Optimal pain management has become a concern across many medical conditions, especially when addictive pharmacologic interventions, mood-altering interventions, or both are prescribed for extended periods of time. Vulvodynia, characterized by burning and stinging pain of the vulva, is a chronic pain syndrome with a 7–16% lifetime prevalence.1 To date, vulvodynia randomized clinical trials (RCTs) have been limited in number, geographic region of sampling, and demographic diversity. The few published vulvodynia RCTs find no difference in pain or other quality-of-life measures between pharmacologic intervention and placebo (Bornstein J, Zarfati D, Azran O, Farjun y. Topical nifedipine for vestibulodynia-a placebo controlled study [abstract]. J Lower Gen Tract Dis 2009;13(suppl)).2–5
Despite lack of evidence-based data, gabapentin is commonly prescribed for vulvodynia and is recommended in several vulvodynia treatment guidelines.6,7 Gabapentin has been found effective in RCTs for neuropathic conditions.8 Women with vulvodynia often present with certain neuropathic characteristics such as dynamic allodynia (pain in response to light touch). Although some women report symptom relief with gabapentin use in clinical practice, evidence supporting its benefit is limited based on descriptive and observational reports that have methodologic flaws, including reliance on subjective outcome measures, sampling bias, and small sample sizes.9–15 No placebo controlled RCTs have been conducted.16
We evaluated the efficacy of gabapentin, in an extended-release formulation, in women diagnosed with localized provoked vulvodynia, defined as superficial vulvar vestibular pain that is provoked by touch, in a demographically diverse sample.
MATERIALS AND METHODS
This was an 18-week, multicenter, placebo-controlled, double-blind RCT with a two-treatment, two-period crossover design that studied the efficacy of extended-release gabapentin (1,200–3,000 mg/d) for localized provoked vulvodynia (previously known as vulvar vestibulitis). The study consisted of eight phases: 1) a 2-week screening phase; 2) randomization; 3) 4-week dose titration; 4) a 2-week maintenance phase; 5) 2-week dose taper; 6) 4-week dose titration after crossover; 7) a 2-week postcrossover maintenance phase; and 8) a 2-week dose taper phase with scheduled visits at 6, 8, 14, and 16 weeks. Clinical response was assessed by the pain intensity from vaginal insertion by the participant of a tampon (tampon test)17 during the last 7 days of the initial maintenance phase and postcrossover maintenance phase.
The study was conducted between August 8, 2012, and January 19, 2016, and received institutional review board approval at the University of Tennessee Health Science Center (#10-00985-FB), Rutgers Robert Wood Johnson Medical School (#0220110309), and the University of Rochester (#31720) (see Acknowledgments in Appendix 1, available online at http://links.lww.com/AOG/B94). All participants provided written informed consent. The GABA RCT was registered in ClinicalTrials.gov (NCT1301001).
Inclusion criteria included women between the ages of 18 and 50 years (later extended to women aged 50 years and older because the reported upper age for vulvodynia is well above 50 years of age),18 reporting greater than 3 continuous months of insertional dyspareunia, pain to vulvar touch, or vulvar pain with tampon insertion or both and during pelvic examination. Participants were allowed to use oral contraceptives, hormone therapy, or selective serotonergic reuptake inhibitors if they were prescribed before randomization and were on a stable dose.
After informed consent, study candidates completed questionnaires on medical and gynecologic history and underwent a physical and pelvic examination. Candidates fulfilled Friedrich's criteria19 by their reporting tenderness of the vulvar vestibule with intercourse or touch, such as with tampon insertion, using modified diagnostic criteria of Bergeron et al.20 A mean score 4 or greater out of 10 on a numeric rating scale of pain intensity was required with the score in the vulvar vestibule greater than the score on the peripheral vulva area or inside the vagina.
Block randomized drug assignments were determined using a computer-generated random number technique and a concealed allocation schedule generated by the Pharmaceuticals Department at the University of Tennessee Health Science Center. Identical-appearing tablets were packaged and distributed by the department. Investigators, research staff, and participants were blinded after assignment to interventions.
The two-period crossover design consisted of 8 weeks per treatment period with weekly telephone contact. Dosing incrementally increased one tablet per week for 4 weeks and plateaued at five tablets daily for study weeks 5 and 6. Participants were asked to take the oral medication at bedtime during week 1 and in divided doses at weeks 2 through 6 and to incrementally increase the dose regardless of point of response (pain relief). In the event of nonserious side effects, participants were asked to decrease tablet dose by one and to remain at that dose for the remainder of the clinical trial. In the event of further nonserious side effects, the reduction by one tablet was repeated.
Participants were analyzed on an intention-to-treat, last observation carried forward basis. When deemed medically necessary, an unblinding protocol was followed. Pain “rescue medication” such as acetaminophen, aspirin, or nonsteroidal antiinflammatory drugs was permitted and documented, if used. The use of opioid analgesics and topical medications was a protocol violation.
Data collection utilized a proprietary database platform, Slim-Prim (scientific laboratory and patient-care research information management system, University of Tennessee),21 a web-accessible, modular data-based system mounted on an Oracle, server acted as the central data repository. Data were entered electronically by participants (or by research staff if diaries were completed by hand) and the accuracy of the database was validated by a research staff member.
The primary trial outcome was measured by the tampon test, a surrogate marker for vaginal penetration pain, performed once weekly, according to a previously validated method.17 The outcome measure uses an 11-point numeric rating scale (0=no pain at all; 10=worst pain ever) and has been shown to have reliability, construct validity, and responsiveness.17 It is often used as the primary outcome in vulvodynia research because pain with sexual intercourse may be so severe that women with vulvodynia may abstain, limiting the number of data points for vaginal penetration pain analysis; and pain with elicited tampon insertion is included within the definition of vulvodynia.19
Secondary outcomes included daily pain and pain with sexual intercourse. Participants were asked to record intensity of general pain experienced over the previous 24 hours and sexual intercourse, if it occurred within the evaluation period, using an 11-point (0–10) numeric rating scale.
During the prerandomization visit, women were instructed and demonstrated proficiency on performance of the tampon test and completion of electronic or handwritten diary including daily 24-hour pain and intercourse pain. All information was reviewed and approved during weekly telephone calls by the team and later confirmed by data entry validation. A baseline level of pain (average 4 or greater out of 10 on the 11-point tampon test [0=no pain at all; 10=worst pain ever]) was required to proceed to randomization.
Participants also were instructed to record intensity of general pain experienced over the previous 24 hours on an 11-point (0–10) numeric rating scale and to record any side effects experienced with study medication. Side effects were listed individually and included a severity estimate (mild, moderate, or severe). They also were instructed to refrain from using lubricants or moisturizers throughout the trial. If lubricants were used, the participant was to report this.
Exploratory analyses included determining the effect of age, race, duration, oral contraceptive use, onset (pain always present with sexual intercourse or whether there was a pain-free period), and sexual abuse history (single item on the questionnaire) on treatment outcome, because more recent literature suggests that demographic characteristics may play a role.22
During scheduled study visits 1 through 5, participants were evaluated by pelvic examination, a cotton swab test, pelvic muscle tenderness testing (pelvic muscle algometry), and assessment of vaginal milieu; the cotton swab test was performed at the last study visit. The cotton swab test was performed on predefined points of the labia majora, minora, and lower vagina, as described.20 We performed pelvic muscle algometry by a random staircase method and an 11-point (0–10) numeric rating scale direct scaling of pain response to a load cell-mediated, digitally applied force stimulus to selected pelvic floor muscle groups including levator ani, obturator internus, and piriformis muscles.
Vaginal milieu assessment included microscopic wet mount vaginal smears, Rakoff stain23 for vaginal maturation index, the Affirm test to assess for vaginitis, a phenazine test tape for vaginal pH, and a urine pregnancy test. Those with vulvovaginal atrophy assessed by maturation index were treated with hormone therapy for at least 6 weeks before randomization. Those with vaginitis were treated and rescreened for eligibility and treated, when necessary, throughout the trial.
The primary outcome was participant-reported pain intensity by an 11-point (0–10) numeric rating scale of the last participant-inserted tampon during the last 7 days of the maintenance phase. Sexual intercourse and daily pain, secondary outcome measures, also were measured by the 11-point numeric rating scale during the same 7-day period. The study was an intent-to-treat design, last observation carried forward,24 which meant once a participant was randomized, if she was lost to follow-up, all future values were assumed to be equal to her last observed value.
All analyses were done using the Mixed Procedure in SAS 9.4 according to the crossover design. The mixed model included sequence, period, and treatment. If the center effect was significant, it would be included in the model. Efficacy parameters are reported as least squares means (95% CI). Statistical significance was defined as a P value <.05 using two-tailed tests.
The exploratory analyses were conducted in two stages. In the first stage, univariate analysis was used to test for associations of the demographic variables with tampon test pain according to the crossover design. The model also included interaction terms with treatment. The P value was set at .15 in the univariate analysis to avoid missing any potential variables significantly associated with tampon test pain in the first stage toward multivariate analysis. Those found significant were all included in the multivariate analysis in the final stage, in which statistical significance was set at the 1% level.
Demographic characteristics were analyzed with the χ2 test and adverse events were analyzed with the McNemar test; both are reported as percentages. Statistical significance was set at the 5% level.
Power analysis was based on data from neuropathic pain RCTs using gabapentin because there were no clinical trial data available in participants with vulvodynia.25 To have a power of 90% and a significance level of 5% to detect a 1-point difference between the two phases on a scale of 1–10 of the tampon test, a sample size of 53 was needed, assuming the following assumptions were made: no carryover effect; no interactions among participants, treatments, and periods; no period effect; no center effect; a SD during the gabapentin and placebo cycles of 2.2; and a correlation between gabapentin and placebo tampon test measure of 0.5. A multiplicity adjustment was not performed for the secondary measures because it was not the intent of the study to assess these measures at the same experimental significance level as established for the primary outcome variable. Assuming a 40% dropout rate, 89 participants were randomized to complete 53.
Figure 1 summarizes the flow diagram of progression from the baseline visit to week 18. Of the 230 women screened, 89 met entry criteria and were randomized and 66 completed the trial. Of the 141 participants who were excluded, 101 did not meet inclusion criteria, 16 decided not to participate in the trial, and 24 did not return for drug randomization. Of the 23 individuals randomly assigned to the study drug who did not complete the trial, eight were lost to follow-up, seven withdrew consent, seven were removed by research staff because of adverse events, and one was removed for a protocol deviation.
Of the 26% of participants who discontinued treatment, a greater proportion discontinued during the placebo treatment arm compared with the intervention arm (32% vs 20%). The 74% attrition rate is comparable with that in other RCTs in vulvodynia (Bornstein J, et al. J Lower Gen Tract Dis 2009;13(suppl)).2–5 Analyses were based on the 89 participants who met entry criteria.
Demographic and baseline characteristics at randomization are presented in Table 1. There were no statistically significant differences in distribution of any of the variables between the gabapentin and placebo crossover phases. The average patient was 37 years of age with a large proportion of participants reporting their race as black. Most had attended college, the majority had vulvodynia pain duration of more than 5 years, approximately 25% had a history of sexual abuse, approximately 25% were taking oral contraceptives, seven participants were using hormone therapy, and two were taking selective serotonergic reuptake inhibitors. Approximately half of the participants had primary onset and half had secondary onset.
Nearly all participants (88/89) were therapeutically naive to gabapentin. Comparison of the 23 individuals who failed to complete the randomized phase found no difference in age, race, years of education, marital status, or duration of disease compared with participants completing the randomized phase.
The primary outcome measure of this study, the tampon test, failed to demonstrate improved pain with gabapentin over placebo (unadjusted mean 3.9, 95% CI 3.4–4.5 vs 4.3, 95% CI 3.7–4.9, adjusted mean 4.0, 95% CI 3.0–4.9 vs 4.3, 95% CI 3.4–5.2; P=.07) (Table 2). Based on the multicenter, crossover design, primary and secondary outcomes were analyzed as group means (unadjusted) and least square means (adjusted for center, sequence, and period). A center effect was found for the primary outcome, tampon test pain (P=.02), and thus was included in all mixed model analyses. No effect was observed on sequence (P=.67) or period (P=.13).
Similar to the tampon test, gabapentin failed to improve pain over placebo for secondary outcome measures of sexual intercourse pain (unadjusted mean 4.2, 95% CI 3.3–5.0 vs 4.3, 95% CI 3.5–5.1, adjusted mean 3.9, 95% CI 2.4–5.3 vs 4.0, 95% CI 2.5–5.4; P=.76) and daily pain (unadjusted mean 2.9, 95% CI 2.3–3.4 vs 3.0, 95% CI 2.5–3.6, adjusted mean 2.7, 95% CI 1.8–3.6 vs 2.9, 95% CI 2.0–3.8; P=.36) adjusted for center, sequence, and period, as described previously.
Exploratory analyses of gabapentin effect on selected demographic subsets were also adjusted for center, sequence, and period based on the multicenter, crossover design. Gabapentin reduced tampon test pain in women with vulvar pain for more than 5 years (unadjusted difference −0.6, 95% CI −1.1 to 0.0, adjusted difference −0.6, 95% CI −1.1 to −0.1; P=.01); in women aged 52 years or older (unadjusted difference −1.3, 95% CI −3.1 to 0.6, adjusted difference −1.2, 95% CI −2.3 to −0.1; P=.03); in white women (unadjusted difference −0.6, 95% CI −1.3 to 0.0, adjusted difference −0.7, 95% CI −1.3 to 0.0; P=.04); in women not taking oral contraceptives (unadjusted difference −0.4, 95% CI −0.9 to 0.0, adjusted difference −0.5, 95% CI −0.9 to −0.1; P=.03); and in women with secondary-onset vulvodynia (unadjusted difference −0.4, 95% CI −0.9 to 0.1, adjusted difference −0.4, 95% CI −1.0 to −0.1; P=.10). There was no significant treatment effect difference by sexual abuse history.
We subsequently developed a multivariate mixed model, which included age, race, duration of pain, onset, oral contraceptive use, center, sequence, and period. Controlling for other variables in the model, a gabapentin treatment (improvement) difference over placebo was associated with duration of pain (greater than 5 years) (unadjusted difference −0.6, 95% CI −1.1 to 0.0, adjusted difference −1.0, 95% CI −1.8 to −0.2; P=.01); white racial category (unadjusted difference −0.6, 95% CI −1.33 to −0.0, adjusted difference −0.9, 95% CI −1.6 to −0.2; P=.02); and oral contraceptive nonuse (unadjusted difference −0.4, 95% CI −0.9 to 0.0, adjusted difference −0.8, 95% CI −1.4 to −0.2; P=.01). There was no treatment effect difference by age or onset (Table 3). Demographic variables that differed by center included race (P=.003) and age 52 years or older (P<.001). No effect was observed on sequence (P=.67) or period (P=.13).
Figure 2 displays longitudinal changes in the numeric rating scale tampon test score (mean, ±95% CI) over the phase 1 and phase 2 treatment sequences of the study. Phase 1 (week 0 to week 6) displays a 28% decline in tampon test pain with placebo: baseline 6.4 (95% CI 5.7 to −6.1) to end phase 1: 4.6 (95% CI 5.4 to −3.7, t=5.34; P<.001) vs a 37% decline in tampon test pain with gabapentin: baseline 6.3 (95% CI 5.6 to −7.1) to end phase 1: 3.9 (95% CI 3.32 to −4.7, t=5.89; P<.001). No further decline is evident with placebo (after crossover): end phase 2: 4.0 (95% CI 3.3 to −4.8, t=0.09; P=nonsignificant) vs a further 15% decline with gabapentin (after crossover) end phase 2: 3.9 (95% CI 3.2 to −4.7, t=2.49; P<.02).
During the last 7 days of the maintenance phase, the average daily dose of gabapentin was 2,476±866 mg. Compliance rate, determined by retained container pill count, was 94.7%. The incidence of adverse effects was slightly higher, but not significantly different, with gabapentin vs placebo: rhinitis (11.2% vs 4.5%; P=.08), dizziness (10.1% vs 3.4%; P=.08), nausea (8.9% vs 3.4%: P=.10), headache (7.9% vs 5.6%; P=.53), somnolence (7.9% vs 4.5%: P=.32), bacterial vaginosis (7.9% vs 4.5%; P=.37), and fatigue (5.6% vs 1.1%: P=.10). No serious adverse events occurred during gabapentin treatment.
During the placebo treatment arm, five (6%) participants withdrew from the study as a result of adverse events and two (3%) withdrew because of adverse events during the gabapentin arm. At study completion, 42% of the participants correctly identified when they were taking gabapentin.
Gabapentin in the treatment of vulvodynia in this cohort was not more effective than placebo on the primary outcome measure, the tampon test (a surrogate marker for dyspareunia), or on secondary outcomes: sexual intercourse pain and daily pain. A lack of gabapentin treatment effect over placebo is consistent with previous controlled studies investigating other pharmacologic treatments for vulvodynia (Bornstein J, et al. J Lower Gen Tract Dis 2009;13(suppl)).2–5
We found improvement in tampon scores for both active treatment and placebo during the first treatment arm (Fig. 2), suggesting an early placebo effect, which leveled off for phase 2 placebo participants but continued for phase 2 gabapentin participants, suggesting a modest treatment effect. It remains difficult to distinguish a placebo effect from the therapeutic benefit of interacting with research staff (Hawthorne effect)26 or from spontaneous improvement (natural history).27 The likelihood for an effect resulting from natural history is lessened by the lack of a period effect, but only a no-treatment arm would be able to dissect out placebo and placebo-independent effects. As well, it is unlikely that low pain severity was a contributor, because previous trials reporting greater pain intensity also reported negative findings (Bornstein J, et al. J Lower Gen Tract Dis 2009;13(suppl)).2–5
Our findings contrast with previous descriptive and observational studies in which most women reported improvement with gabapentin.9–15 Although the placebo effect and other methodologic flaws most likely accounted for the discrepant findings, it is possible that women with more generalized symptoms may have obtained benefit; one small, retrospective study revealed that 55% (6/11) of those with generalized vulvodynia achieved complete pain relief posttreatment with topical gabapentin as compared with 17% (4/17) of those with provoked vulvodynia.9
The strength of this multicenter controlled trial is that it included a demographically and geographically diverse sample. Another strength of this RCT is that participants entered their pain ratings electronically, which may have minimized recall bias.
We investigated the possibility that gabapentin therapy may benefit women with certain demographic characteristics such as onset, age, pain duration, race, and oral contraceptive use. Because the sample was too small in these subsets of women and the differences found indicated “minimal” change,28 no definitive statement can be made based on these findings. Further research is necessary to determine whether symptom presentation or demographic characteristics predict treatment outcome.
Regarding study limitations, this study did not include a no-treatment arm to better define the true placebo effect. Also, power analysis and calculation of sample size were based on a previously reported parallel-design RCT of gabapentin on neuropathic pain.25 Because the analysis was not based on a vulvodynia population, it is possible that a type II error may have occurred. However, crossover designs are statistically efficient, and the multiple outcomes of the trial show little evidence of trends in data that might achieve statistical significance with a larger sample size.
Carryover effects from placebo to active phases and failure to measure gabapentin plasma concentrations during each phase may also have clouded the treatment effect. In prior gabapentin studies, crossover trial period effect and plasma concentrations have not correlated with clinical response.29 The choice of treatment duration may have been too brief to detect a clinical response, because one retrospective report found improvement in patient pain ratings during gabapentin treatment only after 12 to 18 months of continuous treatment.10 Although external validity was enhanced by the multicenter design, it may have been strengthened with a larger sample.
This RCT provides insufficient evidence to support the recommendation of gabapentin alone as first-line treatment of vulvodynia. Because previous RCTs studying pharmacologic management options also have been negative, practitioners may want to consider all therapeutic options, including nonpharmacologic management interventions such as physical therapy and behavioral and sexual counseling.
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