagnosis of exclusion, which requires ruling out other potential sources of pain, and the pain must be at least 3 months in duration.¹

Table 1.

2015 Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia^a.

A. Vulvar pain caused by a specific disorderb

• Infectious (eg, recurrent candidiasis, herpes)

• Inflammatory (eg, lichen sclerosus, lichen planus, immunobullous disorders)

• Neoplastic (eg, Paget disease, squamous cell carcinoma)

• Neurologic (eg, postherpetic neuralgia, nerve compression or injury, neuroma)

• Trauma (eg, female genital cutting, obstetrical)

• Iatrogenic (eg, postoperative, chemotherapy, radiation)

• Hormonal deficiencies (eg, genitourinary syndrome of menopause [vulvovaginal atrophy], lactational amenorrhea)

B. Vulvodynia—vulvar pain of at least 3 months’ duration, without clear identifiable cause, which may have potential associated factors. The following are the descriptors:

• Localized (eg, vestibulodynia, clitorodynia) or generalized or mixed (localized and generalized)

• Provoked (eg, insertional, contact) or spontaneous or mixed (provoked and spontaneous)

• Onset (primary or secondary)

• Temporal pattern (intermittent, persistent, constant, immediate, delayed)

^aPermission obtained from Wolters Kluwer Health, Inc. for use of the Table.

^bWomen may have both a specific disorder (eg, lichen sclerosus) and vulvodynia.

Due to the complexity and increasing prevalence of the disease, a thorough look at the available research is warranted. The objective of this article is to inform the pharmacy community about vulvodynia treatments and to suggest individualized treatment options to patients and healthcare providers.

Data Sources

The literature review included an English language and human trial literature search through MEDLINE (1946-May 2018) using OVID and EBSCOhost, and Excerpta Medica (1974-May 2018) using EMBASE. Search terms included vulvar vestibulitis syndrome, vestibulodynia, vulvodynia, vulvar pain, provoked vulvar vestibulitis, and vulvodynia treatment. References of all relevant articles were then used to find additional applicable articles. This search yielded 4 randomized-controlled trials, 11 prospective nonrandomized trials, 7 retrospective reviews, and 3 case reports over oral and/or topical therapies, which are the focus of this article. Additional studies and review articles over injectable and alternative therapies were also included for completeness.

Treatment Considerations

Since vulvodynia was initially assumed to be a psychological problem, early treatment focused on oral antidepressant therapy. As research grew, neurological modes of treatment were explored to include topical therapies and combinations of both oral and topical treatments. While oral and topical therapies remain the predominant strategies for treatment, there have been several alternative and nonpharmacological therapies that have also been explored. Patients should expect to take several months to achieve maximal symptom reduction due to dose titrations and potential changes in medication therapy. Since women of childbearing age can be affected by this condition, medication pregnancy risk factor should be considered when selecting therapy.

Oral Therapies

Oral medications have historically been a favored treatment option. In a survey of women’s preferences when dealing with intravaginal medications, 72.1% of patients with prior experience using vaginal products preferred the oral route over the vaginal route. This percentage increased to 83.2% in women without experience using vaginal products. Their reasoning for preferring the oral route was due to comfort (98.0%), safety (9.0%), and efficacy (6.9%).⁸ First-line therapy for vulvodynia matches closely with neuropathic pain strategies, which includes use of certain antidepressants and anticonvulsants.⁵ Table 2 provides a condensed view of the 13 oral therapy studies that tested systemic treatment options.

Table 2.

Oral Treatment of Vulvodynia^a.

Reference	Study Design	N	Treatment	Results	Limitations
Brown et al (2009)9	Prospective, randomized trial	53	PO amitriptyline 10-20 mg/day (n = 13), PO amitriptyline 10-20 mg/day plus 0.1% triamcinolone acetonide topical cream applied intravaginally (n = 14), or self-managementb interventions (n = 26) for 12 weeks	• Amitriptyline group showed significant decreases in PRI-T scores (P = 0.017) and significant decreases in the PPI (P = 0.031) • Mean PRI-T scores were not significantly different in either the amitriptyline or the amitriptyline plus triamcinolone group • Self-management showed a trending difference on the PPI (P = 0.094)	• Inadequate power to detect differences • Lack of consistent dosing • SSRIs and SNRIs could be confounders • No negative control group • 6 of the 26 patients sorted into the self-management group received classes that taught the components of self-management, but the reason the other 20 women did not participate in the classes remained unclear
Reed et al (2006)10	Prospective, nonrandomized trial	271	PO amitriptyline from 10 mg/day to 225 mg/day (n = 183), PO desipramine (n = 23), or other unspecified PO TCA (n = 3) upon initial visit If TCA contraindicated (coronary heart disease, marked constipation, or allergy), PO paroxetine (n = 25) or other unspecified SSRI (n = 7), or PO gabapentin (n = 14) was used None of the above listed medications (n = 16)	• Taking a TCA at time of first follow-up was significantly associated with improvement in pain scores (P < 0.001) • No significant changes in pain scores were noted with the other treatment groups	• Potential confounder in starting patients on a TCA and switching to new medication • Wide range of treatment doses • Reasoning for when SSRIs were chosen over gabapentin or vice versa were unclear • Power too low on any treatment other than TCAs • Dosing for desipramine, paroxetine, and gabapentin were never specified • Unspecified TCA never identified • Length of therapy never specified
Foster et al (2010)13	Prospective, randomized, placebo-controlled, double-blind trial	133	Lidocaine 5% cream applied intravaginally 4 times daily plus PO placebo (n = 33), PO desipramine titrated to 150 mg at bedtime plus intravaginal placebo cream (n = 33), PO desipramine plus intravaginal lidocaine cream (n = 34), or PO placebo plus intravaginal placebo cream (n = 33)	• No significant difference in pain scores recorded while inserting a tampon when comparing placebo with desipramine (P = 0.37) or lidocaine (P = 0.21) • Desipramine improved on the Index of Sexual Satisfaction over placebo (P = 0.006)	• PO acetaminophen used as needed could be a confounder • Some results did not include all study subjects due to missing baseline data • 67% of participants guessed randomization into the desipramine treatment arm (unblinding) based on adverse effects
Pagano (1999)11	Prospective, nonrandomized trial	230	Oil-based lubricants plus use of lidocaine 5% cream intravaginally prior to penetration (n = 48) If above treatment failed and tested positive for Candida, PO Candida treatment ketoconazole 200 mg daily or fluconazole 150 mg weekly for 6 months (n = 48) If Candida tested negative, PO amitriptyline started from 10 mg/day to 75 mg/day for duration of 6 months if response was positive (n = 148) If amitriptyline failed, trial of carbamazepine 100 mg 3 times daily (n = 30) If no response, surgical vestibulectomy (n = 22) No further treatment (stopped before having surgery) (n = 37)	• 60% of amitriptyline patients had a significant reduction in at least one point of the Marinoffc grading scale of dyspareunia • 91% of surgical intervention patients had significant improvement of pain	• No inferential statistics performed • Participants progressed through various treatment therapies rather than having only one treatment carried to the end • Length of time before determining failure of amitriptyline and carbamazepine was unclear
van Beekhuizen et al (2018)12	Retrospective review	241	PO amitriptyline started at 10 mg daily and increased up to 60 mg daily, depending on pain relief, and maintained for 3 months (n = 147) If amitriptyline failed, was contraindicated, or had adverse effects, then started on PO gabapentin 300 mg BID (n = 8, all trying amitriptyline first) or PO pregabalin 75 mg daily or BID (n = 24, 17 started on amitriptyline first and 7 started with pregabalin) 24 patients elected not to be treated due to potential adverse effects, and 38 were lost to follow-up	• 88 (60%) of amitriptyline patients reported between 60% and 100% symptom relief, with higher dosages correlating with a higher effect on pain (P < 0.01); 43 (29%) reported 0% to 19% relief • 2 (25%) of the gabapentin patients reported 80% to 100% pain relief, while 4 (50%) reported 0% to 19% relief • 10 (42%) of the pregabalin patients reported 80% to 100% pain relief, while 8 (33%) reported 0% to 19% relief	• Lack of placebo control • Possible Hawthorne effect (therapeutic benefit generated from attention from caregivers to pain and distress) • Subjective estimation of percentage of symptom relief by patient
Eisen (1996)14	Case report	1	PO venlafaxine 75 mg/day for 2.5 months	• After 2 weeks of therapy, pain had almost disappeared • Complete remission of symptoms at 2-month follow-up	• Singular patient, although author claims 3 additional patients have shown improvement of symptoms on venlafaxine therapy • Follow-up limited to 2 months • No objective measures
Brown et al (2015)15	Open label, nonrandomized trial	22	PO milnacipran titrated up to 200 mg/day (or maximally tolerated lower dose) for a total of 18 weeks (6 weeks of dose escalation plus 12 weeks of stable dosage)	• Pain reduction scores met statistical significance for moderate difference in the McGill Pain Rating Indexd (P = 0.001), coital pain (P = 0.001), tampon pain (P = 0.003), and 24-hour vulvar pain (P < 0.001) categories	• Patients with a satisfying sexual relationship prior to treatment were most likely to have a response to treatment • Did not meet power, but performed inferential statistics • Excluded postmenopausal women and prohibited use of any other centrally acting agents while in the study
Tribó et al (2008)16	Prospective cohort study	88	Combination of PO escitalopram 10 to 20 mg/day in the morning plus PO amitriptyline 10 mg/day plus PO perphenazine 2 to 4 mg/day in the evening (n = 55), or no treatment (n = 33) for 6 months	• 52.7% of patients receiving combination therapy reported complete remission of symptoms as reported by the VAS and the Pain Intensity Verbal Scale	• No inferential statistics performed • Total number of participants was unclear and seemed to overlap • Limitations of the study never discussed • No report of any adverse effects
Jerome (2007)17	Case report	1	PO citalopram 20 mg daily plus PO pregabalin 250 mg at nighttime	• Patient reported 80% relief of symptoms with reduction in anxiety	• Self-estimated percentage of relief; no objective data • 12 weeks to achieve maximum effect
Harris et al (2007)18	Retrospective chart review	152	PO gabapentin ranging from 100 mg to 3,000 mg/day in divided doses for unspecified amount of time during 30-month study period	• 67% had resolution of at least 80% of their symptoms within the 30-month study period • 32% did not have adequate resolution after 6 months of treatment	• No standardized scoring of pain, rather a subjective estimate of relief of at least 80% of symptoms • 17 patients (11%) discontinued use secondary to adverse effects
Ben-David and Friedman (1999)19	Retrospective case series	17	PO gabapentin 300 to 1200 mg/day Once relief was achieved or 1200 mg daily was reached, dose was maintained for at least 12 weeks then tapered Follow-up between 26 and 32 weeks for all patients	• 41% of patients had complete relief of symptoms • 41% of patients had partial relief of symptoms • 18% of patients failed therapy • Symptom relief reported between 2 and 4 weeks of therapy	• 70% of patients were postmenopausal • Pain relief categorized as either excellent, good, poor, or none, resulting in subjective reporting
Jeon et al (2013)20	Retrospective review	73	PO gabapentin 300 to 900 mg/day for 0.5 to 6 months (n = 62) or intravaginal botulinum toxin A 20 IU per injection site up to 5 sites totaling 100 IU in one visit (n = 11)	• VAS decreased from 8.6 initially to 3.2 after treatment in gabapentin group (P < 0.001) and 80.6% satisfaction • VAS decreased from 8.1 to 2.5 in botulinum toxin A group (P < 0.001)	• Wide range of dosing for both treatment groups • 4 of the gabapentin patients later received botulinum toxin A injections
Meltzer-Brody et al (2009)21	Open-label pilot study	17	PO lamotrigine for 13 weeks in the following phases: (1) 8-week dose escalation phase up to 200 mg BID (2) 3-week dose maintenance phase of 200 mg BID (3) 2-week dose tapering phase where dose was reduced by 50% every 5 days until discontinuation	• Women had reductions in pain as compared to pretreatment measures • 8 weeks: McGill Pain Rating Indexd P = 0.002; McGill VAS overall pain intensity P = 0.001; and McGill pelvic pain intensity P = 0.0001 • 12 weeks: McGill Pain Rating Index P = 0.015; McGill VAS overall pain intensity P = 0.0003; and McGill pelvic pain intensity P = 0.002	• Study failed to meet power, which may affect the interpretation of P values • Lacked a control arm • 28% dropout rate • Population referred from a pelvic pain clinic that was already refractory to previous treatments • Subjects were allowed to continue previous treatments, which could include TCAs, opioids, and NSAIDs

Abbreviations: BID, twice daily; NRS, Numerical Rating Scale; NSAIDs, nonsteroidal anti-inflammatory drugs; PPI, Present Pain Index; PRI-S, Pain Rating Index–Sensory; PRI-T, Pain Rating Index–Total; PO, by mouth; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; VAS, Visual Analogue Scale.

^aNone of the medications listed have been approved by the US Food and Drug Administration for the treatment of vulvodynia.

^bSelf-management included components of education and cognitive-behavioral, physical, and sex therapy.

^cMarinoff dyspareunia scale: I = causes discomfort but does not prevent sexual intercourse; II = frequently prevents sexual intercourse; III = completely prevents sexual intercourse.

^dMcGill Pain Rating Index: consisting of 15 pain descriptors ranging from 0 (none) to 3 (severe) describing pain for the previous month.

Antidepressants

Tricyclic antidepressants (TCAs) have been the focus for both oral and topical therapies due to their dual effects in treating depression and neuropathic pain. Amitriptyline has thus far been the most researched TCA and is widely used by healthcare professionals. However, the wide range of amitriptyline dosing (10 mg to 225 mg taken by mouth daily) and lack of a consistent method of assessing pain further complicate the ability to extrapolate useful efficacy data from studies.^9-12 Additionally, TCA use is associated with adverse effects such as weight gain, fatigue, tachycardia, and seizures.^9,12,13

The only other TCA researched in vulvodynia is desipramine. The singular placebo-controlled trial that tested desipramine both alone and in combination with topical lidocaine 5% demonstrated improvement in pain scores in both the treatment and placebo arms, but found no significant difference between these groups.¹³

Newer antidepressants have also been utilized due to their more favorable adverse effect profile compared with TCAs and their effectiveness in the management of other pain syndromes, such as fibromyalgia. One case report on the use of a low-dose serotonin–norepinephrine reuptake inhibitor (SNRI), venlafaxine 75 mg daily, showed that the patient was able to achieve complete remission of symptoms.¹⁴ In another SNRI study, milnacipran (titrated up to 200 mg daily) also showed some lowering of pain scores when studied in provoked vestibulodynia. Although these results were statistically significant, the trial recognized that women with a sexually satisfying relationship at baseline were 3 times more likely to show improvement compared with those who did not have a sexually satisfying relationship. The major adverse effects experienced with milnacipran in this study were nausea, headaches, hot flushes, and dizziness.¹⁵

Selective serotonin reuptake inhibitors (SSRIs) have not been studied individually but rather in a combination regimen or after the failure of a TCA. These include escitalopram, paroxetine, and citalopram. Oral escitalopram, amitriptyline, and perphenazine were researched in vulvodynia patients in one study. Although 52.7% of patients in the treatment arm reported complete remission, the study lacked a placebo.¹⁶ Reed et al¹⁰ conducted a study where participants were initiated on a TCA, unless contraindicated, and progressed to either another antidepressant (paroxetine or another unspecified SSRI) or an anticonvulsant (gabapentin). While the TCA pain reduction scores were statistically significant, the SSRI and gabapentin scores were not statistically significant. In another study, citalopram was also used in conjunction with pregabalin, but citalopram was not the focus of that study since the patient had been taking it at baseline.¹⁷

Anticonvulsants

When neuropathic pain is suspected, the practitioner may consider starting an anticonvulsant as either monotherapy or in combination with an antidepressant. Thus far, studies have been limited to gabapentin, pregabalin, lamotrigine, and carbamazepine.

Although initially marketed as an anticonvulsant, gabapentin has shown efficacy in treating neuropathic pain. For this reason, investigators have studied its use in vulvodynia both topically and orally. In 3 out of 4 trials using oral gabapentin, the dosage was titrated up gradually based on tolerability and efficacy. Therefore, there are wide-ranging dosages (100 mg to 3000 mg orally each day in divided doses), making it difficult to extrapolate specific dose-response relationships. These 3 studies resulted in at least a partial response to therapy of roughly 60% to 80% of patients.^18-20 In contrast, the fourth study used a standard dose of 300 mg twice daily for all patients versus the wide-ranging dosages seen in the other 3 studies. Pain relief between 80% and 100% was reported for 25% of the patients, while 50% of the patients reported 0% to 19% pain relief. The study was limited to just 8 patients who started gabapentin only after failing amitriptyline therapy.¹² Potential adverse effects from gabapentin therapy reported in these studies included fatigue, dizziness, and headaches.^12,18-20

Pregabalin studies have been limited to a case report and a study where it was initiated only if there was a contraindication or adverse effect to amitriptyline. In these trials, patients subjectively stated the percentage of pain relief that treatment had accomplished. In the case study,¹⁷ the patient stated that she had 80% relief of symptoms while taking oral pregabalin 250 mg nightly and also taking oral citalopram 20 mg daily, while the retrospective study¹² showed that 42% of patients had between 80% and 100% relief of symptoms after progressing from TCA therapy failure. Adverse effects from pregabalin included abdominal discomfort, drowsiness, dry mouth, and headache.¹² Although pregabalin shows some efficacy, there were wide dosing ranges and potential confounders with medications used concomitantly.

The only study involving lamotrigine was an open-label pilot study including patients proven to be refractory to other medications that included TCAs, opioids, and nonsteroidal anti-inflammatory drugs. If the patient had been taking one of these medications for longer than 4 weeks, she was allowed to continue taking that medication after starting lamotrigine. These concomitantly used medications potentially confounded the results of this study. Although vulvodynia patients taking lamotrigine showed improvement in pain and mood scores, the study failed to meet power and lacked a control arm. Reported adverse effects included minor rash, headache, and fatigue.²¹

Carbamazepine has similarly been limited to a singular study. As seen in the Pagano study,¹¹ the treatment progressed from topical therapy to yeast infection therapy (if indicated) that included ketoconazole or fluconazole, to amitriptyline, then to carbamazepine if amitriptyline failed. These results showed only 4 of the 30 (13%) patients treated with carbamazepine had a positive response to the anticonvulsant (ie, reduction of at least one grading of severity of painful intercourse).

Topical Therapies

When oral therapy is ineffective, intolerable, or undesirable, vaginal administration is an alternative route of delivery. For the purposes of this article, vaginal administration refers to applying the medication where the patient feels pain, whether that is a localized or generalized area of the vulva. This is most commonly accomplished by compounding the drug into an ointment or cream. The vaginal route provides targeted therapy with decreased systemic adverse effects while avoiding complications associated with oral dosing such as interpatient variability and first-pass metabolism.^22,23 Disadvantages to vaginal topical therapy are personal hygiene, timing of application with sexual intercourse, and local irritation.²⁴ Another potential hindrance is dosage frequency, which can be as often as 7 times per day. Application frequencies for individual drugs can be seen in Table 3.

Table 3.

Topical Treatments for Vulvodynia.

Reference	Study Design	N	Intravaginal Treatment	Results	Limitations
Pagano and Wong (2012)26	Prospective, nonrandomized trial	150	Amitriptyline 2% cream applied BID for 3 months	• 56% had positive responses (• 25 patients with slight improvement, 44 with moderate improvement, and 15 with an excellent response in Marinoffa dyspareunia scores) • 44% had no response	• No identification of washout period from oral vulvodynia medications • No statistical analysis of results • Included pre- and postmenopausal women
Nyirjesy et al (2009)27	Retrospective review	38	Amitriptyline 2% plus baclofen 2% cream applied BID for a median of 33 weeks	• 29% had no or little improvement (defined as <30% change), 18% moderate improvement (30% to 60% change), and 53% much improvement (>60% change) in symptoms • Improvement in social activity interference (P = 0.02), lubrication (P = 0.02), and intercourse discomfort (P = 0.05)	• Follow-up period varied between patients from 8 to 55 weeks • Lack of complete intake questionnaires for 18% of patients
Boardman et al (2008)23	Retrospective review	51	Gabapentin 2% (n = 18), 4% (n = 10), or 6% (n = 22) cream applied TID for a minimum of 8 weeks; one patient lost to follow-up	• 80% of patients with evaluable responses had at least 50% improvement in pain scores • 29% reported complete pain relief • Mean pain scores decreased from 7.26 to 2.49 (CI −5.47 to −4.07) on a VAS of 0 (no pain) to 10 (worse possible pain)	• Initial strength of cream was chosen at the physician’s discretion • Did not specify the actual length of treatment for patients • Did not specify minimum number of subjects to meet power • 31% of patients treated had no evaluable treatment data • Did not give Marinoffa dyspareunia score evaluations of localized vulvodynia patients • Did not address dropout of one patient before treatment began
Zolnoun et al (2003)28	Prospective, nonrandomized trial	61	Lidocaine 5% ointment applied to the affected area at bedtime plus placement of a lidocaine-coated cotton ball in the vestibule overnight (⩾8 hours) for 7 weeks	• Daily pain rating was decreased 10.37 points from pretreatment (P = 0.004), and intercourse-related pain scores decreased 39.11 points from pretreatment (P < 0.001) on a VAS of 0 (no pain) to 100 (most severe) • 76% of women were able to have intercourse after treatment compared to 36% before treatment (P = 0.002)	• Was unable to obtain 6-month follow-up data from 51% of patients, so long-term efficacy is unknown • 13% of participants have concomitant contributing disease states including types of dermatologic, STI, musculoskeletal, and behavioral • Did not specify washout period of previously used vulvodynia therapies
Danielsson et al (2006)29	Prospective, randomized trial	46	Lidocaine 2% gel for 2 months then lidocaine 5% ointment (n = 19) for 2 months, each applied 5 to 7 times per day or 3 daily 10-minute sessions with an EMG vaginal sensor and biofeedback instrument (n = 18) for 4 months; 9 patients dropped out	• Median pain thresholds increased in anterior and posterior sites for EMG biofeedback (P = 0.002, P = 0.02) • Median pain thresholds increased in anterior and posterior sites for topical lidocaine (P = 0.008, P = 0.007) • Sexual desire increased from 16 to 42 on a VAS positive of 0 (worst pain) to 100 (least pain) for topical lidocaine • No significant difference was found between the treatment groups	• Poor compliance with EMG biofeedback treatment • 50% of lidocaine group was unable to increase to the 5% strength due to adverse effects • No placebo control due to difficulty recruiting subjects
Kim et al (2018)30	Prospective, nonrandomized trial	8	Combination meloxicam 0.3% and lidocaine 5% gel applied BID for 1 week	Six patients had pain scale score reductions from 1 to 4 points	• Small study population • Results were taken after only 1 week of treatment • No defined parameters of Likert scale
Keppel Hesselink et al (2014)34	Case study, prospective	1	Baclofen 5% cream applied BID to TID daily plus PEA 400 mg orally TID for 3 months	• Pain NRS decreased from 6-7 to 2 on an 11-point scale • Patient gained ability for undisturbed intercourse, to sit for hours, and to cycle	PEA is an herbal supplement with no FDA approval
Gardella et al (2015)35	Prospective, nonrandomized trial	34	Estriol 0.5 mg cream applied 3 times weekly for 12 weeks	Improved VHIS (P = 0.0001), MI score estrogenic (P = 0.04), MI score progestogenic (P = 0.004), and FSFI score (P = 0.001)	Patients were asked to stop CHC therapy, which had been used for varying lengths of time
Burrows and Goldstein (2013)36	Prospective, nonrandomized trial	50	Estradiol 0.03% plus testosterone 0.01% cream applied BID for 20 weeks	Vestibular pain scores decreased from 7.5 to 2 (P = 0.001)	• Used subjective cotton swab testing for pain levels • Lack of standardized questionnaire • Blood draws of hormones and proteins at random times in the menstrual cycle • No identification of washout time between discontinuing CHCs and study treatment
Walsh et al (2002)57	Prospective, nonrandomized trial	34	Nitroglycerin 0.2% cream applied at least 3 times per week, 5-10 minutes prior to sexual relations	• Decrease in pain intensity on a 0-5 scale (P < 0.000) and in frequency of overall painful episodes on a 0-4 scale (P < 0.006) • All patients who completed the study (21) reported “improvement” of their pain during sex	• 38% of patients did not complete a pretreatment pain questionnaire • Does not specify where patients were found or baseline characteristics • Does not include results analyzed by vulvodynia classification • No specified minimum number of subjects to reach power
Steinberg et al (2005)59	Retrospective chart review	52	Capsaicin 0.025% cream applied daily for 20 minutes for 12 weeks; pretreatment with lidocaine 2% gel and/or ice packs	Kaufmanb touch test scores improved (P < 0.001) and Marinoffa dyspareunia scores improved (P < 0.001)	• Per-protocol analysis • Did not report the number of patients with positive responses • Does not define number parameters on Kaufmanb touch test
Murina et al (2004)60	Prospective, nonrandomized trial	33	• Capsaicin 0.05% cream applied BID for 30 days, daily for 30 days, then twice weekly for 4 months. Pretreatment with lidocaine plus prilocaine cream	• 59% saw improvement and 41% showed no improvement in a VAS of 0 to 100 • No complete remission of pain	• No statistical analysis of results • Baseline characteristics of participants not given • Only gives 8-week evaluation results

Abbreviations: BID, twice daily; CHC, combined hormonal contraceptive; EMG, electromyographic; FDA, Food and Drug Administration; FSFI, Female Sexual Function Index; MI, Maturation Index; NRS, Numeric Rating Scale; OC, oral contraceptives; PEA, palmitoylethanolamide; STI, sexually transmitted infection; TID, 3 times daily; VAS, Visual Analogue Scale; VHIS, Vaginal Health Index Score.

^aMarinoff dyspareunia scale: I = causes discomfort but does not prevent sexual intercourse; II = frequently prevents sexual intercourse; III = completely prevents sexual intercourse.

^bKaufman touch test: clinical rating scale of pain in response to touches with a cotton swab on glandular areas of the vulvar vestibule.

When compounding medications for vaginal use, it is key to consider the anatomical features of the vagina. The compounded agents should be buffered to a pH of 4.5 to match the normal vaginal pH of 3 to 5.5 during childbearing years.²² A hydrophilic base, such as petrolatum, should be used due to the vagina’s mucosal membrane properties. Since indications are seldom included on compounded prescriptions, the pharmacist should ask the patient her intended use to make sure the correct base is chosen.²⁵ Last, care should be taken to ensure sterility of the final product. Table 3 provides a condensed view of the 12 studies discussing topical treatment options. Please note that a study by Foster et al¹³ was also listed in Table 2 and was not repeated in Table 3.

Oral antidepressants, specifically amitriptyline, continue to be widely used for the treatment of vulvodynia. However, there are limited studies utilizing this medication in a topical route. In one study when amitriptyline was administered in a cream, 56% of patients responded to therapy with 10% of those being completely pain free at the end of 3 months. This study also showed improvement in patients who had previously failed treatment with oral amitriptyline. The most common adverse effects were local skin irritation and burning. The authors suggested if a patient cannot tolerate a higher dose of systemic amitriptyline, a lower dose of oral therapy could be combined with topical amitriptyline cream.²⁶

In addition to being studied alone, amitriptyline has also been studied as a mixture with baclofen in a cream. According to Nyirjesy et al,²⁷ this combination cream significantly decreased the patients’ social activity interference, difficulty lubricating, and overall intercourse pain level.

Since oral gabapentin is frequently used for neuropathic pain, Boardman et al²³ hypothesized that topical gabapentin could be effective in treating vulvodynia. Records were gathered of pre- and postmenopausal women diagnosed with localized or generalized vulvodynia over a 6-year period and were narrowed to those treated with topical gabapentin. Gabapentin cream was dispensed to patients in strengths of 2%, 4%, or 6% with the initial treatment strength chosen by the provider. Out of the 35 women available to evaluate, 80% saw at least a 50% reduction in pain scores with 29% having complete remission of pain. However, the authors did not control for concomitant use of other vulvodynia therapies during treatment and did not use consistent dosing practices in the strength of cream chosen for each patient. Therefore, it is difficult to assess the true magnitude of topical gabapentin’s efficacy in vulvodynia. Adverse effects causing discontinuation of therapy included local irritation and urinary problems such as retention, frequency, and recurrent urinary tract infections.

Topical lidocaine has become a popular vulvodynia treatment due to vulvodynia’s similarity to post-herpetic neuralgia. One randomized placebo-controlled study¹³ was performed using topical lidocaine and demonstrated no efficacy over placebo. However, other trials have demonstrated increased quality of life. In a trial by Zolnoun et al,²⁸ 76% of participants reported the ability to have intercourse after treatment compared with 36% beforehand. Another study included subjects using topical lidocaine that saw significant increases in sexual desire and satisfaction.²⁹ Despite disagreement in efficacy results between studies, if a patient finds relief with topical lidocaine, it can be applied in the 2% strength up to 6 times per day without concerns for toxicity.²⁹ It gives rapid relief with an onset of action in as little as 20 minutes. If being used to facilitate intercourse, patients should be counseled that residual product could transfer to their partner causing numbness, but a condom can help prevent this adverse effect.⁵

A study was recently published showing early data of combination meloxicam 0.3% and lidocaine 5% gel used to treat vulvodynia. These drugs were used together locally in an attempt to decrease inflammation and nociceptive pain thresholds. Seventy-five percent of participants had a subjective improvement in their symptoms and reported a 1- to 4-point pain scale reduction. Adverse effects included burning and stinging.³⁰

Pelvic floor hypertonicity and vulvodynia are frequently present concomitantly.^31,32 Baclofen’s muscle relaxation actions and decreased adverse effect profile make it a feasible treatment option.^33,34 One study found baclofen an effective treatment when combined in a cream with amitriptyline.²⁷ Additionally, a case report used a compounded baclofen cream with oral palmitoylethanolamide, which is a fatty acid produced naturally and taken orally as a food supplement to decrease inflammation. The patient’s pain had decreased 30% after 1 month, and she had an increased quality of life after 3 months.³⁴ Although no research has been performed on baclofen as monotherapy, this could be a treatment option for patients with suspected pelvic floor hypertonicity.

Levels of gonadal hormones (ie, estrogen and testosterone) appear to play a role in pain transmission at various sites. Recently, topical creams containing gonadal hormones have been tested to target premenopausal vulvodynia along with the comorbidity of interstitial cystitis/bladder pain syndrome (IC/BPS). IC/BPS and vulvodynia both belong to a larger category of chronic pelvic pain syndromes, which may often overlap. A study of premenopausal patients using estriol cream saw significant improvement in both bladder and vaginal pain symptoms.³⁵

Since vulvodynia symptoms can be similar to those experienced during menopause, it has been hypothesized that vulvodynia could be caused by hypoestrogenism, even in premenopausal patients.³⁵ This hypoestrogenic state could come from continued use of combined hormonal contraceptives, which modify the vestibular tissue by decreasing endogenous estrogen synthesis and altering free levels of testosterone.^36,37 This could also result in lower vestibular pain tolerances and thresholds when compared with controls.³⁸ In one study, after discontinuing the combined hormonal contraceptives and initiating treatment with topical estradiol and testosterone, vestibular pain scores were reduced.³⁶ Care should be used when treating premenopausal patients with topical hormones due to the risk of fetal malformations if pregnancy were to occur.³⁹

Regardless of the cause, hypoestrogenism appears to correlate with increased nerve fiber hypertrophy and thickening in primary vestibulodynia.⁴⁰ Although more research is needed, topical hormonal therapy seems effective and should be considered in patients with other comorbidities or etiologies that may be hormone related.

Injectable Therapies

Several injectable therapies exist for vulvodynia pain that is more localized in nature. Those showing efficacy include enoxaparin, botulinum toxin A, and corticosteroids. Although effective, injectable therapies are not often recommended due to their inconvenience and cost. In general, the frequency of injections, administration in a practitioner’s office (botulinum toxin and corticosteroids), and specialized patient education (enoxaparin) may make this route of administration difficult for patients.^5,41

It has been hypothesized that vulvodynia is caused by heparanase proteins weakening cellular membranes and allowing nerve fibers to penetrate through and proliferate. Therefore, enoxaparin, with its antiheparanase properties, has been studied to help alleviate vulvodynia pain. When administered subcutaneously at 40 mg once daily, enoxaparin was shown to decrease Q-tip touch test pain scores at the end of the 90-day trial and continued 3 months later. Bleeding risk is increased, and treatment duration is unclear for vulvodynia outside of a trial setting.⁴¹

Due to its anticholinergic effects and subsequent reduction in muscle spasm frequency, botulinum toxin A has been shown to decrease and even cure vulvodynia pain in case studies.⁵ However, the only randomized-controlled trial performed using botulinum toxin A in vulvodynia found no difference from placebo.⁶ Although rare, botulinum toxin A carries a risk of systemic effects if it spreads beyond the site of injection.

Finally, locally injected triamcinolone, betamethasone, and methylprednisolone have been studied due to their anti-inflammatory effects and in some cases have improved pain in as less as 1 to 2 weeks.⁵ Due to the use of other medications in combination with the corticosteroids, it is difficult to assess their efficacy in these studies.

Nonpharmacologic Therapies

Many treatment modalities have been researched outside of traditional pharmacological strategies due to the multifactorial symptomatic nature of vulvodynia. More promising evidence supports a combination approach of pharmacological therapy, psychotherapy, and physiotherapy, reserving surgery as a last-line option.

Vulvodynia can affect a woman’s relationships and quality of life, with depression being a common comorbidity. Antidepressants and psychotherapy used concomitantly can assist in reducing pain, fear, and anxiety. Behavioral modifications may also play a role in reestablishing satisfying sexual functioning. It should again be emphasized with the patient that this combination approach is to treat the pain, which is a real disease and not an imagined condition.⁵ Physical therapy via the use of pelvic floor exercises has become a mainstay of therapy. One study compared pelvic floor muscles of patient groups with vulvar pain versus a control patient group with no vulvar pain. The study showed that the patients with provoked vulvodynia had the highest average muscle tension, followed by patients with generalized vulvodynia, then the no-pain control group. These results led researchers to believe that the chronic pelvic pain experienced in each group was due to varying levels of hypertonicity that could be treated with physical therapy.⁴² The primary goal of physical therapy is to retrain the pelvic floor muscles in order to improve muscle floor strength and voluntary muscle relaxation, while also decreasing the fear of penetration.^43-45

Surgery, typically consisting of vulvar excision and vestibulectomy, has shown positive results; however, it should be reserved as last-line therapy due to successes of first-line therapy, risks of surgery, and the long recovery process. Success rates vary from 60% to 90%, depending partially on the surgeon’s experience and technique.^46-48 A study attempting to assess the long-term success of surgery found that while 66.7% of women experienced improvement in pain associated with sexual intercourse, 78.1% receiving less invasive treatment also felt improvement of pain scores.⁴⁸

Other alternative therapies requiring more controlled studies include acupuncture, localized transcutaneous electrical nerve stimulation (TENS) therapy applied to the labia majora, and avoiding diets high in oxalates.

As an alternative to Western medicine techniques, patients may elect to try acupuncture. It is proposed that positioning acupuncture needles at specific pain points across the body can cause a natural release of endorphins and opioids, which may increase the flow of pain-killing chemicals to problematic areas.⁴⁹ There have been 3 studies testing its utility in treating vulvodynia, with each study including less than 40 patients.^50-52 One randomized-controlled study did show statistically significant pain score reductions for sensory pain (P = 0.01) and total pain (P = 0.02). However, this was a pilot study limited to a onetime acupuncture session.⁵⁰ The other 2 studies lasted for 5 to 10 weeks, but lacked a control and did not include specifics on how the pain was assessed.^51,52

Due to the ongoing evidence of nerve involvement, researchers have explored the use of TENS therapy. One study showed statistically significant (P < 0.01) lowered pain scores when the TENS unit was placed on the labia majora. The recommended use of TENS was 3 times daily for a total duration of 90 minutes.⁵³

It has been hypothesized that certain foods result in high concentrations of oxalates in the urine, which may exacerbate pain associated with vulvodynia. However, it has not been proven to be a direct cause. Rhubarb, nuts, spinach, celery, beets, chocolate, tea, wheat bran, and strawberries have been shown to increase urinary oxalate excretion.^54,55 Due to its ability to bind oxalates, calcium citrate containing 200 mg of calcium and 950 mg of citrate taken 2 tablets 3 times daily was used in a case study to limit urinary oxalates.⁵⁵ While the case study showed positive results for this patient, other studies have not shown a direct correlation between vulvodynia and urinary oxalate levels. Limiting these foods and using calcium citrate as an oxalate binder may be advantageous for patients continuing to struggle with pain control despite trying multiple other modes of therapy.⁵⁶

Ineffective and/or Inconvenient Therapies

Nitroglycerin cream and capsaicin cream have shown some efficacy when treating vulvodynia. However, they are not frequently used due to the adverse effects experienced exceeding the possible benefits.

In a pilot study using 0.2% nitroglycerin cream, the authors hypothesized that the metabolite nitric oxide would relax smooth muscle and inhibit inflammatory cascades. However, the adverse effect of headache was prevalent⁵⁷ and limits nitroglycerin’s use as a viable treatment option.

Capsaicin has additionally been studied due to its actions on substance P, which causes a burning-like sensation.⁵⁸ In 2 studies, capsaicin’s use was limited due to a cumbersome application process, which included pretreatment with lidocaine and in some cases ice packs as numbing agents.^59,60 In patients with positive responses, discontinuation of therapy caused symptoms to return in an average of 15 days. Reinstitution of a twice-weekly application regimen resulted in symptoms fading in an additional 20 days.⁶⁰ This lack of long-term effectiveness limits treatment of a chronic pain condition. This evidence shows that even though some positive responses have been seen, this therapy should be considered as a last-line option when no other treatment modalities have worked.

Other agents that have been studied are topical nifedipine, topical cromolyn sodium, topical corticosteroids, oral narcotics, and other oral analgesics such as nonsteroidal anti-inflammatory drugs and acetaminophen. However, studies have shown they lack efficacy in vulvodynia and therefore are not used in therapy.^61,62 Additionally, an injectable therapy that has been studied is interferon-α.⁴⁶ Studies have found it to be ineffective and not tolerated due to its adverse effects of flu-like symptoms and malaise.⁵

Final Considerations

There are several patient-specific factors that should be considered when selecting therapy. As mentioned previously,⁸ patients prefer oral therapy to topical therapy due to comfort and convenience. However, topical administration may be desired due to targeted therapy and decreased risk of adverse effects. Since this disease affects women of childbearing age, pregnancy risk of medications should also be considered, especially with use of topical gonadal hormones. Adverse effects of medications, the patient’s symptoms on presentation, and comorbidities all need to be considered when selecting initial therapy. Although oral TCAs are the most studied, other therapies that have less research may also be considered as first line. Therefore, it is difficult to make any step-wise recommendations for clinicians.

Conclusion

Vulvodynia is a multifactorial disorder with no one proven etiology; therefore, several therapies exist for treatment. Although some prospective studies have shown trends toward efficacy, there are noted limitations, including lack of consistent randomization and placebo controls, as well as small sample sizes. Treatment should be individualized to patients’ needs and typically includes elements of psychotherapy, physical therapy, and pharmacological therapy. Both oral and topical medications can be considered and should be optimized based on the patients’ symptoms and adverse effects. Patients should expect to take several months to achieve maximal symptom reduction due to dose titrations and potential changes in medication therapy. Additional research is needed to increase knowledge and further develop vulvodynia treatments.