Design
This study was a parallel group randomized controlled trial, which utilized blinded outcome assessors, and an intention-to-treat analysis. After meeting the eligibility criteria for the study, participants were randomly allocated by the primary researcher to two experimental groups according to a computer-generated block randomization.
Registration
The study followed the Declaration of Helsinki and was approved by our Research Ethics Committee (process number:10272/2007, University Hospital, Ribeirão Preto Medical School). All subjects signed the informed consent prior to participation. This study was registered on ClinicalTrials.gov- NCT00628355 on date February 25, 2008.
Setting
Center of Chronic Pelvic Pain and Gynecologic Endoscopy of the Universitary Hospital, Ribeirão Preto Medical School, University of Sao Paulo.
Participants
Thirty women of reproductive age with CPP and trigger points of the inferior abdominal wall were included in the study. The flow of subjects and location of the trigger points are presented in Figs. 1 and 2, respectively. We excluded women with anticoagulation or bleeding disorders; local or systemic infections; an allergy to anaesthetic agents; acute muscle trauma; extreme fear of needles; a history of chronic musculoskeletal pain complaints such as fibromyalgia, chronic fatigue syndrome, and neurologic or neuropsychiatric conditions; and hypertension or diabetes. We also excluded those who had ingested aspirin within three days of the injection and users of antidepressants or corticosteroids that were administered for at least 30 days. All patients with suspected endometriosis and/or irritable bowel syndrome, interstitial cystitis, and painful bladder syndrome were also excluded. Pelvic/abdominal ultrasound was used to exclude the presence of endometriomas or hernias.
All women were evaluated at baseline and 1, 4, and 12 weeks after the intervention, and were instructed to perform pharmacological washout of central analgesics and/or NSAIDs for at least 72 h prior to all clinical evaluations.
Interview and examination
All women completed a clinical evaluation. Each woman filled out a form containing the hospital anxiety and depression scale (HAD), visual analogue scale (VAS), McGill Pain Index, and a World Health Organization instrument to assess quality of life (WHOQoL).
Measurements
Pain threshold (minimal pressure that causes pain or discomfort) and pain tolerance (maximal pressure that the patient can withstand) were measured with an algometer, which is a 1 cm diameter disk attached to the plunger of a pressure gauge. The dial of the gauge is calibrated in kg/cm2, with a measuring capacity of 5 kg (Instrutherm Ltda, São Paulo, Brazil). The algometer was placed perpendicularly on the trigger point, and the pressure was increased gradually (0.1 kgf/s) until the patient reported the first painful discomfort (threshold) and until the maximum stimulus withstood (tolerance). Two measurements were made with an interval of three minutes and the mean value was used for analysis.
Interventions
Group 1: Local anaesthetic injection of 2 mL 0.5 % lidocaine without a vasoconstrictor, directly and perpendicularly applied into the trigger point. No direct pressure was applied after the injection was administered weekly for four weeks.
Group 2: Ischemic compression was applied by sustained pressure on the trigger point. This pressure was sufficient to cause moderate local pain evoking the referred pain pattern [16]. This therapy was applied three times, lasting for 60 s for each session, with a rest period of 30 s between applications [17] for four sessions weekly. The compression was preceded by TENS, which delivers electric stimulation lasting for 30 min using a Dualpex 961 device with a frequency of 100 Hz, pulse of 250 μs, and intensity according to the pain threshold of the patient in order to promote initial analgesia [18].
Outcomes
Primary outcomes: satisfactory clinical response rate (defined by the Health Ministry of Brazil as a VAS reduction of at least 50 % or as a significant subjective impact on daily life activities (http://bvsms.saude.gov.br/bvs/saudelegis/sas/2012/prt1083_02_10_2012.html).
Secondary outcomes: proportion of pain relief ([VAS before and after treatment]/[VAS before treatment]), threshold, and tolerance on the trigger point.
Sample size
Sample size estimation was based on the differences between proportions in the satisfactory clinical response rate between the two groups. We considered a 30 % relative change in the between groups rate to be clinically significant. In order to have 90 % power to detect this change with an overall two-sided type I error rate of 5 %, this trial required a total of 60 subjects, or 30 for each group. This sample size was estimated using an online calculator (lee.dante.br).
The trial design included an interim analysis in order to determine if the trial needed to be discontinued early for efficacy or futility. Based on the results of the interim analysis, the study was stopped early, after including five blocks of six subjects each, because we considered the clinical response rate of intervention 2 to be significantly lower than that of intervention 1, after follow-up. At the time of the interim analysis, 15 subjects were enrolled in each group. Based on the O’Brien-Fleming approach group sequential boundary, the significance level for the primary end point was 0.025.
Randomization
Sequence generation
Block randomization, consisting of ten blocks of six subjects each, with three patients in each group of treatment, was generated online (http://www.randomization.com).
Control of bias
The first evaluation and the clinical diagnosis were performed by two experts (OBPN, JCRS) using the criteria developed by Travell and Simons [8], in order to recognize active trigger points. A third and fourth researcher, who were blinded to all clinical data except for the location of the trigger point, performed either intervention 1 or 2. An independent observer, who was blind to the previous clinical data and therapy modality, performed the follow-up measurements. A professional who was blinded to all information performed the statistical analysis.
Statistical analysis
Normal distribution of the data was determined using the Shapiro-Wilk test. Once normal distribution was confirmed, the comparison of quantitative variables between different groups was performed by the t-test. When normal distribution was not confirmed, the analysis was performed using the Wilcoxon test. The Chi-square/Fisher’s exact test was used, when appropriate, to analyse nominal variables.
Primary outcome was analysis using generalized linear mixed models. This model was implemented in the SAS program software using the PROC GENMOD. This model estimates the relative risk, independent of time, to verify the relationship between clinical response rate and group. It also estimated the relative risk within each study period. All statistical tests were two-sided. The significance level for the primary end point was adjusted for a single interim analysis to 0.025. Otherwise, we considered P values of less than 0.05 to indicate statistical significance.
In order to compare the times for each group separately, a nonparametric mixed-effects model for longitudinal data [19] was proposed in the analysis of the secondary endpoints. To compare the times for each group separately, we can apply multiple comparisons with Bonferroni adjustment. To compare the groups at each time point separately, the Mann–Whitney test, (a nonparametric technique), was used to compare distributions of two or more groups that require no assumptions about the distribution of data. The level of significance was considered as 5 %. The analysis was conducted by the package nparLD using the R software. Additional file 1: Supplementary material is disponible.