Combined electroacupuncture and auricular acupuncture for postoperative pain after abdominal surgery for gynecological diseases: study protocol for a randomized controlled trial

Results from an earlier study of EA as an adjunct treatment in postoperative pain were used for sample size consideration [10], and the expected mean difference and standard deviations of AUC in 5 days for the treatment group and control group were obtained by simulation using R [21].

The mean difference of AUC between treatment group and sham group in the previous study [10] is 3.4 with standard deviations of 2.9 for the treatment group and 3.6 for the sham group (effect size = 1.04). A lower limit of the 70% confidence interval of the effect size which is 0.75 is applied [22]. A sample size of 30 per group can provide 80% power to reject the null hypothesis with a significance level of 0.05 using a two-sided, two-sample, unequal-variance t test. With an expected dropout rate of 15%, the final sample size is 72 (36 per group). AUC is used to calculate the primary outcome measure because it provides information regarding the pain relief across the whole period, which is more meaningful than comparing the pain score at a particular time point. AUC also has an advantage in that it avoids multiple comparisons and thus will not inflate type I error. This statistical analysis approach has been widely used and reported by previous studies, including those published in leading pain journals [23, 24].

This randomized, sham-controlled, double-blind (subject- and assessor-blind) trial will be conducted in the Department of Obstetrics and Gynecology, at Queen Mary Hospital. Potentially eligible subjects who have scheduled for abdominal surgery for gynecological diseases will be invited to participate. Patients will be referred from a surgeon or gynecologist, and then a research assistant will approach the subjects at the pre-admission clinic or in the general ward pre operation. Patients will be screened and consented for the study. Following the consent, eligible participants will be block randomized into two groups: (I) acupuncture (n = 36) and (II) sham acupuncture (n = 36). All participants will undergo a standard operative procedure and receive postoperative analgesics according to usual practice. Treatment will be given within 2 h prior to the surgery, immediately after arrival on the ward, and daily following surgery for 5 days. Assessments will be conducted upon recovery, hourly at 6 h after surgery, then 4-hourly until day 2 and then 6-hourly until discharge. (See Fig. 1 for the study flowchart, and Fig. 2 for the assessment schedule).

Bowel preparation begins 1 day before the operation. Participants will fast from midnight before the operation. Within 2 h before the operation, participants will receive the first acupuncture treatment, which consists of auricular acupuncture (AA) using filiform needles and electroacupuncture (EA).

The acupuncture procedure will be performed following the Hospital Authority (HA) Guideline on Safety in Acupuncture for Chinese Medicine Practitioners [25]. AA will be performed in the supine position. Following skin preparation with 75% alcohol swabs, sterilized, disposable, filiform needles, each 15 mm long and 0.30 mm in diameter, will be inserted through a needle-guiding tube at the bilateral auricular acupoints Shenmen and a reflex point of the pain site corresponding to the abdominal region (four points in total). The needle-guiding tube will be removed. A piece of adhesive tape will then be immediately applied to the surface of the auricle. The reflex point will be detected with an acupoint detector, which works by detecting the low electrical resistance of the auricular acupoints. The auricular acupoint selection is based on previous studies [26, 27] and the traditional auriculotherapy theory of using corresponding anatomical body areas on the ears [28]. After that, a screening curtain will be placed on a rack above the participant’s chest to prevent the patient from watching the treatment procedure. Acupuncture points (see Table 1): bilateral LI4 (Hegu), ST36 (Zusanli), SP8 (Diji), SP10 (Xuehai), and LR3 (Taichong) will be used in all sessions. In addition, bilateral LR14 (Qimen), ST25 (Tianshu), EX-CA1 (Zigong), and unilateral CV4 (Guanyuan) and CV12 (Zhongwan) will also be used in the first session. All acupoints will be located with reference to the most recent acupuncture textbook of the International Standard Library of Chinese Medicine written by Zhang, Zhao, and Lao [29]. A 75% alcohol swab will be used to sterilize the points and skin around. Sterilized, disposable filiform needle, each 25–30 mm long and 0.30 mm in diameter, will be inserted at each point through a needle-guiding tube with reference to the suggested technique written in the textbook [29]. The needle-guiding tube will be removed after the insertion of needles. The needles will be manipulated to initiate a sensation of “De qi.” An electric stimulator (AWQ-104 L) will then be connected to eight pairs of needles: LI4-ST36, SP8-LR3, bilateral LR14, bilateral ST25, CV4-CV12, and bilateral EX-CA1. A low-frequency, 4-Hz continuous wave will be selected. Treatment will be carried on for 30 min. After the removal of needles, clean cotton wool will be used to prevent bleeding by compressing the points. The selection of acupoints is based on the principle of traditional acupuncture practice with a history of thousands of years [28, 29], previous clinical trials [3‐5, 12, 13, 30, 31], and experts’ opinions (Prof. L Lao). A total number of 18 acupoints will be used in the first treatment and 14 acupoints will be used in the subsequent treatments. The acupoint selection and rationale are summarized in Table 1.

After the operation, the patient will be transferred to the ward after about 1 h. The subject will receive the second acupuncture treatment on the arrival to the ward. Afterwards, the subject will receive an acupuncture treatment every 24 h after the operation in the following 5 days (third to seventh acupuncture sessions). From the second acupuncture session onwards, a combined treatment approach of EA and AA using AA needles will be used.

The treatment procedure of EA, including needling procedure and electric-stimulation parameters, will be the same as the first acupuncture treatment described above, except that only four acupoints will be chosen from the additional acupoints list: GB26, GB34, GB41, HT3, HT7, KI4, KI6, LI11, LR5, LR14, LU7, PC6, SP6, SP14, SP15, SP16, SP21, ST23, ST25, ST27, ST34, CV4, CV12, and EX-CA1 with PC6 as the first choice. After completion of EA, AA will be performed as the first acupuncture treatment mentioned previously, but AA needles will be used. AA needles inserted will be retained and replaced every 3 days until discharge (in case of discharging before day 5) or day 5.

To ensure standardization of the needling technique and how we convey to the subjects about “sham acupuncture,” all acupuncture will be performed by the same registered Chinese medicine practitioner. A backup practitioner will also be trained in case the primary practitioner is unavailable.

The acupuncture treatment procedure, including the acupoints selection principle, sterilization procedure, and treatment schedule (treatment time point, duration, and total number of treatments) will be the same as the treatment group except that non-invasive, retractable. sham needles, an inactivated electric stimulator, a non-invasive, sham-acupuncture procedure and dummy auricular intradermal needles will be used on points 1–2 cun away from the true acupoints where no meridians cross [32, 33]. Non-invasive, retractable, sham needles designed by Streitberger will be used [34] for sham EA. The sham needles are blunt needles that will not penetrate the skin during needle insertion. The handles of these sham needles will slide over the needle when it is compressed, giving the appearance of a needle penetrating the skin. The needles are held by surgical tape to imitate the acupuncture procedure. The needles will be connected to an electric stimulator with zero frequency and amplitude. For the sham AA in the first session, a validated sham-acupuncture procedure [35] will be adopted with small modification. A plastic needle-guiding tube will be taped to the points on the auricle to stimulate some discernible sensation. A needle with a piece of adhesive tape will then be immediately applied to the surface of the auricular acupoint [35]. For the sham AA from the second session onwards, dummy auricular intradermal needles with only circular handles will be used. The dummy auricular intradermal needles will be covered by adhesive tape.

No participant will receive sedative premedication. On arrival in the operating theatre, a 16-gauge intravenous cannula will be inserted under local analgesia. Propofol 2 mg/kg, fentanyl 1.5 μg/kg, and atracurium 0.5 mg/kg will be used for general anesthesia induction. A bolus dose of 0.1 mg/kg morphine sulphate will be given intravenously prior to incision. Pulse, pulse oximetry, and non-invasive blood pressure measurement will be checked every 5 min throughout the operation.

Anesthesia will be maintained with a mixture of sevoflurane, air, and oxygen. The sevoflurane concentration will be titrated to optimal heart rate and blood pressure by the anesthesiologist (Dr. CW Cheung and his team members). At hours 3 and 4, morphine sulphate 0.1 mg/kg may be given in divided dose titrated to the patient’s response.

A thermal blanket and infusion fluid warmer will be used to maintain core body temperature at 35.5 to 37.5 °C. A urinary catheter will be inserted to monitor urine output. An intermittent pneumatic compression device will be applied to the lower limbs for deep vein thrombosis prophylaxis.

At the discretion of the anesthesiologist (Dr. CW Cheung and his team members), hypotension will be treated with intravenously administered ephedrine or phenylephrine. Hypertension or tachycardia will be treated with isoflurane up to 2% end-tidal concentration (approximately 1.5 MAC). If persistent, beta-blockers, such as labetalol, or arterial vasodilators, such as hydralazine, may be given. Sevoflurane will be switched off after the closure of the inner layer of the wounds. All participants will have local analgesia infiltrated to their wounds at the end of operation. Reversal will be achieved by intravenously administered neostigmine 50 μg/kg and atropine 20 μg/kg after the operation. The patient will then be transferred to the recovery room for monitoring then to the ward after about 1 h.

All participants will be prescribed paracetamol 1 g every 6 h for 3 days and Celebrex 200 mg twice daily for 3 days. On arrival in the recovery room, boluses of 2 mg of intravenously administered morphine will be given every 5 min until the patient’s NRS pain score is less than 4. The patient will be offered patient-controlled analgesia (PCA). The PCA pump will be configured to give 1 mg of morphine at a time and the lockout duration will be set to 5 min. No basal infusion will be given and the maximum dose limit will be 0.1 mg/kg/h.

From postoperative day 0, rescue analgesic in the form of intramuscularly administered morphine 0.1 mg/kg will be prescribed every 4 h if necessary. During the administration of PCA morphine, the patient will be seen by an anesthesiologist, who is blinded to treatment allocation (Dr. CW Cheung and his team members), every day to assess the adequacy of analgesia.

PCA morphine will be administered for at least 2 days. On postoperative day 2, if the participant’s NRS pain score during cough is less than 4 on a clinically low morphine consumption, PCA will be stopped; if the NRS pain score is 4 or above, or her PCA consumption is still high, it will be continued. Assessment will be repeated daily. If a patient’s NRS pain score during a cough remains at 4 or above on day 5, she will be evaluated for complications and managed at the discretion of the anesthesiologist (Dr. CW Cheung and his team members).

Subjects will be closely monitored during and after the operation. The primary outcome will be participants’ postoperative pain scores at rest measured by Numerical Rating Scale (NRS) for the first 5 days after operation. The secondary outcomes include postoperative NRS pain scores while coughing; dose and frequency of rescue analgesic use during hospital stay; time to recovery variables; QoR-9, SF-6D, and EQ-5D-5 L. If at any time point after the operation, a participant is unable to be managed according to the protocol for any reason, such as the development of complications, no further data will be collected. Telephone follow-up will be offered for participants discharged before day 5 (Fig. 2).

The NRS for pain is a 0–10-point scale with 0 indicating no pain and 10 indicating worst possible pain. NRS pain scores will be measured at rest upon recovery, hourly at 6 h after surgery, then 4-hourly until day 2, 6-hourly until day 3 and then once daily until discharge. The NRS is a commonly used scale for clinical pain research. NRS is chosen because it is easier for patients to grade their pain intensity with numbers and it has been shown to correlate well with the Visual Analog Scale and Brief Pain Inventory as well as other pain measurements [36‐39].

The NRS for pain while coughing will be measured hourly at 6 h after surgery, then 4-hourly until day 2, then 6-hourly until day 3 and then once daily until discharge.

Postoperative PCA morphine consumption will be recorded in each participant’s medication log during the hospital stay.

The time to first postoperative use, dose, and frequency of rescue analgesic will be monitored and recorded in each subject’s medication log during the hospital stay.

The time to recovery of postoperative bowel function and food intake; time to ambulation and time to discharge will be assessed and recorded by physicians during the hospital stay.

The QoR-9 is a nine-item questionnaire, which has been extensively utilized and validated to assess the patients’ quality of recovery after anesthesia [40].

Quality of life will be assessed by using a Chinese-translated and validated Medical Outcomes SF-6D and EQ-5D-5 L. The SF-6D and EQ-5D-5 L are a preference-based measure of health (PBMH) for economic evaluation. The SF-6D is composed of six multi-level dimensions, namely, physical functioning, role participation, social functioning, bodily pain, mental health, and vitality, whereas the EQ-5D-5 L has five dimensions for health status description: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The SF-6D and EQ-5D-5 L value set [41, 42] for the Chinese population will be used to derive utility scores.

When a participant withdraws before completing the study, the reasons for withdrawal will be recorded.

Adverse events occurring during the study period will be recorded. Vital signs, including heart rate, respiratory rate and blood pressure, will be assessed. The researcher will interview participants using an adverse event record form daily during the hospital stay.

A Data and Safety Monitoring Board (DSMB) will be formed according to the National Institutes of Health (NIH) to monitor the study progress and review safety and quality of data [44]. The committee consists of three members, including a senior acupuncturist, a pain specialist, and a biostatistician. The DSMB is independent of the proposed study and all the committee members will have to declare any conflict of interest in the study. Regular board meetings will be held to ensure that data are collected scientifically and ethically and subjects are not exposed to unnecessary risks [44].

Data will be collected by blinded assessors. All data will be double-entered and checked for consistency prior to analyses. If an immediate entry is not possible, data collected in paper form will be scanned and coded with subjects’ codes. All the data collected will be locked, and the Personal Data (Privacy) Ordinance (CAP 486) in Hong Kong will be complied with.

Statistical analyses will be performed using Statistical Product and Service Solutions (SPSS) 22 (or above) for Windows (SPSS, Chicago, IL, USA) or SAS. The intention-to-treat (ITT) approach will be used. Descriptive analyses will be done on baseline demographics.

The NRS pain scores while coughing will be analyzed in the same way as the pain scores at rest. For other secondary outcomes, cumulative morphine assumption between the two groups will be compared with Student’s t test or the Wilcoxon rank-sum test; time-to-event data will be analyzed by the method of survival analysis. Median time to event will be calculated using the Kaplan-Meier product limit estimator, and log-rank test will be used to determine the statistical significance of the treatment difference in the survival curves for those time-to-event variables. Analyses of secondary outcomes are not part of the power calculations of the study, and should, therefore, be considered exploratory. All tests are two-tailed, and a p value of less than 0.05 is considered statistically significant. The effect size will be estimated by Cohen’s d which is the mean difference between groups per pooled standard deviation. The mean difference and its 95% confidence interval will also be calculated using SPSS.