Methods
Participants were recruited from the Gynecologic Department at the Edith Wolfson Medical Center, Holon, Israel, from December 1st, 2016 until July 31st, 2019. Inclusion criteria included patients with good general health (defined as American Society of Anesthesiologists grade 1–2), who were undergoing a laparoscopic surgery for benign indications. Exclusion criteria included patients who suffered from chronic pelvic pain (non-menstrual pain of 6 or more months, that alters daily function or necessitates medical or surgical treatment), pregnancy, allergy to Bupivacaine hydrochloride, emergency surgeries, execution of additional vaginal procedures, and surgeries performed for the following indications: active pelvic infection, ectopic pregnancy, or malignancy. In order to eliminate possible confounders that might increase the level of postoperative pain independently, post-assignment exclusion was executed in cases of conversion to laparotomy and intraoperative diagnosis of malignancy (confirmed by frozen section pathology).
This study was approved by the Wolfson medical center review board (approval number 0198-16-WOMC, dated 03/11/2016), and written informed consent was obtained from all subjects participating in the trial. The trial was registered prior to patient enrollment at clinicaltrials.gov (NCT02976571, Principal investigator Ohad Gluck, date of trial registration 11/23/2016). This manuscript adheres to the applicable CONSORT guidelines 15.
This is a double-blinded study, with parallel assignments, to one of the four following groups:
Group 1- SC Bupivacaine hydrochloride (AstraZeneca, Sodertalje, Sweden) 0.5% and IP Bupivacaine hydrochloride 0.5%.
Group 2- SC Bupivacaine hydrochloride 0.5% and IP Sodium Chloride 0.9% (NaCl).
Group 3- SC NaCl 0.9% and IP Bupivacaine hydrochloride 0.5%.
Group 4- SC NaCl 0.9% and IP NaCl 0.9%.
After providing written informed consent, patients were randomly assigned to one of the study groups.
The randomization was performed in blocks of 40, using an on-line randomization program (http://www.randomization.com). In order to ensure allocation concealment the random allocation sequence was kept with the lead author (OG), which was not a part of the recruiting, operating, or pain assessment team.
An assigned nurse (IW) prepared syringes prior to each surgery, outside of the operation room, according to the randomization list, and unlabeled syringes were provided to the surgeons upon commencing surgery. The content of each syringe was written in the concealed list only. Patients, surgeons, anesthesiologists, and pain assessment researchers were all blinded to patients’ allocations.
Syringes were prepared according to the following instructions:
The first syringe, for SC injection, contained 9 ml of Bupivacaine hydrochloride 0.5% or NaCl 0.9%, as placebo. Three ml of this solution were injected subcutaneously (exclusively beneath the skin) at each trocar site, prior to skin incision.
The second syringe, for IP instillation, contained 10 ml of Bupivacaine hydrochloride 0.5% or 10 ml of NaCl 0.9%, as placebo, with an additional 40 ml of NaCl 0.9% (50ml total volume). This solution was instilled intra-abdominally prior to abdominal closure by irrigating the diaphragm and the pelvis (15 ml under each diaphragm, and 20 ml in the pelvis). All surgeons administered the solutions at the same locations and in the same manner.
In order to study the short-term and long-term effects of intervention, postoperative pain at rest was evaluated at 3, 8, and 24 hours after surgery. According to our protocol, patient ambulation starts 8 hours following surgery; therefore, postoperative pain with change of position was evaluated at 8 and 24 hours after surgery.
Prior studies have utilized the visual analog scale (VAS) for evaluating similar outcomes 12,16,17. Therefore, we used a 10-cm VAS to scale the level of pain. For assessing pain at rest, prone patients were asked to grade the level of pain in the abdomen and at the tip of the shoulder on a scale of 0 (defined as no pain) to 10 (defined as the worst pain ever experienced). For assessing pain with change of position , patients were asked to grade their pain using the same scale, while shifting from lying in bed to sitting in a chair. A member of the surgical team who was not involved in the index surgical case administered the VAS scale.
We conducted a preoperative fasting of 6 hours for solids and liquids, and formulated a standardized protocol for preoperative management, anesthesia and analgesia.
All patients received general anesthetic induction and maintenance. Patients were premedicated with 2mg intravenous (IV) Midazolam (Rafa, Jerusalem, Israel). General anesthesia was induced with 2mg/kg IV Propofol (Fresenius Kabi, Graz, Austria), 2 mg/kg IV Meperidine (Panpharma, Luitre, France), and 0.6 mg/kg IV Rocuronium Bromide (Unipharm, Melsungen, Germany). General anesthesia was maintained with an infusion of 50–150 mg/kg/minute IV Propofol, combined with inhaled Sevoflurane (LGM pharma, USA) and oxygen. Under general anesthesia with endotracheal intubation, the patient was positioned properly and draped. Antibiotics and thrombophylaxis were given when indicated.
In the recovery ward, pain medication was provided by the attending nurses upon demand, and consisted of either 2-3 mg IV Morphine (As Kalceks, Riga, Latvia), 20-30mg IV Meperidine , 1g IV Dipyrone (Teva, Petah-Tikva, Israel), or 1g IV Paracetamol (B. Braun, Melsungen, Germany), or a combination of both.
Upon transfer to the postoperative ward, a uniform, standardized, postoperative pain-relief regime was applied for all patients, consisting of:
  1. First-line: 1g IV Paracetamol, up to 4 times per day upon demand
  2. Second-line: 1g oral Dipyrone (not available in the USA), up to 4 times per day upon demand
  3. Third-line: 75mg Intramuscular Diclofenac Sodium (Teva, Petah-Tikva, Israel) 75mg, up to 3 times per day upon demand
  4. Fourth-line: 100 mg IV Tramadol Hydrochloride (Dexcel, Or-Yehuda, Israel), up to 3 times per day upon demand, usually along with 10mg IV Metoclopramide (Rafa, Jerusalem, Israel).
All procedures were performed by one of three senior surgeons in our department. Three trocars were placed in all laparoscopies - umbilical (5-mm), another 5-mm trocar, positioned at the left lower abdomen, and an additional 10-mm trocar placed in the supra-pubic area. Both SC and IP solution administration was performed in the same manner by all surgeons, as described above. At the end of each surgery, the fascia was closed using absorbable suture (Vicryl 1, Ethicon), and the skin was closed using skin glue (Dermabond, Johnson and Johnson).
All but 8 patients were discharged on postoperative day 1, according to our departmental protocol. The latter requested later discharge and therefore discharged on postoperative day 2-3. The patients were instructed to use non-opioid, over-the-counter analgesics (oral paracetamol 1000mg, Ibuprofen 200mg, or Dipyrone 1000mg) at home, and refer to unit when these interventions were not helpful- no patient referred for this reason. All patients returned for a routine follow-up visit 2-3 weeks after surgery.