Topical Nifedipine for the Treatment of Localized Provoked Vulvodynia: A Placebo-Controlled Study

The Journal of Pain, Vol 11, No 12 (December), 2010: pp 1403-1409 Available online at www.sciencedirect.com

Topical Nifedipine for the Treatment of Localized Provoked Vulvodynia: A Placebo-Controlled Study Jacob Bornstein,*,y Ruba Tuma,* Yaniv Farajun,* Audrey Azran,* and Doron Zarfati*,y * Department of Obstetrics and Gynecology, Western Galilee Hospital, Nahariya, Israel. y The Rappaport Faculty of Medicine, Technion University, Haifa, Israel.

Abstract: Topical application of the calcium antagonist nifedipine has demonstrated effectiveness in treating chronic anal fissure, without adverse effects. Like chronic anal fissure, vulvodynia is associated with muscle hypertonicity and an inflammatory infiltrate. We conducted a double-blind placebo-controlled study to investigate the effectiveness of 2 concentrations of topical nifedipine cream in the treatment of vulvodynia. Thirty participants were alternately assigned to 3 topical treatment groups: .2% nifedipine, .4% nifedipine, and placebo. All administered the cream to the vestibule 4 times daily for 6 weeks. For all 3 treatment groups, mean pain intensity on vestibular touch, assessed by the Q-tipped cotton test, pain from speculum insertion, and reports of pain during sexual intercourse was reduced at post-treatment compared with pre-treatment. These improvements remained at 3 months’ follow-up. The effectiveness of nifedipine in treating vulvodynia did not exceed that of placebo. Perspective: The topical application of both nifedipine and a placebo reduced pain in women with vulvodynia. This study highlights the need for controlled trials of treatments for vulvodynia and raises doubts about studies conducted without comparison to placebo. ª 2010 by the American Pain Society Key words: Vulvodynia, localized provoked vulvodynia, nifedipine, chronic anal fissure, physical therapy.

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ocalized provoked vulvodynia, the primary cause of superficial dyspareunia, is recognized by clinicians and researchers as a multi-factorial condition. Patient profiles are diverse, with no single treatment effective for all.23 Pelvic floor muscle dysfunction, manifesting as vaginal hypertonicity and lack of vaginal muscle strength,37 may be more recalcitrant than other characteristics of the syndrome.21 Pelvic dysfunction is apparently associated with localized sensitivity resulting from the pain of attempted intercourse and neurogenic inflammation,43 the latter evidenced by increased inflammatory infiltrate.6 A vicious cycle of sensitivity and muscle contraction exacerbates irritation and pain46 and may lead to vaginismus and spasm of the muscles of the vagina.14,36,40 The effectiveness of pelvic floor Received August 20, 2009; Revised March 6, 2010; Accepted March 23, 2010. Supported by the Department of Obstetrics and Gynecology of Western Galilee Hospital-Nahariya. The authors have no conflicts of interest. Address reprint requests to Prof Jacob Bornstein, Department of Obstetrics and Gynecology, PO Box 21, Nahariya 22100, Israel. E-mail: mdjacob@ tx.technion.ac.il 1526-5900/$36.00 ª 2010 by the American Pain Society doi:10.1016/j.jpain.2010.03.016

physical therapy by biofeedback in both the diagnosis14 and resolution2,20,28 of pelvic floor muscle dysfunction is empirical evidence of its role in vulvodynia. The effectiveness of botulinum toxin injections and topical nitroglycerin applications8,13,38,42,44 is further support for the role of vaginal muscle spasm in vulvodynia Muscle hypertonicity characterizes also chronic anal fissure (CAF), in this case of the internal anal sphincter (IAS).16 Treatment is aimed at reducing resting anal pressure by diminishing sphincter tone. Muscle relaxation is central to fissure healing.26 As with vulvodynia, the continuous hypertonicity of the IAS in patients with CAF has been associated with the formation of an inflammatory infiltrate.7 Also similarly, botulinum toxin injections and topical nitroglycerin applications have been used to treat CAF.32 Nifedipine, a calcium channel blocker that became popular for the treatment of vascular hypertonicity in the 1980s,17 has since demonstrated effectiveness in reducing intrauterine post-partum pressure in in vivo and in vitro studies18 and in attenuating contractions of smooth muscle from the internal anal sphincter and abolishing resting tone in vitro.10 In 2 small studies without control groups, oral11 and sublingual9 nifedipine reduced anal pressure in patients suffering from CAF. In another study, oral 1403

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nifedipine demonstrated effectiveness in treating sphincter hypertonicity in individuals who were refractory to topical glyceryl trinitrate ointment.41 Three randomized double-blind studies of CAF showed higher healing rates after treatment with topical nifedipine than with alternative ointments: 89% and 58% for .2% nifedipine and .2% glyceryl trinitrate, respectively, n = 52, P < .0415; 95% for .2% nifedipine combined with 1% lidocaine, compared with 50% for 1% lidocaine alone, n = 2831; and 94.5% for .3% topical nifedipine combined with 1.5% lidocaine, and 16.4% for 1.5% lidocaine alone, n = 110.34 In another randomized trial, 96.7% (30 of 31) patients treated with .5% topical nifedipine recovered completely from CAF, compared with 100% (32 of 32) of those who underwent lateral internal sphincterotomy, the most common treatment for CAF.24 The investigators of the latter study suggested that the exceptionally high healing rate after topical application of nifedipine could be attributed not only to reduction of the anal pressure through the inhibition of the flow of calcium into the sarcoplasm of the IAS, but also to its anti-inflammatory action. Based on the similarities between vulvodynia and CAF, namely muscle hypertonicity and increased inflammatory infiltrate, and the effectiveness of topical nifedipine in treating CAF, we conducted a double-blind placebo-controlled study to investigate the effectiveness of topical application of nifedipine on the treatment of vulvodynia.

Materials and Methods This study was conducted in the vulvar clinic of the Western Galilee Hospital, Nahariya, Israel. Participation was offered to women who suffered for at least 6 months from localized provoked vulvodynia according to Friedrich’s first 2 criteria: severe pain on vestibular touch or attempted vaginal entry and tenderness to localized pressure within the vulvar vestibule.19 Other inclusion criteria were ages 18 to 45, not pregnant, use of effective contraception, a desire not to become pregnant during the study period, and a severe degree of vulvodynia, according to Marinoff.27 Exclusion criteria were known allergy to nifedipine, vestibulectomy, active vaginal or pelvic infection, diabetes mellitus, and immune suppression. All participants completed a detailed questionnaire. Demographic characteristics assessed included age, marital status, ethnic origin, the number of sexual partners, and the use of contraception. Women rated on a 100point scale the worst pain they experienced at sexual intercourse. In addition, they were asked how often they stopped sexual intercourse due to pain, the physical area affected, whether pain is felt with deep penetration, and whether pain is felt without intercourse such as upon insertion of a tampon, during bicycling, urination, or unprovoked. Participants were also asked to assess their relationship with their partner (very good, good, fair, poor), the frequency they had sexual intercourse, the frequency that they had sexual intercourse without wanting it, the degree to which they felt sexual

A Placebo Study of Nifedipine for LPV desire, the frequency they discussed with their partners sexual relations, and the frequency they had orgasms. Women who stated that their vulvar pain started from their first experience of intercourse were classified with primary vulvodynia. During a gynecological examination, including colposcopy, women were asked to rate on a 100-point scale the pain felt when a Q-tipped cotton applicator was pressed on foci around the vestibule and the pain they felt when a small vaginal speculum was inserted into the vestibule. The participants were alternately assigned to 3 study groups. The hospital pharmacist prepared the topical preparations as follows: placebo (Caropol 940, EDTA, Propylen Glycol, Nipagin, Distilled TEA, Yellow Color) (group 1); .2% nifedipine (Schutz & Co, Hamburg, Germany) (group 2); and .4% nifedipine (group 3). The concentrations of nifedipine were similar to those used in studies of the treatment of CAF. Neither the investigators nor the participants knew the composition of the 3 preparations. We used the alternating assignment method because the sample size was small, and we wanted to maintain equal sized groups throughout the study. All women were instructed to apply the cream they received to the vestibule 4 times daily for 6 weeks, not including days of menses. During this time period, and the 6 weeks following (until follow-up examination), they were requested to refrain from all other treatments for vulvodynia. Immediately at the end of the 6-week treatment period and 3 months later, the women underwent colposcopic examinations, at which they again assessed their pain by the same 2 measures as in the pre-treatment test. They also completed the same questionnaire as at pre-treatment. We hypothesized that 6 weeks’ treatment with nifedipine would reduce pain intensity of vulvodynia by 30%. The primary outcome was a 30% reduction in pain intensity during sexual intercourse and during the Q-tipped cotton test and gynecological examination. Secondary outcomes were satisfaction with the treatment, capability of completing intercourse, pain-free intercourse, frequency of intercourse, and good relations with partner. Sample size was determined using the independent 1-sided sample t test to compare differences between groups. We assumed mean differences in pain intensity (during sexual intercourse, and during the gynecological examination) between pre- and post-treatment as 10 6 15 and 40 6 30 for the placebo and treatment groups, respectively, a = .05. The power calculated for 10 participants in each group was 86%. Mean and median values were calculated. The Kruskall-Wallis test, Fisher exact test, c2 test, and Wilcoxon signed rank test were used as appropriate to compare between the 3 study groups and between data from the 3 time points. The Helsinki Committee (Institutional Review Board) of Western Galilee Hospital, Nahariya, approved this study. It was registered in ClinicalTrials.gov NCT00496184. All women signed informed consent before their participation.

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Results Recruitment, treatment, and follow-up examinations were conducted between February and December of 2006. Of 100 women meeting inclusion criteria, 50 agreed to participate. Twenty participants of this study were lost to follow-up, predominantly because of temporary security situations in their home towns. Additional women were consecutively assigned to the study groups until a total of 10 completions were reached in each (Fig 1). The participants all reported high compliance with the study protocol. There were no statistically significant differences between the study groups in demographic or clinical characteristics before treatment (Table 1). Tables 2, 3, and 4 present the mean levels of pain intensity at pre-treatment, post-treatment and 3 months’ follow-up as assessed by 3 measures: the Q-tipped cotton test, the speculum insertion, and reporting of pain during sexual intercourse. For all 3 study groups, the mean levels of pain assessed by all 3 measures were lower at post-treatment than at pre-treatment, though statistical significance was not reached for all assessments. Mean reductions that were statistically significant at immediate post-treatment remained statistically significant at 3 months’ follow-up. Three mean reductions in pain intensity that were not statistically significant at immediate post-treatment became statistically significant at 3 months’ follow-up: Q-tipped cotton test in the .2% (low concentration) group and speculum insertion and sexual intercourse in the .4% (high concentration) group. For the Q-tipped cotton test (Table 2), reduction in the mean level of pain intensity at post-treatment reached statistical significance only in the placebo group and at 3 months’ follow-up in both the placebo and the .2% (low concentration) group. For speculum insertion (Table 3), reduction in the mean level of pain intensity at post-treatment reached statistical significance only in the .2% (low concentration) group and at 3 months’ follow- up in both the .2% (low concentration) group

and the .4% (high concentration) group. During sexual intercourse (Table 4), reduction in the mean levels of pain intensity at post treatment reached statistical significance in the placebo group and the .2% (low concentration) group and at 3 months’ follow-up in all groups. Table 5 presents additional outcome measures accessed from the questionnaires. Half of the women in the placebo group (5 of 10) reported pain-free intercourse at 3 months’ follow-up. The number of women who reported intercourse frequency of at least once a week increased in both the low- and highconcentration nifedipine groups. Neither did the type of vulvodynia, primary or secondary, nor initial pain intensity, associate with any of the treatment outcomes. However, we did find pain to decrease from a mean of 91.4 6 9.7 to a mean of 46.8 6 35.9 in women who reported pain when urinating after sexual intercourse (n = 14) and from 89.4 6 30.1 to 72.7 6 31.4 in women who reported not to have pain urinating (n = 16) (P = .041 for the 1-sided Wilcoxon rank sum test, and P = .082 for the 2-sided Wilcoxon rank sum test, respectively). Among those with dysuria, no differences were observed in treatment outcomes between the study groups. The only side effect reported was a mild irritation felt by some of the participants in groups 2 and 3, but not in the placebo group. With continued use of the ointment, the irritation ceased.

Discussion The main finding of this study is that for low and high concentrations of topical nifedipine, as well as placebo ointment, mean pain intensity, assessed by the Q-tipped cotton test, speculum insertion, and reports of sexual intercourse, was reduced at post-treatment compared with pre-treatment. These improvements were maintained at 3 months’ follow-up. The main strength of this study is its placebocontrolled design. Few placebo-controlled studies have been conducted on medical treatments for vulvodynia.

100 met inclusion criteria

The 50 who agreed to participate were alternatively assigned to the 3 study groups, until 10 completions were reached in each.

Discontinued study (n = 20)

Placebo (n =10)

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.2% nifedipine (n = 10)

.4% nifedipine (n = 10)

Figure 1. Flow chart of participation in the study.

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Table 1.

Topical Nifedipine Cream for Vulvodynia: Pretreatment Characteristics CHARACTERISTIC

GROUP 1 (PLACEBO)

GROUP 2 (.2% NIFEDIPINE)

GROUP 3 (.4% NIFEDIPINE)

P

Age (average 6SD), y Years of education (average 6SD) Number of partners (1 vs 2-5) Use of oral contraceptives during last year (yes vs no) Primary / secondary vulvodynia Q-tipped cotton test (median pain level) PV gynecological exam (median pain level) Unprovoked vulvodynia (yes vs no) Tampon use causes pain (yes vs no) Generalized vulvodynia (yes vs no) Capability of completing intercourse despite the pain (yes vs no) Intensity of pain during intercourse (on a 0- to 100-point scale) Deep, in addition to superficial dyspareunia (yes vs no) Frequency of intercourse: at least once/week (yes vs no) Self-report of relationship with partner (good to excellent vs mediocre to poor)

24.5 6 2.8 13.9 6 2.0 9/0 8/2 5/5 87.5 87.5 3/7 2/5 2/8 5/5

24.4 6 3.5 13.3 6 1.2 10 / 0 4/6 5/5 95.0 87.5 1/9 5/4 1/9 4/6

25.1 6 2.1 14.9 6 1.6 6/3 5/5 7/3 90.0 90.0 2/8 7/2 2/8 2/8

NS* NS* NSy NSy NSy NS* NS* NSy NSy NSy NSy

88.0 6 12.9

90.5 6 9.0

92.5 6 7.2

NS*

1/9 8/2

1/8 4/6

4/6 2/5

NSy NSy

10 / 0

8/2

5/3

NSy

Abbreviation: NS, Not significant. NOTE. Each group comprised 10 participants. Note that the women did not answer all the questions. *Kruskal-Wallis test. yFisher exact test, 2-sided.

In a recent review of 38 treatment studies of vulvodynia that were published from 1996 to 2006,25 only 2 of the 14 investigating medical treatments were placebocontrolled. Our team5 showed improvement after a fluconazole and placebo regime of 15% (3 of 20) and 30% (6 of 20), respectively. The other placebocontrolled study33 reported greater than 50% reduction in symptoms in 5 of 13 (38%) and 6 of 13 (46%) women treated by cromolyn cream and a placebo, respectively. Initiation of the latter study followed an uncontrolled pilot in which women treated with cromolyn cream improved dramatically. Results of the current study, together with the other 2 placebo-controlled studies, highlight the need for randomized placebo-controlled trials and raise doubts about vulvodynia treatment studies conducted without comparison to a placebo. None-

theless, non-randomized studies without placebo control continue to be published. An example is a recently published study that demonstrated a significant reduction in pain after treatment with Gabapentin.3 Understanding the considerable improvement reported by the women who received an inert cream may help elucidate the etiology and treatment possibilities of vulvodynia. Recently, a 22% spontaneous resolution rate in a 2-year period was reported for vulvodynia,35 yet this clearly does not explain the improvements observed within the 3-month duration of the current study. Nyirjesy et al33 suggested that counseling participants about exposure to irritants such as soaps, topical antifungicides, and monitoring infection could explain, in part, the large placebo effect in their study. This is not relevant to the current study because the participants

Pain Intensity as Measured by the Q-Tipped Cotton Test

Table 3.

Table 2.

GROUP 1 (PLACEBO) Pre-treatment: Mean value Post-treatment: Mean value P value: Post- and pre-treatment 3-Month follow-up: Mean value P value: Follow-up and pre-treatment

GROUP 2 (.2% NIFEDIPINE)

GROUP 3 (.4% NIFEDIPINE)

91.5 6 10.0 86.0 6 24.9 87.0 6 12.5 53.4 6 35.4 56.2 6 35.5 63.5 6 34.2 .006

.066

.066

52.7 6 46.6 47.0 6 37.7 73.5 6 29.4 .031

.014

NOTE. All calculations are by Wilcoxon signed rank test, 1-sided. Pain was assessed on a 0- to 100-point scale.

Pain Intensity as Measured With Insertion of a Small Speculum

.109

GROUP 1 (PLACEBO) Pre-treatment: Mean value Post-treatment: Mean value P value: Post- and pre-treatment 3-Month follow-up: Mean value P value: Follow-up and pre-treatment

GROUP 2 (.2% NIFEDIPINE)

GROUP 3 (.4% NIFEDIPINE)

83.5 6 18.6 84.5 6 18.0 88.3 6 6.3 63.2 6 42.7 50.1 6 40.5 70.9 6 31.7 .093

.029

.098

66.1 6 43.2 43.5 6 38.7 71.0 6 29.2 .191

.027

NOTE. All calculations are by Wilcoxon signed rank test, 1-sided. Pain was assessed on a 0-100 point scale.

.047

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Pain Intensity Reported During Sexual Intercourse

Table 4.

GROUP 1 (PLACEBO)

GROUP 2 (.2% NIFEDIPINE)

GROUP 3 (.4% NIFEDIPINE)

Pre-treatment: Mean value 88.0 6 12.9 90.5 6 9.0 92.5 6 7.2 Post-treatment: Mean value 48.1 6 42.8 61.9 6 34.2 72.5 6 27.6 P value: Post- and .039 .008 .063 pre-treatment 3-Month follow-up: 57.6 6 40.4 51.5 6 36.1 69.7 6 36.6 Mean value P value: Follow-up and .047 .004 .047 pre-treatment NOTE. All calculations are by Wilcoxon signed rank test, 1-sided. Pain was assessed on a 0- to 100-point scale.

received no particular instructions other than that relating to application of the cream. It is possible that the application of the ointment in itself, and not the action of the nifedipine, contributed to the reduction in pain intensity in all study groups. On the basis of our data, we would not expect oral administration of nifedipine to reduce pain beyond that of a placebo; however, such an investigation could help isolate

Outcome Measures Assessed by Questionnaire at Pre-treatment, Posttreatment, and 3-Month Follow-up

Table 5.

GROUP 2 GROUP 3 GROUP 1 (PLACEBO) (.2% NIFEDIPINE) (.4% NIFEDIPINE) Satisfaction with treatment (good to excellent /low) Post-treatment 4/5 3-Month follow-up 6/4 Capability of completing intercourse despite the pain (yes/no) Pre-treatment 5/5 Post-treatment 6/2 3-Month follow-up 6/3 Pain-free intercourse (no pain or almost no pain/ painful) Pre-treatment 0 / 10 Post-treatment 2/6 3-Month follow-up 5/4 Frequency of intercourse: at least once / week (yes/no) Pre-treatment 8/2 Post-treatment 7/1 3-Month follow-up 6/3 Self-report of relationship with partner (good to excellent/mediocre to poor) Pre-treatment 10 / 0 Post-treatment 8/0 3-Month follow-up 9/0

4/5 6/4

3/6 2/8

4/6 6/2 4/4

2/8 6/2 4/5

0 / 10 3/6 3/5

0 / 10 1/7 1/8

4/6 6/3 7/3

2/5 5/2 6/4

8/2 7/1 9/1

5/3 4/3 5/4

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the effect of application of a cream on vulvar pain. Landry et al25 documented 4 non-placebo controlled studies of topical applications. One found ketoconazole ineffective,30 2 did not find capsaicin combined with lidocaine to be more effective than lidocaine alone,31,39 and 1 reported efficacy of long-term nightly application of 5% lidocaine.45 In addition, a randomized trial showed lidocaine to be as effective as EMG biofeedback.12 Although some active ingredients such as capsaicin and ketoconazole may increase irritation, application of an inert cream may itself serve as a protective agent by facilitating skin changes and reducing pain that is not associated with muscle spasm. The observation that 5 of the 10 in the placebo group reported pain-free intercourse at 3 months’ follow-up, compared with only 2 at the immediate post-treatment visit, suggests that a factor other than physical application of the cream was responsible for the maintained benefit or late effect 6 weeks later. The concept of the ‘‘meaning response’’ may be informative. In their intriguing analysis of the placebo effect, Moerman and Jonas29 explained how the so-called placebo effect is actually induced by human meaning elicited with the use of a placebo and not by placebos themselves. After all, by definition, placebos are inert. In the current study, it is possible that the high level of support the participants received from their partners and from the research team may have provided a context that helped alleviate pain. Of note, 27 women reported good or very good relations with their partners, 3 did not respond, and none reported poor or fair relations. Further, reduction of cognitive dissonance, suggested by Goldstein22 as a factor in women’s assessment of their surgical treatment for vulvodynia, may have played a role in the pain reduction reported in the current study. The 6-week, 4-times daily compliance with the treatment regiment may have prompted women to respond more positively to their condition rather than to feel cognitive dissonance from ineffectiveness of their actions. It is possible that for some of the women, a positive effect itself may have contributed to muscle relaxation, which may in turn have helped maintain a lower level of pain over time. Interestingly, a placebo effect apparently plays an important role also in the success of nifedipine treatment for CAFs. A recent Cochrane database systematic review32 concluded that the effectiveness of topical application of nifedipine for treatment of CAF is marginally though significantly better than that of a placebo. Nitroglycerin ointment and Botox demonstrated similar effects; however, Botox and nifedipine resulted in fewer adverse effects than nitroglycerin ointment. No medication approached the efficacy of surgical sphincterotomy. Similar to vulvodynia, surgical treatment has demonstrated more effectiveness than any other treatment, with success rates ranging from 61% to 94%.25 Though we cannot draw conclusions from this study regarding differences between outcome measures, possibly due to the small sample size, we believe that treatment efficacy for vulvodynia must be assessed both by pain intensity at a gynecological examination and by pain reported during sexual intercourse.

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A Placebo Study of Nifedipine for LPV

We did not find any of the following to account for the lack of difference between the treatment groups: ethnic origin (Ashkenazi Jews, Sephardi Jews, and Moslems), the number of sexual partners, the use of oral contraceptives, reports of pain from tampon use, the presence of deep in addition to superficial dyspareunia, the ability to complete sexual intercourse, the quality of relationship with one’s partner, and the frequency of intercourse. Though there were no statistically significant differences in the pre-treatment characteristics of the individuals in the 3 groups, the group that received the higher concentration of nifedipine appears to be more treatment refractory. More of them reported less capability in completing sexual intercourse due to pain, lower frequency of intercourse, deep pain during intercourse, pain with tampon insertion, and fair rather than good relations with their partners. More had primary vulvodynia. In addition, more abstained from questions about frequency of intercourse, sexual desire, and talking to their partners about sexual relations. Nevertheless, we did not find any of the characteristics listed above to associate with less pain reduction; nor were we able to identify a subgroup who shared a number of the above characteristics, and who was less responsive to nifedipine treatment. The multi-factorial nature of vulvodynia raises expectations that some treatments may be effective for women with particular characteristics, and not for others. Our earlier findings of differential success rates for vestibulectomy support such.4 Consequently, we investigated the possibility that nifedipine therapy may benefit women with certain characteristics. We did not

find initial pain intensity or the type of vulvodynia, primary or secondary, to affect treatment outcome. Pain reduction was greater, with borderline statistical significance, for women who felt pain when urinating after sexual intercourse than for those who did not feel pain, regardless of which study group they were in. However, among those with dysuria, no differences were found in pain reduction between the study groups. Although these findings do not indicate greater effectiveness for nifedipine in women with dysuria, it appears that either the effect of the ointment itself or the meaning response may have benefited them more. Although the main limitation of this study is its small sample size, the number of participants was sufficient to meet the primary aims. Another limitation is that though all participants had vulvodynia for at least 6 months, we did not collect data to investigate the association between the duration of their vulvar pain preceding their participation in the study and treatment outcome. This study highlights the importance of placebocontrolled studies of vulvodynia treatments and questions the true effectiveness of medications for this condition, particularly of creams. Possible future directions of research include investigation of the effect of inert creams and other types of placebo on vulvodynia and the effect of nifedipine on women with vulvodynia who share particular characteristics, such as vaginismus. The observations that the topical nifedipine did not result in adverse effects, and that women in the placebo group also benefited, support the performance of further studies.

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