By Tricia Heitman, PharmD, PCCA Clinical Compounding Pharmacist

Painful vaginal and vulvar conditions can be difficult to resolve successfully without a comprehensive treatment plan. Often, that treatment plan will include physical therapy, psychological counseling and intravaginal treatment. These conditions are challenging for practitioners because age, hormonal status, dysbiosis, traumatic events, mental health, genetics and general state of health represent only a few factors that they may need to address. Depression and anxiety can complicate the pain and sexual dysfunction that can result from vaginal and vulvar conditions. Some researchers believe that the mental status causes the dysfunction, while others believe that the sexual dysfunction is the cause of the depression and anxiety.¹ We may not always know which came first in each patient, but what we do know is that this group of disorders often cause a reduction in quality of life for patients experiencing them. Fortunately, there are unique customizable treatment options that compounding pharmacies can offer to patients with atrophic vaginitis, vulvar lichen sclerosis, desquamative inflammatory vaginitis, vaginismus, vulvodynia and high-tone pelvic floor dysfunction.

In addition to the patient-specific treatment, PCCA’s recently released compounding base, Ellage^™ Anhydrous Vaginal (PCCA #30-5110), may improve patient compliance and therefore patient outcomes. Ellage is an anhydrous vaginal vehicle that can extend the default beyond-use date of compounded vulvar and intravaginal medications. This special feature is especially helpful when treating chronic conditions: A longer beyond-use date means a reduction in the number of pharmacy visits for refills. Regardless of the base used, working together with the practitioner to create an effective treatment plan with minimal side effects will provide the best outcome possible for patients.

Atrophic Vaginitis

Atrophic vaginitis, or vaginal atrophy, is possibly the most common vaginal condition facing postmenopausal and perimenopausal women. It is characterized by vaginal dryness, thinning of the vaginal mucosa, and in some cases, inflammation and bleeding. Atrophic vaginitis is a condition caused by estrogen deficiency and can also occur in patients following radiation therapy, chemotherapy, removal of one or both ovaries (oophorectomy), premature ovarian failure or endocrine disorders as well as in patients receiving antiestrogen medication. Atrophic vaginitis can cause painful intercourse (dyspareunia) and burning pain and can lead to other symptoms, including urinary symptoms if the condition is not addressed. In recent years, health care professionals have begun referring to atrophic vaginitis and its symptoms collectively as genitourinary syndrome of menopause, or GSM.

Treatment with intravaginal estrogen creams, gels and inserts (specifically estradiol) are the gold standard treatment.² Unfortunately, this therapy is not the best therapeutic option for every patient. Estriol or oxytocin may be an alternative for patients who are not good candidates for intravaginal estradiol. A small clinical trial evaluated the use of 0.03 mg estriol and Lactobacillus combination vaginal tablets. The study included 16 postmenopausal patients, all of whom had resolution of their atrophic vaginitis symptoms. The treatment caused a small increase in estriol levels in half of the patients observed but did not produce increases in estrone or estradiol. Although current regulations do not allow compounding of Lactobacillus, data from this trial can be deduced regarding the kinetics of vaginal estriol used in postmenopausal women.³ Further evidence includes a phase III study with 167 patients. Participating women received either 1 Gm of vaginal gel containing 50 μg of estriol or placebo. Patients were instructed to use the gel daily for three weeks and then twice weekly up to 12 weeks. The results of this study support the use of estriol in women with atrophic vaginitis. Estriol was superior to placebo in reducing vaginal dryness, atrophy, dyspareunia, pruritis, burning, vaginal pH and painful urination (dysuria). ⁴ This option could be a potential alternative for those patients who respond to estrogen therapy but may be sensitive to more potent estrogens such as estradiol.

“Estriol or oxytocin may be an alternative for patients who are not good candidates for intravaginal estradiol.”

Patients who have a personal history of estrogen-receptor-positive cancer, who have a high risk of such cancer types or who are receiving antiestrogen medication will need alternative treatment options. Intravaginal oxytocin has recently emerged as another option that may improve the vaginal hormone environment, improve subjective symptoms of vaginal atrophy and reduce the vaginal pH in patients suffering from atrophic vaginitis.⁵ A randomized, controlled trial studied 140 postmenopausal women who received intravaginal oxytocin gel or placebo for a period of 30 days. The oxytocin gel consisted of 600 IU oxytocin in a sodium carboxymethylcellulose gel. Of the 70 participants in the oxytocin arm, 47 improved versus no improvement in the placebo arm.⁶ Researchers in Sweden conducted a larger double-blind, randomized, controlled study in which participants used 400 IU or 100 IU oxytocin gels once daily for seven weeks. The oxytocin gel was made with sodium carboxymethylcellulose and had the pH adjusted to 3.75. The most substantial results of this study show that in the women receiving 400 IU oxytocin, there was a significant improvement in their most troublesome symptom. In fact, 53% of participants claimed complete resolution of their most troublesome symptom.⁷

Vulvar Lichen Sclerosis

Vulvar lichen sclerosis (VLS) is a chronic inflammatory disorder of unknown cause and can affect women of all ages. The risk factors for it include genetic predisposition, autoimmunity, repeated tissue trauma, infection and low hormone levels. VLS is characterized by atrophic, white plaques that cause pruritis, pain, burning, and potentially genital scarring and adhesion if not treated effectively and early. It is typically isolated to the labial, perineal and perianal areas, but in some patients, other areas such as the trunk, buttock and thigh can be involved.⁸ VLS has also been associated with an increased risk of squamous cell carcinoma. ⁹ Research has shown an increase in the inflammatory markers TNF-α and interleukin-6 in the tissue of patients with this condition. Researchers conclude that VLS has at least in part an autoimmune etiology. ¹⁰

While high-dose topical steroids such as mometasone furoate 0.05% or clobetasol propionate 0.05% are the current mainstay of treatment, there are other options for patients who do not improve with this treatment. ¹¹ In an Italian study, 12 women who were unresponsive or poorly responsive to high-potency topical corticosteroids were prescribed a 0.1% tacrolimus ointment. The ointment was applied twice daily for six weeks, then once daily for 15 days and then twice daily for the last four weeks of the trial. Of the 11 patients who completed the trial, eight had good to complete remission of symptoms.¹² Researchers conducted another trial of topical 0.1% tacrolimus including 16 total patients, 10 with anogenital and six with extragenital localization. Of the 10 patients with anogenital involvement, nine responded to therapy, while only one of the six extragenital patients saw response. Therefore, response to tacrolimus may be more likely in patients without extragenital involvement. ¹³

“While high-dose topical steroids such as mometasone furoate 0.05% or clobetasol propionate 0.05% are the current mainstay of treatment, there are other options for patients who do not improve with this treatment.”

Naltrexone may be another topical option for these patients. We know that naltrexone can inhibit the production of interleukin-6 and TNF-α, which are part of the pathogenic picture of many inflammatory conditions, including VLS.¹⁴ Although there are no large-scale clinical trials, topical naltrexone has been used successfully in other autoimmune diseases and may be worth considering for VLS patients as well.

Desquamative Inflammatory Vaginitis

Desquamative inflammatory vaginitis is a challenging, chronic condition of unknown etiology that causes purulent vaginal discharge, red vaginal inflammation, bleeding, spotted rash, dyspareunia and pain. It is associated with a vaginal pH greater than 4.5 and a near absence of vaginal Lactobacilli in almost all women.¹⁵ Some researchers have given this spectrum of symptoms the term “aerobic vaginitis” due to the severe disruption of vaginal flora.^16,17 First-line treatment of this condition with intravaginal 2% clindamycin is commonly used, although most patients also experience relapse after the treatment is discontinued.

High-dose intravaginal hydrocortisone is another widely used treatment option.¹⁷ Typically, 3–5 Gm of 10% hydrocortisone cream is inserted daily for three weeks. Alternatively, hydrocortisone acetate 25 mg suppositories twice daily have been used successfully. Maintenance therapy is recommended for all treatment options to prevent relapse. Maintenance therapy of the initial therapeutic option should be recommended three times weekly for at least two months.¹⁸

Vaginismus

Vaginismus is characterized by persistent involuntary spasm of the vaginal musculature. It is a painful condition that can make gynecological exam, sexual intercourse and tampon insertion difficult or impossible. Primary vaginismus, also called lifelong vaginismus, occurs when a woman has never been able to experience non-painful vaginal intercourse. Secondary vaginismus, also called acquired vaginismus, occurs if the woman has been able to have non-painful penetration of the vaginal opening previously but has since developed the painful condition. Both conditions are involuntary and cannot be overcome without treatment. It is not clear if the condition is caused by fear or anxiety, or if the fear and anxiety stem from the pain of the condition. In many cases, the condition is related to past sexual trauma or fear of painful intercourse.

Patients experiencing vaginismus can benefit from counseling and education as well as pharmacotherapy.^19,20 As an adjunct, lidocaine 5% gel and lubricants have been used to help with painful vaginal intercourse. Combining lidocaine with a lubricant could prove to be a successful combination for patients dealing with this condition.^20,21 Additionally, a retrospective review of 13 patient medical records revealed that a combination of ketamine 0.5% and amitriptyline 1–2% have been used to successfully treat genital pain and could be considered for patients who are unresponsive to other treatments.²² A quick improvement in symptoms will greatly improve quality of life for these patients.

Vulvodynia

Vulvodynia, also called vulvar vestibulitis syndrome, is a chronic pain condition involving the vulva. It involves complex neuropathic pain with symptoms of burning, stinging, itching or rawness typically lasting more than three months.²³ The pain can be spontaneous or provoked and can range in severity among patients. This condition is a common cause of dyspareunia and decreased quality of life.²⁴ There is currently no known cause, but risk factors include sleep disturbances, chronic pain conditions and psychological disorders such as PTSD.²⁵

While lidocaine 4% cream or gel applied to the vestibule prior to intercourse may reduce provoked pain in some patients, other treatments may be necessary in more severe pain.²⁵ Gabapentin, ketamine and amitriptyline have been used as well due to their neuromodulating effects. ^{22,26,27,28,29,30} In a multicenter, double-blind, randomized crossover trial, gabapentin improved sexual function, including arousal, desire and satisfaction in patients with vulvodynia.²⁷ The previously mentioned review of 13 patient charts where ketamine 0.5% and amitriptyline 1–2% were prescribed for rectal, perineal or genital pain revealed that 54% of patients had complete to substantial relief of pain. ²² Another treatment option, estriol 0.03% and amitriptyline 0.5% topical gel applied to the vulvar vestibule, was evaluated in a retrospective clinical audit of 1,174 patients with entry dyspareunia. This combination treatment was rated effective by 51.2% of patients less than 30 years of age, 66.7% of patients 30–50 years of age, and 58.3% of patients over 50.²⁸

“While lidocaine 4% cream or gel applied to the vestibule prior to intercourse may reduce provoked pain in some patients, other treatments may be necessary in more severe pain.”

Topical treatments for vulvodynia are typically applied at the vaginal opening nightly. Twice daily application can be of benefit in patients with spontaneous pain that causes discomfort throughout the day. Topical pain therapy for these patients could reduce side effects resulting from oral treatment.

High-Tone Pelvic Floor Dysfunction

High-tone pelvic floor dysfunction (HTPFD) in women is a condition of elevated resting tone of the pelvic floor muscles that is persistent and results in lactic acid buildup and pain that radiates to the groin, abdomen and back. HTPFD is also associated with dyspareunia, painful menstrual periods, constipation, urinary urgency and stress incontinence. Some risk factors include traumatic injury to the pelvic area, pregnancy, pelvic surgery, obesity and advancing age. Patients may find vaginal exam painful and uncomfortable as the tissues will be resistant to stretch.³¹ Muscles that contract continually generate pain, edema and inflammation due to cytokine release.

Diazepam, due to its muscle-relaxant activity, has been used to reduce pain in patients with HTPFD. Diazepam 10 mg suppositories used nightly for 30 days may improve pelvic floor function, which improves comfort with intercourse and muscle tone upon digital exam. In a study of this treatment, no patients noted adverse effects.³² Pharmacokinetic studies show that vaginal administration of diazepam results in a lower bioavailability compared to standard oral use. However, diazepam may accumulate with chronic daily intravaginal doses. Intermittent dosing following the initial course may be favorable to allow intimacy and reduce accumulation.³³ Practitioners have also prescribed compounded diazepam combined with baclofen, lidocaine, ketamine or amitriptyline to further reduce pain and dyspareunia, which has shown promise.

“Practitioners have also prescribed compounded diazepam combined with baclofen, lidocaine, ketamine or amitriptyline to further reduce pain and dyspareunia, which has shown promise.”

Vaginal and vulvar pain conditions affect quality of life for many women. Some may feel there is little help after exhausting the limit of commercially available treatment options. Depression and relationship difficulty can be a devastating consequence if not treated successfully. Equipped with supportive literature, a better understanding of each condition and formulation support, compounding pharmacists can assist practitioners with effective treatment strategies for the most challenging cases. PCCA members with Clinical Services support can find a list of related PCCA formulas in our formula database.

Patricia Heitman, PharmD, is a clinical compounding pharmacist at PCCA. She is a graduate of the University of Houston College of Pharmacy and served as a PCCA PharmD resident for one year post-graduation, which included a teaching position at her alma mater. She has been a full-time PCCA clinical compounding pharmacist since completing her residency in 2000, answering compounding-related calls daily from pharmacists in the United States and Canada. She lectures frequently at PCCA International Seminars and symposiums. Her passions include pediatric compounding—especially options for patients with autism—as well as women’s health, gastrointestinal health and pain management.

A version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.

References

1. Basson, R., & Gilks, T. (2018). Women's sexual dysfunction associated with psychiatric disorders and their treatment. Women's Health. https://doi.org/10.1177/1745506518762664

2. Hainer, B. L., & Gibson, M. V. (2011). Vaginitis. American Family Physician, 83(7), 807–815. https://www.aafp.org/afp/2011/0401/p807.html

3. Donders, G., Neven, P., Moegele, M., Lintermans, A., Bellen, G., Prasauskas, V., Grob, P., Ortmann, O., & Buchholz, S. (2014). Ultra-low-dose estriol and Lactobacillus acidophilus vaginal tablets (Gynoflor^®) for vaginal atrophy in postmenopausal breast cancer patients on aromatase inhibitors: Pharmacokinetic, safety, and efficacy phase I clinical study. Breast Cancer Research and Treatment, 145, 371–379. https://doi.org/10.1007/s10549-014-2930-x

4. Cano, A., Estévez, J., Usandizaga, R., Gallo, J. L., Guinot, M., Delgado, J. L., Castellanos, E., Moral, E., Nieto, C., del Prado, J. M., & Ferrer, J. (2012). The therapeutic effect of a new ultra-low concentration estriol gel formulation (0.005% estriol vaginal gel) on symptoms and signs of postmenopausal vaginal atrophy: Results from a pivotal phase III study. Menopause, 19(10), 1130–1139. https://doi.org/10.1097/gme.0b013e3182518e9a

5. Zohrabi, I., Abedi, P., Ansari, S., Maraghi, E., Shakiba Maram, N., & Houshmand, G. (2020). The effect of oxytocin vaginal gel on vaginal atrophy in postmenopausal women: A randomized controlled trial. BMC Women’s Health, 20. https://doi.org/10.1186/s12905-020-00935-5

6. Torky, H. A., Taha, A., Marie, H., El-Desouky, E., Raslan, O., Moussa, A. A., Ahmad, A. M., Abo-Louz, A., Zaki, S., Fares, T., & Eesa, A. (2018). Role of topical oxytocin in improving vaginal atrophy in postmenopausal women: A randomized, controlled trial. Climacteric, 21(2), 174–178. https://doi.org/10.1080/13697137.2017.1421924

7. Al-Saqi, S. H., Uvnäs-Moberg, K., & Jonasson, A. F. (2015). Intravaginally applied oxytocin improves post-menopausal vaginal atrophy. Post Reproductive Health, 21(3), 88–97. https://doi.org/10.1177/2053369115577328

8. Singh, N., & Ghatage, P. (2020). Etiology, clinical features, and diagnosis of vulvar lichen sclerosus: A scoping review. Obstetrics and Gynecology International, 2020. https://doi.org/10.1155/2020/7480754

9. Carlson, J. A., Ambros, R., Malfetano, J., Ross, J., Grabowski, R., Lamb, P., Figge, H., & Mihm, M. C., Jr. (1998). Vulvar lichen sclerosus and squamous cell carcinoma: A cohort, case control, and investigational study with historical perspective; implications for chronic inflammation and sclerosis in the development of neoplasia. Human Pathology, 29(9), 932–948. https://doi.org/10.1016/s0046-8177(98)90198-8

10. Tran, D. A., Tan, X., Macri, C. J., Goldstein, A. T., & Fu, S. W. (2019). Lichen sclerosus: An autoimmunopathogenic and genomic enigma with emerging genetic and immune targets. International Journal of Biological Sciences, 15(7), 1429–1439. https://doi.org/10.7150/ijbs.34613

11. Chi, C.-C., Baldo, M., Kirtschig, G., Brackenbury, F., Lewis, F., & Wojnarowska, F. (2011). Topical interventions for genital lichen sclerosus. The Cochrane Database of Systematic Reviews. https://doi.org/10.1002/14651858.CD008240

12. Virgili, A., Lauriola, M. M., Mantovani, L., & Corazza, M. (2007). Vulvar lichen sclerosus: 11 women treated with tacrolimus 0.1% ointment. Acta Dermato-Venereologica, 87(1), 69–72. https://doi.org/10.2340/00015555-0171

13. Kim, G.-W., Park, H.-J., Kim, H.-S., Kim, S.-H., Ko, H.-C., Kim, B.-S., & Kim, M.-B. (2012). Topical tacrolimus ointment for the treatment of lichen sclerosus, comparing genital and extragenital involvement. The Journal of Dermatology, 39(2), 145–150. https://doi.org/10.1111/j.1346-8138.2011.01384.x

14. Cant, R., Dalgleish, A. G., & Allen, R. L. (2017). Naltrexone inhibits IL-6 and TNFα production in human immune cell subsets following stimulation with ligands for intracellular toll-like receptors. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2017.00809

15. Murphy, R., & Edwards, L. (2008). Desquamative inflammatory vaginitis: What is it? The Journal of Reproductive Medicine, 53(2), 124–128.

16. Sonthalia, S., Aggarwal, P., Das, S., Sharma, P., Sharma, R., & Singh, S. (2020). Aerobic vaginitis — An underdiagnosed cause of vaginal discharge — Narrative review. International journal of STD & AIDS, 31(11), 1018–1027. https://doi.org/10.1177/0956462420913435

17. Murphy R. (2004). Desquamative inflammatory vaginitis. Dermatologic Therapy, 17(1), 47–49. https://doi.org/10.1111/j.1396-0296.2004.04006.x

18. Sobel, J. D., Reichman, O., Misra, D., & Yoo, W. (2011). Prognosis and treatment of desquamative inflammatory vaginitis. Obstetrics & Gynecology, 117(4), 850–855. https://doi.org/10.1097/AOG.0b013e3182117c9e

19. Pacik, P. T. (2014). Understanding and treating vaginismus: A multimodal approach. International Urogynecology Journal, 25, 1613–1620. https://doi.org/10.1007/s00192-014-2421-y

20. Harish, T., Muliyala, K. P., & Murthy, P. (2011). Successful management of vaginismus: An eclectic approach. Indian Journal of Psychiatry, 53(2), 154–155. https://doi.org/10.4103/0019-5545.82548

21. Hassel, B. (1997). Resolution of primary vaginismus and introital hyperesthesia by topical anesthesia. Anesthesia & Analgesia, 85(6), 1415–1416. https://doi.org/10.1097/00000539-199712000-00055

22. Poterucha, T. J., Murphy, S. L., Rho, R. H., Sandroni, P., Warndahl, R. A., Weiss, W. T., & Davis, M. D. P. (2012). Topical amitriptyline-ketamine for treatment of rectal, genital, and perineal pain and discomfort. Pain Physician, 15(6), 485–488. https://www.painphysicianjournal.com/current/pdf?article=MTc5Ng%3D%3D&journal=71

23. Edwards, L. (2015). Vulvodynia. Clinical Obstetrics and Gynecology, 58(1), 143–152. https://doi.org/10.1097/GRF.0000000000000093

24. Metts, J. F. (1999). Vulvodynia and vulvar vestibulitis: Challenges in diagnosis and management. American Family Physician, 59 (6), 1547–1556.

25. Reed, B. D., Legocki, L. J., Plegue, M. A., Sen, A., Haefner, H. K., & Harlow, S. D. (2014). Factors associated with vulvodynia incidence. Obstetrics & Gynecology, 123(2 Pt. 1), 225–231. https://doi.org/10.1097/AOG.0000000000000066

26. Goetsch, M. F., Lim, J. Y., & Caughey, A. B. (2015). A practical solution for dyspareunia in breast cancer survivors: A randomized controlled trial. Journal of Clinical Oncology, 33(30), 3394–3400. https://doi.org/10.1200/JCO.2014.60.7366

27. Bachmann, G. A., Brown, C. S., Phillips, N. A., Rawlinson, L. A., Yu, X., Wood, R., Foster, D. C., & Gabapentin Study Group (2019). Effect of gabapentin on sexual function in vulvodynia: A randomized, placebo-controlled trial. American Journal of Obstetrics & Gynecology, 220(1), 89.E1–89.E8. https://doi.org/10.1016/j.ajog.2018.10.021

28. Ruoss, C. M., Howard, E. A., Chan, K., Stevenson, P. G., & Vancaillie, T. (2021). Topical treatment of vulvodynia, dyspareunia and pudendal neuralgia: A single clinic audit of amitriptyline and oestriol in organogels. ANZJOG. Advance online publication. https://doi.org/10.1111/ajo.13292

29. Pagano, R., & Wong, S. (2012). Use of amitriptyline cream in the management of entry dyspareunia due to provoked vestibulodynia. Journal of Lower Genital Tract Disease, 16(4), 394–397. https://doi.org/10.1097/LGT.0b013e3182449bd6

30. Goldstein, A. T., Pukall, C. F., Brown, C., Bergeron, S., Stein, A., & Kellogg-Spadt, S. (2016). Vulvodynia: Assessment and treatment. The Journal of Sexual Medicine, 13(4), 572–590. https://doi.org/10.1016/j.jsxm.2016.01.020

31. Faubion, S. S., Shuster, L. T., & Bharucha, A. E. (2012). Recognition and management of nonrelaxing pelvic floor dysfunction. Mayo Clinic Proceedings, 87(2), 187–193. https://doi.org/10.1016/j.mayocp.2011.09.004

32. Rogalski, M. J., Kellogg-Spadt, S., Hoffmann, A. R., Fariello, J. Y., & Whitmore, K. E. (2010). Retrospective chart review of vaginal diazepam suppository use in high-tone pelvic floor dysfunction. International Urogynecology Journal, 21(7), 895–899. https://doi.org/10.1007/s00192-009-1075-7

33. Larish, A. M., Dickson, R. R., Kudgus, R. A., McGovern, R. M., Reid, J. M., Hooten, W. M., Nicholson, W. T., Vaughan, L. E., Burnett, T. L., Laughlin-Tommaso, S. K., Faubion, S. S., & Green, I. C. (2019). Vaginal diazepam for nonrelaxing pelvic floor dysfunction: The pharmacokinetic profile. The Journal of Sexual Medicine, 16(6), 763–766. https://doi.org/10.1016/j.jsxm.2019.03.003
 

These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The information contained herein is not intended to replace or substitute for conventional medical care, or encourage its abandonment.