Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT06354478 |
| Other study ID # |
ms-103-2021 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2021 |
| Est. completion date |
July 1, 2022 |
Study information
| Verified date |
March 2023 |
| Source |
National Cancer Institute, Egypt |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Breast cancer is the most common malignant tumour among females with an incidence of about
2.1 million women every year.Nearly about 40-60% of breast surgery patients develop severe
acute postoperative pain.⁴ Opioids are the current best standard drugs for postoperative pain
relief, however, exposure to large doses of opioids leads to multiple side effects like
prolonged sedation, respiratory depression, nausea, and vomiting.We are comparing two
different drugs and their combination for perioperative analgesia for MRM.
This work is a comparative study that aims to compare the analgesic effects of perioperative
IV infusion of dexmedetomidine, preoperative oral gabapentin, and their combination in
patients undergoing modified radical mastectomy surgery regarding the time of first rescue
analgesia, postoperative morphine consumption, and possible complications.
Description:
Introduction:
Breast cancer is the most common malignant tumour among females with an incidence of about
2.1 million women every year. It is the greatest cancer-related mortality among women
approximately 15% of all cancer mortality. In addition to that, Egypt follows the
international incidence with breast cancer being the most common malignancy among females
with 18,660 patients each year.¹ Modified Radical Mastectomy (MRM) is one of the main
surgical treatments of breast cancer. Accordingly, it is an account for 31% of all breast
surgery cases.² The common modality for anaesthesia for MRM is general anaesthesia with or
without regional blocks.³
Nearly about 40-60% of breast surgery patients develop severe acute postoperative pain.⁴
Opioids are the current best standard drugs for postoperative pain relief, however, exposure
to large doses of opioids leads to multiple side effects like prolonged sedation, respiratory
depression, nausea, and vomiting.⁵ Moreover, the use of opioids inhibits cell-mediated
immunity with an increase in tumour angiogenesis, cell migration, and metastasis in addition
to the progression of the cell cycle. Therefore, plans other than opioids are recommended
without losing proper and effective analgesia, especially in breast cancer patients who are
more sensitive to develop opioid tolerance and addiction.⁶ So it became a necessity to find
safe analgesic techniques for these patients by using different techniques like adjuvant
therapies or multimodal analgesia by combining different drugs with different mechanisms of
action together to increase the quality of postoperative analgesia and to decrease the need
for high doses of systemic opioids and their related side addiction.⁷'⁸
Alpha-2 agonists including clonidine and dexmedetomidine have been used perioperatively.
Dexmedetomidine is different from clonidine in two properties. It has more affinity for the
alpha-2 receptor (8 times that of clonidine) and is easier to titrate.⁹ Also, dexmedetomidine
is a highly selective alpha-2 adrenergic receptor agonist that has sedative, analgesic,
anaesthetic-sparing properties without causing any respiratory depression.¹⁰ Dexmedetomidine
can be a good anaesthetic premedication because of its sympatholytic effect to attenuate the
sympathetic stress response to perioperative stresses like laryngoscopy and intubation.¹¹ The
analgesic effect provided by dexmedetomidine is mediated mainly through interaction at
alpha-2a within the spinal cord, where drug activity attenuates nociceptive signal
transduction. And although dexmedetomidine when given alone has been documented to reduce
pain, it has a synergistic or additive effect when combined with opioids.¹²
Another promising drug for postoperative pain management is gabapentin. It binds to the α-2 δ
subunit of voltage-gated calcium channels and preventing the release of nociceptive
neurotransmitters like glutamate, substance P, and noradrenaline.¹³ Evidence suggests that,
in addition to its effectiveness as an analgesic for patients with neuropathic pain and
chronic pain syndromes, gabapentin also provides effective postoperative analgesia when given
before an operation.¹⁴'¹⁵ Therefore the combination of IV dexmedetomidine and oral gabapentin
due to their analgesic effects would be more effective in reducing postoperative analgesic
consumption and providing prolonged postoperative analgesia after a modified radical
mastectomy.
To the best of researchers' knowledge, comparing the effect of perioperative intravenous
dexmedetomidine infusion, preoperative oral gabapentin and their combination on the total
consumption of intraoperative and postoperative opioids in patients undergoing modified
radical mastectomy was not investigated before.
Aim of the work:
This work is a comparative study that aims to compare the analgesic effects of perioperative
IV infusion of dexmedetomidine, preoperative oral gabapentin, and their combination in
patients undergoing modified radical mastectomy surgery regarding the time of first rescue
analgesia, postoperative morphine consumption, and possible complications.
Objectives:
To assess the analgesic outcomes of perioperative IV infusion of dexmedetomidine,
preoperative oral gabapentin and their combination in controlling acute postoperative pain in
modified radical mastectomy regarding:
- The time of first rescue analgesia during the first 24 hours postoperatively.
- Intraoperative fentanyl consumption.
- Postoperative morphine consumption.
- Postoperative VAS scores.
- Intra & postoperative complications of study drugs.
Hypothesis:
We assume that the combination of preoperative oral gabapentin and intraoperative IV
dexmedetomidine infusion can provide more analgesic effect than either drug alone in the form
of delaying first rescue analgesia time, reducing the total amount of opioid consumption, and
improving postoperative VAS score.
Ethical Considerations:
This study will be conducted after the approval of the research committee of the department
of anaesthesia, surgical ICU, and pain management in Kasr Alainy Hospital, Cairo University,
and the ethical committee of the Faculty Of Medicine, Cairo University. Informed consent will
be taken from all patients included in the study.
Methodology:
Patients will be assessed the day before surgery in a preoperative visit for evaluating their
medical status, laboratory investigations, and for fulfilling all the above inclusion and
exclusion criteria. The patients will be instructed how to report pain using the visual
analogue scale (VAS) score rating, in which 0 = "no pain" and 10 = "worst possible pain. All
groups of the study will be premedicated with I.V 0.02 mg/kg midazolam 30 minutes
preoperatively. Heart rate (HR), mean arterial blood pressure (MBP) will be monitored before
the induction of anaesthesia (baseline values), immediately before surgical incision, and at
15 min intervals intraoperatively. Also, the patients will be randomly assigned into three
equal comparable groups, each of which 30 patients, using computer-generated random numbers.
D group: Patients will receive two oral placebo capsules (starch capsules) 1 hour before
surgery, and then will receive a loading dose of 1µg/kg of dexmedetomidine made to 50 ml
using normal saline and given intravenously just before induction of anaesthesia over 10
minutes while patient vital signs monitored followed by intravenous infusion of
dexmedetomidine diluted in normal saline with a dose of 0.5µg/kg/hour starts with induction
of anaesthesia at a rate of 10 ml/hour through identical syringe pump until skin closure.
G group: Patients will receive two oral gabapentin (300 mg) capsules for a total of 600 mg
gabapentin (Neurontin; Pfizer, Cairo, Egypt) 1 hour before surgery, and then will receive 50
ml of normal saline given intravenously just before induction of anaesthesia over 10 minutes
while patient vital signs monitored followed by intravenous normal saline infusion
intraoperatively starts with induction of anaesthesia at a rate of 10 ml/hour through
identical syringe pump until skin closure.
DG group: Patients will receive two gabapentin (300 mg) capsules for a total of 600 mg
gabapentin 1 hour before surgery, and then will receive a loading dose of 1µg/kg of
dexmedetomidine made to 50 ml using normal saline and given intravenously just before
induction of anaesthesia over 10 minutes while patient vital signs monitored followed by
intravenous infusion of dexmedetomidine diluted in normal saline with a dose of 0.5µg/kg/hour
starts with induction of anaesthesia at a rate of 10 ml/hour through identical syringe pump
until skin closure.
Dexmedetomidine or saline infusion loading started 10 minutes before the induction of
anaesthesia while patient vital signs monitored, and Maintenance started with induction of
anaesthesia and continued until skin closure at the end of surgery.
This study is a double-blind study, so neither the participants nor the experimenters will
know who is receiving a particular treatment. The drugs will be prepared by an
anaesthesiologist who has no further role in the study, the doses of administered IV drugs
will be calculated according to the patient's body weight and they will be supplied as two
syringes labelled respectively as: ( loading ) syringes which will contain 50 ml of normal
saline or a loading dose of dexmedetomidine made to 50 ml using normal saline and both will
be given intravenously over 10 minutes just before induction of anaesthesia while patient
vital signs monitored and ( Maintenance ) syringes that will contain normal saline or a
maintenance dose of dexmedetomidine diluted in normal saline and both will be given
intravenously with the induction of anaesthesia at a rate of 10 ml/hour and continued until
skin closure. All syringes pump will be used in the study will be identical. In addition to
this, both placebo capsules (starch capsules) and gabapentin capsules (Neurontin 300mg) will
be identical-looking capsules yellow in colour and capsule in shape. Also, the surgical team,
the patients, the anaesthesiologists, and the investigators responsible for collecting
intraoperative and postoperative recorded data did not know about the groups' allocation.
3. Anaesthesia Management:
The patients included in the study will be kept fasting for at least six hours before surgery
and will be monitored continuously using electrocardiography, non-invasive blood pressure,
peripheral oxygen saturation, and end-tidal carbon dioxide - using the Datex-Ohmeda S5
anaesthesia monitor, model no: USE1913A - throughout the surgical procedure. The intravenous
(IV) access will be secured using a 20 gauge (G) cannula for IV fluid management and another
IV access for the infusion of the study drugs.
Induction of general anaesthesia in all study groups will be performed using a regimen of IV
2 μcg/kg fentanyl and propofol IV 2 mg /kg. Tracheal intubation will be facilitated using 0.5
mg/kg IV of Atracurium. Anaesthesia will be maintained with inhaled sevoflurane in
oxygen-enriched air (FiO 2=0.5) and top-up doses of atracurium (0.1 mg/kg ) IV will be
administered as required guided by a nerve stimulator. All patients will be mechanically
ventilated aiming to keep end-tidal carbon dioxide within the range of 30-35 mmHg. All
patients will receive 1 g of IV paracetamol. The total intraoperative fentanyl consumption
will be recorded in all study groups. Bispectral index (BIS) will be used for monitoring the
depth of anaesthesia, with target BIS values from 40 to 60, because all the study drugs have
a synergistic effect with inhaled anaesthesia.
Ringer acetate will be infused to replace any fluid deficit, maintenance, and losses.
Hypotension will be defined as MBP less than 60mmHg or less than 70% from baseline. episodes
of hypotension will be treated with ringer acetate boluses and/or 5mg ephedrine in
incremental doses to maintain mean blood pressure above 70 mmHg. Additional bolus doses of
fentanyl 0.5µg/kg will be given if the mean blood pressure or heart rate rises above 20% of
baseline values.
At the end of the surgery, the residual neuromuscular blockade will be reversed using
neostigmine (0.05 mg/kg) and atropine (0.02 mg/kg), and extubation will be performed after
complete recovery of the airway reflexes. The patients will be transferred to the
post-anaesthesia care unit then according to the modified Aldrete discharge scale, the
patients will be shifted to the ward when the patient achieves an Aldrete score of 9/10.¹⁶
MBP, heart rate, and VAS pain score will be noted immediately on arrival in the
post-anaesthesia care unit and at 2, 6, 12, 18, and 24 h postoperatively. All patients will
be given paracetamol postoperatively 1 g IV every 8 hours until discharged. Rescue analgesia
will be provided in the form of IV morphine 3 mg boluses if the pain score was >3 with a
maximum allowed daily dose of 0.5 mg/kg/24 hours. The time of the first rescue analgesia and
the total amount of morphine given in the first 24 hours postoperatively will be recorded in
the three groups.
Side effects such as nausea, vomiting, sedation, hallucination, respiratory depression
(respiratory rate <10/min.), Postoperative nausea and vomiting (PONV) as side effects of
morphine will be recorded upon arrival to PACU and at 2, 6, 12, 18, and 24 h postoperatively
on a four-point verbal scale¹⁷ : (none =no nausea, mild = nausea but no vomiting, moderate =
vomiting one attack, severe = vomiting >one attack). 0.1 mg/kg of IV ondansetron will be
given to patients with moderate or severe postoperative nausea and vomiting.
Sedation will be assessed and scored at the same times of assessment of VAS of pain at 2, 6,
12, 18, and 24 h postoperatively and in the recovery room with Ramsay scores¹⁸ : (1 = anxious
or restless or both; 2 = cooperative, orientated, and tranquil; 3 = responding to commands; 4
= brisk response to a stimulus; 5 = sluggish response to a stimulus, and 6 = no response to
stimulus) excessively high Sedation level with Ramsay 5 or 6, adequate sedation levels
needing observation with Ramsay 2 to 4 and inadequate or insufficient sedation level with
Ramsay 1.
Statistical Methods:
Sample size justification:
The aim of this study is to compare the analgesic effects of perioperative IV infusion of
dexmedetomidine and preoperative oral gabapentin in patients undergoing modified radical
mastectomy surgery. Based on the previous work by (Grover et al., 2009)¹⁹, who reported the
mean duration time of first rescue analgesia was 90±61.1 minutes and (Alzeftawy & Elsheikh
2015)²⁰ who reported 125 ± 25.7 minutes for Dexmedetomidine infusion. Using power 80% and 5%
significance level; 30 patients in every group will be required. The sample size is
calculated using G*Power program²¹ (University of Düsseldorf, Düsseldorf, Germany).
Statistical analysis:
Data will be analyzed using IBM SPSS advanced statistics (Statistical Package for Social
Sciences), version 24 (SPSS Inc., Chicago, IL). Numerical data will be described as mean and
standard deviation or median and range. Data will be explored for normality using
Kolmogrov-Smirnov test and Shapiro-Wilk test. Comparisons between 3 groups for normally
distributed numeric variables will be done using the ANOVA while for non normally distributed
numeric variables will be done by Kruskal Wallis test. A p-value less than or equal to 0.05
will be considered statistically significant. All tests will be two tailed.
Categorical data will be described as numbers and percentages and comparisons will be done by
chi square test or fisher exact as appropriate.
