Vulvodynia Study Endorsing Gabapentin for Pelvic Muscle Pain: An In-depth Look

Sexual pain in women remains a difficult and elusive medical condition to treat. Provoked vulvodynia current recommended therapies include pelvic floor physical therapy and psychological interventions including cognitive behavioral therapy (CBT) and sexual counseling.¹ Pharmacologic options remain limited to topical lidocaine, hormonal cream (typically estrogen + testosterone), and tricyclic antidepressants and their evidence for use remains mixed at best. Vulvodynia etiology is multifactorial and likely involves central sensitization, muscle and tissue nociception, and mucosal mechanoreceptor dysfunction.

Gloria A. Bachmann and colleagues performed a secondary analysis to assess the effect of gabapentin extended release on sexual function after a previous trial had failed to show improvement in mean pain intensity, sexual intercourse pain, and daily pain.² Researchers randomly assigned 89 women with provoked vulvodynia to treatment with gabapentin or placebo and assessed sexual function using the Female Sexual Function Index (FSFI), a 19-question survey divided into 6 domains of sexual function including desire, arousal, lubrication, orgasm, satisfaction and pain.³ By using a more comprehensive endpoint, the researchers were able to demonstrate an improvement in sexual function, specifically in the domains of desire, arousal and satisfaction, and conclude, “gabapentin should be considered for treatment with PVD.”⁴

The study raises a few concerns before we can take this conclusion at face value.

First, although the researchers noted that acetaminophen, aspirin, and nonsteroidal anti-inflammatory (NSAIDs) medications could be used as “rescue medications,” no discussion is presented on the number of women who used those medications or the quantity, dose, or frequency of these adjunctive analgesics. This is significant as the researchers use of gabapentin was theorized to help with muscle pain of the pelvic floor, and all 3 are known analgesics that can be used for muscle pain. Also, the authors stated that 2 subjects were taking specific serotonin reuptake inhibitors (SSRIs) at the time of the study, and although we presume that others were not receiving different antidepressant types, any use of norepinephrine (NE) reuptake inhibiting agents (RX or OTC), such as St. John’s Wort or duloxetine, could have an impact on outcomes since blockade of NE reuptake and serotonin respectively have an effect on pain and/or depression. Use of bupropion, for example, which blocks reuptake of dopamine and NE, could have a profound effect as well. Therefore, clear exclusion criteria for these and any drugs with muscle relaxant properties should have been listed.

Second, while improvements were not seen in pain as in the previous trial, an increase in the FSFI domains of desire, arousal, and satisfaction was shown with the use of gabapentin. However, this may be due to gabapentin’s adverse effect profile, including sedation and relaxation, and/or its secondary GABA-enhancing properties that may have indirect effects on the dopaminergic reward system.⁵ Specifically, gabapentin modulates GABA release indirectly through glutamic acid decarboxylase and the glutamate synthesizing enzyme. The FSFI domain of desire is based on a women’s level and frequency of desire or interest in sexual activity and improvement may be secondary to improved feelings of relaxation from gabapentin. It is also been reported that women with vulvodynia are up to 4 times more likely to have previously been diagnosed with depression and/or anxiety^6,7 so the improvements in desire and satisfaction domains may be secondary to central effects of dopamine following administration of gabapentin.

Consider also that branded Gralise was used in this study, and although absorption is more predictable compared to other immediate release gabapentin products, gabapentin is well-known to have variable absorption compared to pregabalin. Moreover, pregabalin has a significantly higher binding affinity at the alpha-2-delta subunit receptors compared to gabapentin. For these reasons, we believe that pregabalin may have been a cleaner medication to study.⁸

Although the authors conclude that gabapentin should be considered for women with provoked vulvodynia, there is increasing evidence of growing gabapentin abuse to achieve similar recreational mental health benefits as the benzodiazepines or as an opioid alternative/enhancer. Using a drug that increases GABA synthesis and possibly escalates intraneuronal dopamine in a population that is more likely to have behavior health concerns may prove to be an unsafe option. It may be prudent to use a more benign and proven cognitive behavior intervention, such as sex therapy or couple-based therapy, to achieve improved outcomes, rather than to enlist pharmacotherapy with potential for adverse events and abuse potential.

Michelle Krichbaum, PharmD is an Assistant Professor, Department of Clinical Practice, Nova Southeastern College of Pharmacy in Davie, FL.Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP, FFSMB is Chief Executive Officer & Chief Medical Officer, Remitigate, LLC in Delmar, NY; Adjunct Associate Professor of Pharmacy Practice & Pain Management, Albany College of Pharmacy & Health Sciences in Albany, NY; and Adjunct Associate Professor, Western New England University College of Pharmacy in Springfield, MA.

References

• American College of Obstetricians and Gynecologists, & Committee on Gynecologic Practice. Committee Opinion No 673: Persistent Vulvar Pain. Obstet Gynecol. 2016;128(3), e78.
• Brown, CS, Bachmann, GA, Wan J, Foster, DC. Gabapentin for the Treatment of Vulvodynia: A Randomized Controlled Trial. Obstet Gynecol. 2018;131(6):1000-1007.
• Rosen, C. Brown, J. Heiman, S. Leiblum, C. Meston, R. Shabsigh, D. Ferguson, R. D'Agostino, R. The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Therapy. 2000; 26(2):191-208.
• Bachmann GA, Brown CS, Phillips NA., Rawlinson LA., Yu X, Wood R., et al. Effect of gabapentin on sexual function in vulvodynia: a randomized, placebo-controlled trial. American J Obstet Gyn. 2019; 220(1):89-e1.
• Schifano F. Misuse and abuse of pregabalin and gabapentin: cause for concern?. CNS Drugs. 2014;28(6):491-496.
• Khandker M, Brady, SS, Vitonis, AF, MacLehose, RF, Stewart EG, Harlow BL. The influence of depression and anxiety on risk of adult onset vulvodynia. J Women's Health. 2011;20(10):1445-1451.
• Mascherpa F, Bogliatto F, Lynch PJ, et al. Vulvodynia as a possible somatization disorder. More than just an opinion. J Reprod Med. 2007;52:107—110.
• Fudin J, Morgenson DA. How gabapentin differs from pregabalin. Pharmacy Times. September 15, 2018. Last Accessed 1/8/2019 at: https://www.pharmacytimes.com/contributor/jeffrey-fudin/2015/09/how-gabapentin-differs-from-pregabalin?p=3&rel=0" &rel=0"