Duloxetine for Succinylcholine-induced Postoperative Myalgia

Eligibility and type of the study: This prospective randomized placebo-controlled double-blind study will be conducted after approval from the Institutional Ethics Committee and obtaining written informed consent from patients undergoing elective direct microlaryngoscopic surgeries under general anesthesia.

Sample size: Sample size calculation is based on the pilot study, where the incidence of POM in outpatient cases is found to be more than 70% and intervention that can cause 25% reduction in incidence of POM will be interesting. With a power of 90% and type I error of 5%, 32 patients will be required in each group (α=0.05 and β=90%), but to avoid possible loss of samples (dropouts) during the study, the number of patients in each group will be increased to 35 to be a total of 70 patients.

Patients: Seventy patients will be enrolled in this study. They will be equally divided into two groups. Group D (duloxetine group): 35 patients will receive duloxetine (Cymbalta; Eli Lilly \& Company, Indiana, USA) 30 mg orally with sips of water, 2 h before induction of anesthesia. Group C (control group) 35 patients will receive similar-looking placebo capsules (starch capsules) orally with sips of water, 2 h before induction of anesthesia.

Anesthetic Technique and Data Collection: The patients will not be pre-medicated. The study drugs will be given to patients by another anesthesiologist blinded to the envelops coding. No IM injections will be administered during the perioperative period.

Two days before surgery, patients will visit the outpatient clinic for assessment and explanation about the study protocol. Laboratory investigations will be performed and patients will be informed that they can stop participation in the study at any time without any loss of service.

Inside the operating room, standard monitoring (electrocardiogram, non-invasive blood pressure, heart rate, peripheral oxygen saturation) will be attached and the preliminary values will be recorded. An intravenous cannula 18G will be inserted in the dorsum of the non-dominant hand. Anesthesia will be induced with fentanyl 1 mcg/kg, propofol 1.5-2.0 mg/kg and succinylcholine 1.5 mg/kg.

The intensity of fasciculations will be assessed by an anesthesiologist blinded to the patient's group allotment based on a four-point scale: (0) Absent, (1) Mild: fine fasciculations at the eyes, neck, face or fingers without limb movement, (2) Moderate: fasciculations occurring bilaterally or obvious limb movement and (3) Severe: widespread, sustained fasciculations. After end of fasciculations, the values of heart rate, non-invasive blood pressure and oxygen saturation will be measured and recorded.

Patients will be intubated with an appropriate size cuffed endotracheal tube under direct laryngoscopy after complete muscular relaxation. The endotracheal tube then will be fixed at the appropriate length, by adhesive tape at the angle of the mouth. After 5 minutes of tracheal intubation, the previous values will be recorded again. Subsequent values will be recorded every 5 minutes throughout the surgical procedure. Anesthesia will be maintained with oxygen 100% and sevoflurane (2-3 MAC). Atracurium bromide 0.5 mg/kg will be given after endotracheal intubation. The respiratory tidal volume will be adjusted to keep end-tidal CO2 at 35-40 mmHg. All surgical procedures will be completed by the same surgeon.

At the end of the procedure, sevoflurane will be discontinued; residual neuromuscular blocking agents will be pharmacologically reversed with the standard reversal doses of neostigmine bromide 0.05 mg/kg in atropine sulphate 0.02 mg/kg. The patients then will be ventilated by 100% oxygen till full consciousness regains and the patients start following verbal commands. At that point endotracheal tubes will be removed after gentle suction of secretions through the tube and the oropharyngeal cavity. After the desired spontaneous ventilation, the patients will be shifted to post-anesthesia care unit (PACU).

In PACU, Postoperative care will be standardized for all patients. Pain related to surgical intervention will be treated with paracetamol 1g intravenously (perfalgan; Bristol-Myers Squibb, New York, USA) given every 8h in both group. The total dose of analgesic requirement in the first 24 hours will be recorded. After meeting the discharge criteria, the patients will be discharged to be taken home and cared for, by a responsible adult.

The incidence and severity of myalgia in all patients will be determined 24 hours after surgery by an anesthesiologist who is unaware of the grouping. Myalgia is defined as "a pain with no surgical interference" and is graded based on a four-point scale as follows: (0) no muscle pain, (1) muscle stiffness limited to one area of the body, (2) muscle pain or stiffness noticed spontaneously by a patient who requires analgesics, and (3) incapacitating generalized, severe muscle stiffness or pain.

The postoperative sedation level will be assessed by the Ramsay sedation score which consists of the following six grades: (1) anxious and agitated, (2) cooperative, oriented and tranquil, (3) responding to commands only, (4) brisk response to light glabellar tap or loud auditory stimulus, (5) sluggish response to light glabellar tap or loud auditory stimulus, and (6) no response to light glabellar tap.

Any complications like postoperative nausea, vomiting, dizziness, somnolence, vertigo, confusion will be recorded and managed accordingly. Nausea will be treated by 10 mg metoclopramide intravenously, vomiting will be treated by 4 mg ondansetron intravenously.

Patients' Satisfaction: assessment of patients' satisfaction with the overall preoperative care will be recorded and analyzed.

Statistical analysis:

Data will be performed using a standard SPSS software package version 21 (SPSS Inc., Chicago, Illinois, USA). Data will be expressed as mean ± SD, numbers (n), and median (range). The demographic data will be analyzed by Student t-test. Male and female data will be analyzed with the Chi square test. The consumption of analgesia and sedation in groups will be analyzed by using Student t-test. The incidence and severity of fasciculation and POM will be analyzed using Fisher's exact test. Pearson's r correlation will be used to test the correlation between fasciculations and postoperative myalgia. A p-value of <0.05 will be considered statistically significant.