Hysteroscopy is a common, safe, feasible, and accurate procedure used to identify intracavitary uterine lesions, including increased endometrial thickness (greater than 5 mm) in postmenopausal women, suspected endometrial carcinoma, abnormal uterine bleeding, infertility, or recurrent pregnancy loss. It can be performed in an office setting, which has the benefit of increased safety and a low incidence of serious complications.1,2 However, a major obstacle to its successful implementation as a commonplace procedure is pain management. A recent meta-analysis concluded that office-based hysteroscopy is painful,3 even when an experienced surgeon performs a nontraumatic technique.4 Although most women tolerate it well, a sizeable number of hysteroscopies cannot be completed as a result of pain.5
One approach that has not yet been exhaustively explored for pain relief during office-based hysteroscopy is transcutaneous electrical nerve stimulation (TENS). Transcutaneous electrical nerve stimulation is a nonpharmacologic pain-relieving method based on the delivery of pulsed electrical currents through the skin, which reduces pain through both peripheral and central mechanisms.6 It is noninvasive, safe, and inexpensive and, in addition, it has minimal side effects or drug interactions.7
The objective of this double-blind, randomized, placebo-controlled trial was to investigate the pain-relieving effect of a TENS application during office-based hysteroscopy without sedation.
MATERIALS AND METHODS
We conducted a randomized, double-blind, placebo-controlled trial. We enrolled 138 consecutive patients scheduled to undergo office-based hysteroscopy without sedation at the Hospital Provincial de Castellón (Spain) between January 2016 and April 2016. The inclusion criteria were: women who attended an annual gynecologic checkup who were indicated for diagnostic office-based hysteroscopy because of the presence of different pathologies such as postmenopausal endometrial thickening (greater than 5 mm), postmenopausal abnormal uterine bleeding, suspicion of endometrial polyps or leiomyoma, an infertility study, suspicion of endometrial carcinoma, or hypermenorrhea. Exclusion criteria included: age younger than 18 years, a previous cervical surgery, neurologic deficit, chronic or preprocedural use of opioids or psychoactive drugs, cutaneous damage at the TENS application sites, the patient having been fitted with a pacemaker or automatic implanted cardiac defibrillator, inability to understand or refusal to sign the informed consent form, and previous experience with TENS.
This study (ClinicalTrials.gov ID: NCT02647008) was approved by the Hospital's Human Ethics Committee and it followed the ethical guidelines set out in the Declaration of Helsinki. All patients signed an informed consent statement before starting the study.
Before the start of the trial, investigator 1, who was not involved in the selection and inclusion of participants, organized the preparation of numbered, opaque, sealed envelopes containing the group allocation. Investigator 2 generated the random sequence (based on simple randomization) by using a computerized random number generator8; this was concealed from all study personnel throughout the study. On enrollment in the study, the 138 participants were randomly assigned to one of three groups, active TENS (n=46), placebo TENS (n=46), or a control group (n=46). The participants, the gynecologist, and the nurse assessing the outcomes were blinded to the group allocations.
The TENS unit used in this study was an Endomed 482u. In the active TENS group, it emitted asymmetric, balanced, biphasic square waveform at a mixed stimulating frequency that randomly varied between 80 and 100 Hz and had a pulse duration of 400 microseconds. Transcutaneous electrical nerve stimulation therapy was initiated 5 minutes before starting the hysteroscopy and for the duration of the procedure. Two sets of two self-adhesive electrodes (7×13 cm rectangle each) were placed parallel to the spinal cord at the T10–L1 and S2–S4 levels (Fig. 1). The device intensity (amplitude) was individually adjusted to each participant's maximum sensory level (strongest reported tingling feeling without pain and with no muscle contractions). Patients were informed about the importance of maintaining the stimulation at a maximum nonpainful level. Thus, the TENS output intensity was increased during the treatment every time the patient accommodated to the TENS stimulus. All the hysteroscopies were performed by the same experienced gynecologist, who was blinded to the patients' group allocations. The physician used a Richard Wolf Panoview Plus 12° 3.5-mm hysteroscope with a 5-mm-thick outer diagnostic sheath. To distend the uterine cavity with saline solution, they used a Richard Wolf 2222 Hystero Pump II device at a constant flow of 80 mL/min with a constant pressure of 100 mm Hg. Vaginoscopy was performed in all cases. A Richard Wolf 5124 LP Xenon 180 W light source and a Richard Wolf 5512 1CCD Endocam were also used in all the procedures. When appropriate, endometrial biopsy was obtained by hysteroscope direct vision using a hysteroscopy biopsy forceps.
To achieve blinding in the placebo group, participants were connected to the TENS unit in exactly the same way as participants in the active TENS group with the unit emitting the active indicator light and sound but delivering no electrical stimulation.9 At the end of the procedure, the effectiveness of the blinding was assessed by asking the participant, the nurse, and the gynecologist which TENS intervention (active or placebo) they thought had been delivered.
Participants in the control group received the hysteroscopy procedure according to the standard hospital protocol using standard techniques without administration of any kind of sedation or analgesia.
The level of pain during the office hysteroscopy procedure (primary outcome) was measured on a 100-mm-long horizontal line visual analog scale (VAS; 0 mm=no pain and 100 mm=worst possible pain). Evaluations were completed at five distinct stages during the procedure: 1) at baseline, to assess the onset of the TENS effect before introducing the hysteroscope; 2) at the time the hysteroscope was introduced into the cervical channel (entry); 3) on contact, when the endometrium was touched; 4) immediately after biopsy; and 5) 5 minutes after finishing the procedure, to assess any residual feelings. Biopsies were performed only if there was an abnormal finding on hysteroscopic examination.
A discrete, 5-point, verbal Likert scale including the following options: “no pain,” “minimal pain,” “moderate pain,” “severe pain,” and “worst pain possible,” was also used to assess the internal consistency of the pain rating within the study. For analysis, these responses were given numeric values (0–4, respectively).
The duration of the procedure, vital parameters (blood pressure, heart rate, arterial oxygen saturation), vasovagal symptoms (dizziness, nausea, vomiting, shoulder pain, vertigo, sweating, or fainting), and unusual or adverse TENS events (skin allergy, pain, or burning at the electrode site) were also recorded during all the hysteroscopy procedures. Finally, the level of satisfaction with the hysteroscopy, as indicated on a scale of 0–10, was measured at the end of the procedure in all three groups.
The desired sample size was calculated by an external researcher not involved in the procedures, who was therefore blind to the intervention. An a priori analysis of effect size and sample size was conducted at an α level of 0.0125 and for the desired power of 80%. Effect size was estimated based on recommendations for a minimum clinically relevant change of 10 mm on a 0–100 mm VAS for pain.10 The recruitment target was thus 135 participants in total (G*Power 3.0.10).11
We analyzed our data using an intention-to-treat approach. To compare the success of the randomization, we also determined the baseline differences among the groups using preliminary analyses of variance and χ2 tests. To calculate intergroup differences as well as associations between variables, we used one-way analysis of variance for continuous variables followed by Games-Howell/Tukey post hoc tests, and χ2 tests for categorical variables, with an α level of 0.05. Spearman rank correlation coefficients between the VAS and Likert scales were used to assess the strength of the relationship between these variables.
The data are presented as the mean±standard deviation. To avoid the inflation of type I error resulting from repetition of pairwise comparisons, a Bonferroni adjustment was applied to the level of significance (.05) of the four comparisons in the one-way analysis of variance. Thus, the α level for these comparisons was 0.05/4, that is, 0.0125. All the statistical analyses were performed using SPSS 18.0 for Windows.
We enrolled 142 consecutive patients in this clinical trial. Four participants were not allocated for randomization as a result of previous experience with TENS and 138 patients were randomly assigned (allocation ratio one-to-one-to-one) to one of three groups: active TENS, placebo TENS, or control. Figure 2 shows the progression of the participants through the trial. No differences were found among the three groups regarding age, weight, body mass index, parity status, menopausal status, previous hysteroscopy status, or inclusion criteria (Table 1).
The mean VAS pain scores in all the groups at different stages are shown in Table 2. The between-group analysis highlighted a significant decrease in pain, as measured on the VAS, at several stages (entry, contact, biopsy, and residual) in the active TENS group compared with the control group as well as compared with the placebo group.
Regarding the 5-point Likert scale score-outcome data, there were also differences between the active TENS group compared with the placebo TENS and control groups at different stages (Table 3). In addition, there was also a very significant positive correlation between the perceived pain measured on the VAS and Likert scales; the Spearman rank correlation coefficient for the VAS and the 5-point Likert scale was 0.841 for entry, 0.890 for contact, 0.861 for biopsy, and 0.823 5 minutes after the procedure (P<.001).
Application of TENS did not result in a significant difference in the duration of the procedure, although there was a slight decrease in the average time required for the procedure while applying active TENS compared with the control and placebo TENS (281±103 compared with 312±150 seconds and 307±132 seconds, respectively; P=.481). Similarly, there were no differences between the groups with respect to the number of biopsies carried out (22, 28, and 23 in control, placebo TENS, and active TENS, respectively, P=.426) or the patients' vital parameters during the different stages of the procedure (P>.05). Symptoms such as dizziness, nausea, vomiting, shoulder pain, vertigo, sweating, or fainting were rare and we observed no differences between groups (P>.05) (Table 4). No patients in either the active or placebo TENS groups reported adverse events such as skin allergy, pain, or burning at the electrode site.
Regarding satisfaction, the one-way analysis of variance test results revealed differences among groups with higher levels of satisfaction in the active TENS group compared with the control and placebo TENS groups (Table 5). With regard to the effectiveness of the blinding of the participants, the nurse, and the gynecologist, correct responses in the placebo group were not significantly different from those of the active TENS group (P>.05), suggesting adequate blinding in all cases.
The aim of this present study was to investigate the pain-relieving effect of TENS during office-based hysteroscopy by applying varying, high-frequency (80–100 Hz), 400-microseconds, individually adjusted, high-intensity TENS parallel to the spinal cord at the T10–L1 and S2–S4 levels. Our results show that there was a significant decrease in the patients' pain scores in the active TENS group compared with the control and placebo TENS groups during all of the stages of the procedure. Moreover, the reduction in pain reached the minimum clinically relevant difference (10 mm on the VAS), previously validated for endometriosis-associated pelvic pain,10 suggesting that the effectiveness of TENS was sufficient to exclude the influence of any placebo effects in our setting.
As far as we know, only two studies have specifically addressed the effect of TENS on pain relief during office-based hysteroscopy12 and office-based endometrial biopsy,13 and they both failed to show its real potential benefits. De Angelis et al12 investigated the effect of TENS on pain in 142 patients and reported that the women in the TENS group experienced a significantly lower level of pain compared with the control group. However, this study lacked a placebo group and the authors did not clearly report how they performed allocation concealment and double-blinding, thus leaving some potential room for data bias. Furthermore, in our opinion, the location of the electrodes on the patients' abdomens, “in the middle of the line joining the iliac spine to the pubic tubercle,” was not optimal.
The rationale of adequately applying TENS depends on accurately selecting the electrode position, current waveform, waveform duration, frequency, and intensity.6,9 Prior reports indicate that the greatest degree of pain reduction occurs when the electrodes are placed within the receptive field for the nerve roots to alter nociceptive transmission in the dorsal horn of the spinal cord.14,15 In our study, we placed the electrodes parallel to the spinal cord at the T10–L1 and S2–S4 levels (instead of placing them over the abdomen) to stimulate the nerve roots at the dermatomal level, corresponding to the whole uterus. Regarding the intensity of TENS, De Angelis et al12 instructed patients to increase the intensity until they felt a “mild tickle” in the area between the electrodes. However, high intensities are required to generate the antihyperalgesic effect produced by TENS.16 In our study, patients were instructed to increase the TENS intensity to the maximum nonpainful level and to report if they perceived any decrease in their stimulus perception (which happens as a result of nerve accommodation). The mean intensity in the active TENS group increased from 29±14 mA at the beginning of the procedure to 35±20 mA at the end, showing that the participants accurately comprehended our instructions. Furthermore, unlike De Angelis et al,12 who programmed the TENS device with a fixed high-frequency (100 Hz), we used high-frequency TENS that randomly varied between 80 and 100 Hz. We based this choice on evidence suggesting that delivering random frequencies provides superior pain relief compared with conventional fixed-frequency TENS.17,18 With regard to the TENS pulse duration, De Angelis et al12 applied a 100-microsecond pulse width, whereas in our study, we selected 400 microseconds because the consensus appears to indicate that increasing the pulse duration to above 250 microseconds produces better analgesic effects.15
More recently, Yilmazer et al13 also evaluated the efficacy of TENS for reducing perceived pain related to office-based endometrial biopsy. In this study, participants' pain scores on the VAS for the TENS and placebo groups when the cervix was grasped or immediately after biopsy were not statistically different. As stated by Yilmazer et al,13 this finding could be the result of the study's possible limitations, which included implementing a convenience sampling method and recruiting only a small number of patients. As in De Angelis' study, these authors did not report how they concealed group allocation or ensured double-blinding nor did they adequately describe how they placed the electrodes, stating that they were “placed at the pelvic region above the uterus.” In addition, Yilmazer et al did not specifically report the pulse width they used or the intensity applied, and so whether setting these to produce only a “mild tickle” sensation in the patient represents underdosing remains an unknown. Moreover, all the participants in this latter study received oral medication 60 minutes before the endometrial biopsy (550 mg naproxen sodium), and so the specific pain relief effects of TENS could not be isolated. Therefore, considering our findings and those previously reported12,13 as a whole, we suggest that the differences between them can largely be explained by the use of different TENS procedure methodologies.
In our study, satisfaction was significantly higher at the end of the procedure in the TENS group because this intervention resulted in a statistically significant and clinically meaningful reduction in pain. On the one hand, satisfaction influences the choice of service provider made by patients for future endoscopic exploration when a new health problem arises,19 whereas on the other hand, patients who perceive a test as more embarrassing, uncomfortable, time-consuming, or worrisome are less likely to attend the examination.20 Therefore, it seems reasonable to assume that the use of TENS may contribute to greater acceptance and more frequent use of office-based hysteroscopy procedures.
With regard to side effects, vasovagal symptoms were rare; of note, there was no vagal nerve activation in any case. The advantages of TENS include it being inexpensive, quick, easy to use, noninvasive, safe, free from any side effects, and it does not require the injection of any drugs that may cause undesirable reactions. In this sense, side effects resulting from the use of local anesthesia are likely to be underestimated21; these might include, for example, possible vasovagal reactions after instillation of an intrauterine anesthetic agent. Furthermore, the time required for the blocking agent to act also prolongs the procedure, and the injection of local anesthetic is itself a painful procedure. Thus, taking all the aforementioned into account, implementing the use of anesthetics in this type of procedure will also likely increase cost and morbidity. In addition, TENS may be an especially valid and safe option for pain relief for office-based hysteroscopy in patients who are more likely to experience greater pain such as women who have previously undergone cesarean delivery, those who are nulliparous, postmenopausal, have a history of dysmenorrhea or chronic pelvic pain, or who experience anxiety.22
However, our results are not without their own limitations. First, the hysteroscope used was rigid. Although rigid hysteroscope is reported to provide superior optical qualities and permit more rapid performance with higher success rates at much lower cost, flexible hysteroscopy allows for equipment with smaller outer diameters and is correlated with minimal discomfort and higher patient satisfaction.23 Therefore, our findings cannot be generalized to all office-based hysteroscopies. Second, despite its potential role as a confounding factor in studies on pain-reduction interventions, we did not evaluate patient anxiety: women undergoing hysteroscopy experience significant levels of anxiety with repercussions for pain perception, success rates, and satisfaction.24 In our study this possibility was minimized by randomly assigning the participants to the different groups. However, TENS has also been reported to be effective in reducing acute anxiety secondary to pain,7 which may have inadvertently affected the outcome in our active TENS group and thus may warrant further investigation.
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© 2017 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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