This randomized, placebo-controlled, double-blind pilot study was conducted between June 2010 and July 2013. The protocol was approved by local ethics committee of the institution. Each subject signed an informed consent to participate in this trial.
During this period, 76 women complaining of chronic pelvic pain (CPP) for > 6 months and defined as a pain score > VAS 50mm (visual analogue scale) were enrolled. Eligible patients had laparoscopically confirmed pelvic endometriosis (stage I-IV) and patent fallopian tubes. The exclusion criteria were age <18 years, any hormonal therapy in preceding 3 months, a desire to conceive within 1 year, or occluded fallopian tubes with or without pelvic adhesions. Cases with proved non-gynecologic causes of CPP (intestinal, urinary, and/or musculoskletal) were also excluded from the study. Each patient was advised to stop any analgesic medications before enrollment into the study. Patients with a known hypersensitivity or any contraindications to bupivacaine or to any local anesthetic agent of the amide-type were also excluded from the study.
All women in this trial underwent complete pelvic examination and high-resolution transvaginal ultrasonography. Basic work-up investigations to exclude concomitant non-gynecologic causes of CPP including mid-stream urine analysis, stool analysis, intravenous urogram, and full blood count whenever indicated were done. Only subjects with purely diagnosed pelvic endometriosis and patent fallopian tubes were included in this study.
At the time of office recruitment, patients were randomized in a ratio of 1:1 that was performed in accordance with a computer-generated randomization sequence using numbered, sealed envelopes to have either pertubal hysteroscopic-guided diluted bupivacaine (0.25%) infusion [Single-dose vial 10 ml + 100 ml Ringer solution] (group I, n=30) or placebo infusion [100 ml Ringer solution alone] (group II, n=30). All patients and experimenters (while delivering treatment, scanning and analyzing data) were blinded to the type of treatment.
The allocated study solution was provided to the surgeon intraoperatively by senior nursing staff. Solutions were indistinguishable and were preloaded into identical unlabeled Ringer solution bottles.
Pertubal infusion method:
The procedure was carried-out in a day-case endoscopic suite. One treatment setting was to be given preovulatory on cycle Day 7-12. Under paracervical block, and using Ringer solution as a uterine distending medium (Hysteromat, Karl Storz, Germany), an office hysteroscope (2.7 mm, Karl Storz, Tuttlingen, Germany) was passed and one tubal orifice was identified. Under a hysteroscopic guidance, a 3-Fr ureteric catheter was introduced, cannulated through the tubal ostium and passed proximally for 2-3 cm. After successful cannulation, diluted bupivacaine (0.25%, 10 ml with Ringer solution 100 ml) [Marcaine, AstraZenica, Istanbul, Turkey] was then infused through the catheter over a 15-20 min period. None of the patients used any adjunctive measures or analgesics following the original treatment.
Follow-up visits after hysteroscopic pertubal infusion were scheduled after 1, 2, and 3 months. A month before each visit, the patients completed a diary of their pain score. These were collected at the follow-up visit and new diaries given for the next visit. Grading of symptoms and physical findings were assessed at each clinic visit. The duration of treatment was completed in 3 months. Each patient was advised to stop any analgesic medications and to use barrier contraception throughout the study.
For the month preceding the trial, each patient completed a diary for generation of baseline variables, which were used for the assessment of the response to treatment. Response to treatment was assessed subjectively by changes in the variables, which included the patient's perception of pelvic pain severity using a visual analogue scale (VAS), her rating of both types of pelvic pain (dysmenorrheal and/or non-cycling pain) on a daily verbal rating scale (VRS), and a monthly verbal pelvic pain score (VRSmonthly). Satisfaction rates were also assessed.
The VAS was a subjective assessment of the pain on a scale of 0 (no pain) to 10 (most severe pain). It was recorded on a 10cm ruler in the diary at each follow-up visit and reflected the severity of this symptom as perceived by the patient in the preceding month (daily VAS). A monthly score (VRSmonthly) was then generated from the summation of daily VAS over a 28-day period (0, no pain; 100, maximum pain) at 1, 2, and 3 months.
On a multiple-choice questionnaire, an overall patient satisfaction rate that was independent of age, duration or severity of the symptoms was used to assess performance and satisfaction (satisfied, uncertain, dissatisfied) in daily activities at the end of the study taking into account the undesirable side effects.
Sample size justification:
Sample size was calculated using Epi Info® version 6.0, setting the type- I error (α) at 0.05 and the power (1- β) at 0.8, data from previous studies (5-7). According to these values and at 95% confidence interval, a minimal sample size of 60 patients was accepted to reach statistically accepted figure. Therefore, a total number of 76 patients were recruited in this study.
Data collection and statistical analysis:
Data concerning subjects who had undergone the office procedure since June 2010 were collected prospectively. The case notes of those with minimum of 3-months follow-up were further reviewed for the purposes of this report.
Epi Info® version 6.0 was used to record and statistically analyse the data. Values at the time of the hysteroscopic-guided pertubal bupivacaine infusion (i.e time 0) were compared with those at three time points (1, 2 and 3 months) after infusion using the paired t test, Mann-Whitney U test, Wilcoson and Friedman two-way ANOVA tests as appropriate. A level of significance of P<.05 was accepted for the study.