Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03037073 |
| Other study ID # |
Duloxetine POM |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2/Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
April 15, 2017 |
| Est. completion date |
November 30, 2019 |
Study information
| Verified date |
October 2020 |
| Source |
Assiut University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
For >60 years, succinylcholine is still being administered as a selective relaxant for rapid
sequence intubation by anesthesiologists in many countries. It has been shown to possess
unique features such as low cost, fast-acting, short half-life, safe metabolites, and causing
excellent muscle relaxation for intubation. It has many side effects as well. Postoperative
myalgia (POM), with an incidence rate of ~41%-92%, is one of the most common side effects of
this drug and can take several days to cause significant discomfort in patients. However, its
effect is felt more in the throat, neck, shoulder, and abdominal muscles and is common among
patients with outpatient surgery. Due to its unknown real context of pathogenesis and in an
effort to reduce the incidence and severity of succinylcholine-induced myalgia, various
medications including nondepolarizing muscle relaxants, benzodiazepines, magnesium sulfate,
opioids, gabapentin, and nonsteroidal anti-inflammatory drugs have been tested, with varying
degrees of success.
Duloxetine is an US Food and Drug Administration-approved analgesic used for various pain
syndromes, including diabetic peripheral neuropathy and fibromyalgia. The underlying
mechanism for duloxetine against these pain syndromes remains unclear, but it may involve
three major central nervous system (CNS) targets: (1) serotonin transporter (Ki, 4.6 nM), (2)
norepinephrine transporter (Ki, 16 nM), and (3) dopamine transporter (Ki, 370 nM). In the
past, the antidepressant action was often thought to be the primary mechanism for its
analgesic efficacy. This theory was addressed later by "Path Analysis," and the result showed
that duloxetine affects pain directly rather than indirectly through mood improvement. In
addition to these multiple CNS targets, duloxetine, like the antidepressant amitriptyline and
the local anesthetic bupivacaine, blocks voltage-gated Na+ channels. Because neuronal Na+
channels are present in both CNS and peripheral nervous systems, such a finding expands the
possible analgesic action and locus of duloxetine.
Description:
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.
