Arch Gynecol Obstet DOI 10.1007/s00404-014-3190-z

General Gynecology

Randomized trial of long‑term effects of percutaneous tibial nerve stimulation on chronic pelvic pain Ayse Istek · Funda Gungor Ugurlucan · Cenk Yasa · Sule Gokyildiz · Onay Yalcin 

Received: 2 April 2013 / Accepted: 20 February 2014 © Springer-Verlag Berlin Heidelberg 2014

Abstract  Objective  To evaluate the long-term effects of percutaneous tibial nerve stimulation (PTNS) on quality of life in women with chronic pelvic pain. Materials and methods  Thirty-three women with chronic pelvic pain were randomized into PTNS (n = 16) or control (n  = 17) groups. In PTNS group, weekly PTNS in 30-min sessions for 12 weeks was performed whereas the control group received no stimulation. Present pain intensity-visual analog scale (PPI-VAS), short-form McGill pain questionnaire (SF-MPQ), and SF-36 were used at baseline, 12-week, and 6-month follow-up for the evaluation of pain intensity and quality of life. Results  Two women (12.5 %) were cured, 7 (43.8 %) were much improved, 6 (37.5 %) were the same and 1 (6.3 %) was worse after PTNS. Two women (11.8 %) were improved, 10 (58.8 %) were the same, and 5 (29.4 %) were worse in the control group. Mean PPI-VAS of PTNS group at baseline, 12 weeks, and 6 months was 8.4 ± 1.1, 3.8  ± 3.5 and 4.5 ± 3.7, respectively. There was a significant improvement in PPI-VAS scores of PTNS group

A. Istek  Sisli Etfal State Hospital, Istanbul, Turkey F. Gungor Ugurlucan · C. Yasa · O. Yalcin  Division of Urogynecology, Department of Obstetrics and Gynecology, Istanbul Medical School, Istanbul University, Istanbul, Turkey F. Gungor Ugurlucan (*)  Atakoy 9. Kisim, B6 Blok, Daire 40, Atakoy, Bakirkoy, 34156 Istanbul, Turkey e-mail: [email protected] S. Gokyildiz  Cukurova University Adana Health High School, Adana, Turkey

whereas no change was observed in the control group. There was a slight increase in the PPI-VAS scores of the PTNS group at 6-month, but the difference was not statistically significant. There was significant improvement in all domains of SF-MPQ and SF-36 in PTNS group with continuing effects at 6 months whereas no significant change was observed in the control group. Conclusion  PTNS is a minimally invasive treatment method that leads to decrease in pain severity and improvement in quality of life in women with chronic pelvic pain with effects continuing at 6 months. Keywords  Percutaneous tibial nerve stimulation · Chronic pelvic pain · Neuromodulation · Quality of life

Introduction Chronic pelvic pain is defined as intermittent or constant pain in the lower abdomen or pelvis of a woman of at least 6 months in duration, not occurring exclusively with menstruation or intercourse and not associated with pregnancy [1, 2]. Thirty-three percent of women in their lifetime or 12 % of women through their reproductive years suffer from chronic pelvic pain [3, 4]. In the USA, 40 % of gynecologic laparoscopies and 12 % of hysterectomies are performed because of chronic pelvic pain [5]. The type and frequency of laparoscopic findings in women with chronic pelvic pain are no visible pathology in 35 %, endometriosis in 33 %, adhesions in 24 %, chronic pelvic inflammatory disease in 5 %, and ovarian cysts in 3 %, with occasional other diagnoses [2]. Chronic pelvic pain has an adverse effect on quality of life similar to that reported for other chronic diseases, such as diabetes mellitus, Crohn’s disease and congestive heart failure [6]. A complete history of the

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patient’s pain, as well as a thorough review of the urinary tract disease, bowel disease, reproductive tract disease, musculoskeletal disorders, and psychoneurological disorders is essential [7]. The treatment of chronic pelvic pain remains a challenge despite many treatment options such as nonsteroid-antiinflammatory drugs, antidepressants, anticonvulsants, local anesthetics, gamma-aminobutyric acid (GABA) receptor agonists [8, 9]. Quite a number of patients are refractory to treatment. Percutaneous tibial nerve stimulation (PTNS) is a minimally invasive method of neuromodulation used successfully in the treatment of overactive bladder syndrome and non-obstructive urinary retention [10–14]. McGuire et al. [15] were the first to describe inhibition of detrusor activity by PTNS. PTNS has also been shown to have positive effects on chronic pelvic pain [10, 11, 16, 17]. Longterm effects have been observed with stimulation over 2–3 months with minimal side effects [18]. Van Balken et al. [16], in their multicenter prospective study, have shown a significant improvement in the quality of life in women treated with PTNS. Our aim in this randomized controlled study is to evaluate the long-term effects of PTNS on the severity of pain and quality of life in women with chronic pelvic pain.

Patients and methods From January 2006 to December 2008, 33 patients suffering from chronic pelvic pain and willing to participate were included in this prospective randomized controlled study. Chronic pelvic pain was defined as noncyclic pain that persists for six or more months; localizes to the pelvis, infraumbilical anterior abdominal wall, or lumbosacral back or buttocks; and leads to degrees of functional disability [1]. Inclusion criteria were women visual analog scale (VAS) over 5, cessation of analgesics or other medications for pain at least 2 weeks prior to PTNS, and discontinuation of other electrical stimulation methods 3 months prior to PTNS. Exclusion criteria were ongoing pregnancy, history of a cardiac pacemaker, neuropathy or recurrent urinary tract infection, and interstitial cystitis. Individual analgesic usage was restricted throughout the study and in case when the patients complained of severe pain, they were advised to call the physician and appropriate nonsteroidal anti-inflammatory type analgesics were adjusted by the study executors. Randomization was carried out using computer-generated random allocations prepared into envelopes by an investigator with no involvement in the trial. Ethics approval was obtained from the institutional ethics committee. Percutaneous tibial nerve stimulation was performed as suggested by Stoller and Govier et al. [11, 19]. Urgent PC©

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(Cystomedix, Anoka, MN, USA) neuromodulation system was used for stimulation. Frequency was 20 Hz, flow was 200 μs wideness and the amplitude of current was between 0.5 and 10 mA. A 34-gauge needle was placed on the point 1 cm posterior and 3 cm proximal to the medial malleolus. Prior to the start, electrical stimulation was triggered to determine the appropriate stimulation amplitude and to confirm correct needle placement. The stimulation amplitude was set at a maximum tolerable level according to the subject under investigation. Plantar flexion was accepted as the proof of effectiveness. Sessions were performed as once a week for 30 min. Total treatment period was 12 weeks. All patients underwent evaluation for chronic pelvic pain through detailed history, general physical and gynecologic examination, and transvaginal sonography. At the baseline of study, at completion of 12-week treatment and after 6 months of treatment completion, all patients had to fill out general and disease-specific quality of life questionnaires, and regular and irregular use of analgesics was evaluated. VAS was used to determine pain intensity, SF36 quality of life scale validated in Turkish was used for evaluation of quality of life, and short-form McGill pain questionnaire (SF-MPQ) was used to identify the features of the pelvic pain [20, 21]. The SF-36 scale consists of 36 items covering eight distinct health status concepts and one item measuring self-reported health transition: physical function, role, emotional health, social functioning, energy/ fatigue and change in general health. The main component of the SF-MPQ consists of 15 descriptors (11 sensory; 4 affective), which are rated on an intensity scale. Three pain scores are derived from the sum of the intensity rank values of the words chosen for sensory, affective, and total descriptors. The SF-MPQ also includes the Present pain intensity (PPI) index of the standard MPQ scale and VAS. The primary outcome was patient reported improvement in chronic pelvic pain: women who reported being either pain-free or who reported that their pain was improved. Secondary outcomes included the improvement in quality of life and disease-specific questionnaires. Statistical analysis Statistical analysis was performed using with Number Cruncher Statistical System (NCCS) 2007 and Power Analysis and Sample Size (PASS) 2008 Statistical Software (Utah, USA) programs. Data are expressed as mean ± standard deviation. Differences between the two groups for categorical variables were assessed using Chi-square and Fisher’s exact tests. Normality assumption was performed, and Student’s t test and Mann–Whitney U test were used for comparing continuous variables between the two treatment groups where appropriate, and Paired Sample t test and the

Arch Gynecol Obstet

Wilcoxon signed-rank test were used for preoperative and postoperative comparison where appropriate. When type 1 error and sample size in the study group were 0.05 and 16, respectively, the power was calculated as 0.85. A p value less than 0.05 was considered statistically significant.

Results From January 2006 to December 2008; 28,949 women applying to gynecology outpatient clinic were screened and 72 women with chronic pelvic pain according to ACOG guideline on chronic pelvic pain [1] were recruited, as detailed in Fig. 1. Forty-eight women were found eligible; 15 of the patients did not participate in the study. The 33 patients whom were included were randomized into PTNS group (n  = 16) and control group (n  = 17). The control group received oral analgesics, but no PTNS throughout the study. Patient characteristics are summarized in Table 1. There was no significant difference between the two groups

in terms of education, occupation, financial situation, pregnancy and number of births, health problems, duration of pain, operations and drug usage, except for age. Women in the PTNS group were significantly younger than those in the control group. Mean duration of pain was 3.9 ± 2.2 and 4.0 ± 2.3 years for PTNS and control groups, respectively. All of the patients in the PTNS group completed the treatment program. The results of the SF-MPQ are summarized in Table 2. There was a significant improvement in the sensory, affective, and total pain rating index (PRI) domains and in the mean present pain intensity-visual analog scale (PPI-VAS) of the PTNS at 12 weeks and 6-month follow-up. Mean PPI-VAS results of the PTNS and control group at baseline were 8.4 ± 1.1 and 6.5 ± 1.1, respectively. The difference was statistically significant. At 12-weeks follow-up, the mean PPI-VAS results were 3.8 ± 3.5 and 6.0 ± 1.5 for PTNS and control groups, respectively. There was a significant improvement in the PPI-VAS scores of the PTNS group whereas no change was observed in the control

Fig. 1  Flow diagram of patient progression through the study

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Table 1  Patient characteristics of the two groups Age Number of deliveries  None (%)  One (%)  Two and more (%) Smoking  No (%)  Yes (%) Menopause  No (%)  Yes (%) Duration of pain  6 months–1 year (%)  1–2 years (%)  >2 years (%) Treatment history for pain  Analgesics (%)  Physiotherapy (%)  Analgesics + antidepressants (%)  Analgesics + hot packing (%)  Analgesics + acupuncture (%)  Surgery (%)

group. At the 6-month follow-up, though the mean scores were higher in the control group, there was no statistically significant difference. The mean scores for PTNS and control groups were 4.5 ± 3.7 and 5.9 ± 2.2, respectively. Although there was a slight increase in the PPI-VAS scores of the PTNS group at 6-months of follow-up, the difference was not statistically significant. When the results of the SF-36 questionnaire were evaluated, there was a significant improvement in all domains including physical function, physical role, emotional role, energy/fatigue, mental health, social functioning, pain, and general health at 12 weeks and 6 months in the PTNS group. The results are summarized in Table 3. The state of health compared to the previous year was significantly better in the PTNS group at 12 weeks and 6 months when compared to the control group. Two patients (12.5 %) suggested that they were cured after PTNS treatment. Seven patients (43.8 %) were much improved. Six patients (37.5 %) were the same and one patient (6.3 %) was worse than before. In the control group, two patients (11.8 %) were improved, ten patients (58.8 %) were the same, five patients (29.4 %) were worse than before. Accordingly, evaluation of the usage of nonsteroidal anti-inflammatory type analgesics indicated daily analgesic usage in eight patients, at least 3 days per week in four patients, 2 days per week in two patients, irregular in one patient, and none in two patients in the control group.

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PTNS group (n = 16)

Control group (n = 17)

p

38.8 ± 5.4

44.4 ± 8.7

0.036 >0.05

2 (12.5) 2 (12.5)

0 4 (23.5)

12 (75.0)

13 (76.5)

13 (81.3) 3 (18.8)

11 (64.7) 6 (35.3)

16 (100) 0

13 (76.5) 4 (23.5)

>0.05

>0.05

>0.05 2 (12.5) 2 (12.5) 12 (75)

1 (5.9) 8 (47.1) 8 (47.1)

12 (75) 1 (6.3) 1 (6.3) 0 1 (6.3)

13 (76.5) 0 1 (5.9) 3 (17.6) 0

1 (6.3)

1 (5.9)

>0.05

Corresponding values indicated daily nonsteroidal antiinflammatory type analgesic usage in one patient, at least 3 days per week in six patients, and none in nine patients in the PTNS group. Although the results were better in the PTNS group, there was no statistically significant difference between the two groups. No major complications developed during stimulation. Two patients had slight pain at the 3rd session. One patient had slight pain at the 5th session. One patient had slight pain and one had mild ecchymosis at the 8th session. One patient had slight pain at the 9th session. One patient had slight pain and one had mild ecchymosis at the 10th session. One patient had slight pain at the 12th session.

Discussion The primary outcome of this study was patient reported improvement in symptoms. Nine patients (56.3 %) suggested that they were either cured or much improved after 12 weeks of PTNS treatment at 6 months of follow-up whereas in the control group only two patients (11.8 %) were improved. Neuromodulation has been used for the treatment of chronic pelvic pain in the form of sacral neuromodulation, transcutaneous electrical nerve stimulation, and PTNS [22–24]. Posterior tibial nerve stimulation was first

PT pre-treatment, AT  after treatment, Sensory-PRI sensory-pain rating index, Affective-PRI affective-pain rating index, T-PRI total-pain rating index, PPI-VAS present pain intensity-visual analog scale, Evaluative evaluative overall intensity of total pain experience. PPT-AT, P value of the statistical analysis of the difference in the PTNS group before and after treatment; PPT-6 months, P value of the statistical analysis of the difference in the PTNS group before and 6 months after treatment; PAT-6 months, P value of the statistical analysis of the difference in the PTNS group after treatment and 6 months after treatment; PPT-1st visit P value of the statistical analysis of the difference between the two groups at pretreatment/1st visit; PAT-12 weeks, P value of the statistical analysis of the difference between the two groups at 12 weeks; P6 months, P value of the statistical analysis of the difference between the two groups at 6 months

0.213 0.063 0.001 5.9 ± 2.2 6.0 ± 1.5 6.5 ± 1.1 0.480 0.001 0.001 4.5 ± 3.7 3.8 ± 3.5 8.4 ± 1.1 PPI-VAS

15.2 ± 4.1 4.3 ± 2.2 19.5 ± 6.1 15.9 ± 4.1 4.6 ± 1.8 20.6 ± 5.6 17.0 ± 2.7 5.1 ± 1.2 22.1 ± 3.8 0.107 0.015 0.094 0.012 0.043 0.023 0.001 0.001 0.001 12.6 ± 8.6 3.9 ± 3.3 16.4 ± 11.9 10.1 ± 6.1 2.6 ± 2.1 12.6 ± 8.1 Sensory-PRI 18.1 ± 5.6 Affective-PRI 5.4 ± 2.3 T-PRI 23.2 ± 7.7

12-weeks 1 visit PPT-AT 6 months AT PT

PTNS group (n = 16)

Table 2  Results of the SF-MPQ at baseline, 12 weeks, and 6 months

PPT-6 months

PAT-6 months

st

Control group (n = 17)

6-months

0.664 0.882 0.612

PPT-1st visit

0.008 0.004 0.002

PAT-12 weeks

0.139 0.413 0.371

P6 months

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described in 1983 by McGuire et al. [15] in 22 patients with urinary incontinence. It is a peripheral nerve stimulation method that involves a needle electrode temporarily being inserted proximal to the medial malleolus near the posterior tibial nerve. Several studies regarding the use of PTNS have shown positive effects in the treatment of urge incontinence, urgency/frequency, and non-obstructive urinary retention [10–14]. Klingler et al. and Govier et al. [10, 11] also found a significant effect on pain symptoms in their studies as a secondary outcome. Klingler et al. [10], in their study on 15 patients with urgency/frequency, showed a reduction in pain in all patients with a decrease in VAS scores from a mean (SD) of 7.6–3.1. Govier et al. [11] in their prospective multicenter clinical trial on 53 patients with overactive bladder syndrome found a significant reduction in pelvic pain intensity of 30 % and improvement in quality of life. Studies evaluating the effect of PTNS on chronic pelvic pain as a primary outcome are quite few. Van Balken et al. [16] were the first to evaluate the effects of PTNS treatment on chronic pelvic pain. In their prospective multicenter trial in 33 patients with chronic pelvic pain, subjective response was observed in 42 % and there was a significant improvement in VAS and in total pain rare intensity in MPQ. They concluded that PTNS has positive effects in chronic pelvic pain, but placebo-controlled studies are needed. Gokyildiz et al. [17], in their prospective randomized controlled study on the effects of PTNS on chronic pelvic pain, found a significant decrease in the pain frequency and intensity in the PTNS group and a mild improvement in sexual functions. Biemans and van Balken, in their systematic review regarding efficacy and effectiveness of PTNS in the treatment of pelvic organ disorders, have found evidence for the efficacy of PTNS on pain, but concluded that independent highquality randomized controlled trials are needed to confirm the therapeutic effects [25]. The exact mechanism of action of PTNS is unknown; there are some hypotheses regarding modulation of the nervous system or blood flow [26]. In one study, it was shown that stimulation of the posterior tibial nerve inhibits bladder activity by depolarizing somatic sacral and lumbar afferent fibers [27]. How neuromodulation has effects on chronic pelvic pain is not exactly known. Pain modulation is possibly accomplished by the stimulation of large somatic nerve fibers leading to inhibition of A-delta or C fibers, elevation of endorphins at a spinal level, and decrease in c-fos expression in the central nervous system [16, 27–31]. In our study, the primary outcome was patient reported improvement in chronic pelvic pain: women who reported being either pain-free or who reported that their pain was improved. 56.3 % of the patients receiving PTNS suggested that they benefited from treatment and their analgesic use

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13 0.004 0.013 0.001 0.003 0.026

0.001

54.1 ± 28.7 48.4 ± 21.0

0.007 0.004 0.001 0.001 0.029

0.01

PPT-6 months

2.6 ± 0.8 (1–4) 3.8 ± 1.1 (1–5) 3.6 ± 0.9 (1–5) 0.001

60.3 ± 25.1 54.1 ± 20.1

29.7 ± 19.1 35.3 ± 16.9

56.3 ± 35.9 54.8 ± 41.7 59.1 ± 17.5 60.3 ± 13.2 65.6 ± 27.6

0.001

PPT-AT

0.001 0.001

60.9 ± 44.5 64.6 ± 43.0 61.9 ± 16.2 64.3 ± 11.7 66.4 ± 27.3

20.3 ± 33.1 25.0 ± 35.5 35.6 ± 17.4 46.8 ± 16.1 50.0 ± 20.4

63.1 ± 27.8

6 months

0.001 0.001

65.9 ± 26.2

AT

46.9 ± 26.4

PT

PTNS group (n = 16)

0.450

0.312 0.086

0.470 0.063 0.188 0.119 0.774

0.528

49.4 ± 13.0 53.8 ± 14.3

38.2 ± 28.1 39.2 ± 35.8 50.0 ± 13.9 52.9 ± 13.9 51.3 ± 17.0

68.8 ± 12.7

12 weeks

47.6 ± 19.2 54.4 ± 15.0

48.5 ± 38.0 37.2 ± 35.1 51.5 ± 15.5 53.9 ± 15.2 48.2 ± 18.3

70.3 ± 14.5

6 months

2.8 ± 0.6 (1–4) 2.8 ± 0.8 (1–4) 2.8 ± 0.9 (1–5)

47.1 ± 9.2 55.6 ± 9.5

39.7 ± 26.6 39.2 ± 24.2 50.0 ± 10.1 51.8 ± 7.9 52.4 ± 11.7

68.2 ± 11.6

PAT-6 months 1 visit

st

Control group (n = 17)

0.125 0.969

0.004 0.001

0.031

0.074 0.074 0.031 0.017 0.064

0.046 0.187 0.006 0.272 0.691

0.250

0.694

0.007

PPT-1st visit PAT-12 weeks

0.058

0.454 0.352

0.579 0.199 0.196 0.210 0.040

0.367

P6 months

PT pre-treatment, AT after treatment, PPT-AT, P value of the statistical analysis of the difference in the PTNS group before and after treatment; PPT-6 months, P value of the statistical analysis of the difference in the PTNS group before and 6 months after treatment; PAT-6 months, P value of the statistical analysis of the difference in the PTNS group after treatment and 6 months after treatment; PPT-1st visit, P value of the statistical analysis of the difference between the two groups at pretreatment/1st visit; PAT-12 weeks, P value of the statistical analysis of the difference between the two groups at 12 weeks; P6 months, P value of the statistical analysis of the difference between the two groups at 6 months

Comparing health to previous year

Physical function Physical role Emotional role Energy/fatigue Mental health Social functioning Pain General health

Domains

Table 3  Results of the SF-36 of the two groups

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was less than that of the control group. Secondary outcomes were the improvement in quality of life and diseasespecific questionnaires. There was a significant improvement in SF-36 and MPQ domains in the PTNS group after treatment and this effect continued at 6 months, though there was no significant change between 12 weeks and 6 months. This is the first study to show the continuation of positive effects of PTNS on chronic pelvic pain at 6 months after cessation of treatment. Although there was no statistically significant difference at 6 months between the control group and the PTNS group except for social functioning, all of the mean scores of the PTNS group were lower than those of the control group. It must be re-emphasized that the baseline results of the SF-36 questionnaire were significantly different between the two groups in favor of the control group. At the 6-months follow-up, the PTNS group had improved significantly whereas no significant change was observed at the control group, resulting in no statistically significant difference at the 6-months follow-up, which might have been due to difference in the baseline values of the two groups (Table 3). Despite randomization, there was a significant difference between the two groups regarding the mean age of the patients. However, the duration of pain symptoms between the two groups was the same. In addition, there was a significant difference between the baseline mean PPI-VAS of the two groups in favor of the control group. But, at the 12 weeks follow-up, significant improvement was obtained in the PTNS group than the control group despite worse baseline scores. No major complications were encountered during the study, which supports the fact that PTNS is a minimally invasive treatment method with minor side effects. The major limitations of this study are the lack of homogeneity between the two groups despite randomization regarding the age of the patients and the baseline PPI-VAS results. The control group did not receive any placebo or sham stimulation. There is a significant difference between placebo and no treatment in trials involving the treatment of chronic pelvic pain [32]. In this study, the confounder might be the increased patient-physician contact that occurred in the PTNS arm of the study. Lastly, chronic pelvic pain is a subjective entity, which is attempted to be objectively quantified and evaluated using VAS and validated questionnaires, but still the objective nature of the studies regarding chronic pelvic pain is debatable.

Conclusion PTNS is a minimally invasive treatment method that leads to decrease in pain severity and improvement in quality of life in women suffering from chronic pelvic pain with

effects continuing at 6 months. Long-term placebo-controlled studies are needed to further evaluate the long-term effects of PTNS treatment. Acknowledgments  This work was supported by Scientific Research Projects Coordination Unit of Istanbul University. Authors convey sincere gratitude for the support. Conflict of interest  The authors declare no conflict of interest.

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