Clinical trial NCT04495374
Conditions: Pain, Postoperative Analgesia Gabapentin Adverse Reaction Opioid Abuse
Keywords: postoperative pain multimodal analgesia pregabalin preemptive analgesia abdominal hysterectomy gabapentins
Sponsor: Universidade Federal de Alfenas
Start date: 2019-09-02; Completion date: 2020-09-30
Enrollment: 58 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Postoperative pain affects 80% of surgical patients and is one of the main negative symptoms resulting from surgery. It impairs the recovery of patient since it is related to chronic pain, nausea and vomiting and longer hospital stay, generating higher cost to the health system. Thus, the use of new methods to control postoperative pain is recommended and multimodal analgesia, an opioid-sparing strategies, has been widely used by several researchers. Studies show that gabapentins have beneficial effects on postoperative pain control when used as pre-anesthetic medication, also showing a reduction in opioid consumption, with few adverse effects. Among gynecological surgeries, abdominal hysterectomy is one of the procedures that generates the highest degree of acute postoperative pain. Thus, the aim of the present study is to investigate the effect of oral pregabalin (300 mg) two hours before abdominal hysterectomy procedures on postoperative pain. This study is a randomized, double-blind, placebo controlled clinical trial. Patients submitted to abdominal hysterectomy for benign pathologies will be selected and divided into two groups: the placebo controlled group (P0) and the pregabalin 300 mg group (P1). Group P0 will receive a placebo tablet one hour before the procedure, while group P1 will receive a 300 mg tablet of pregabalin identical to the placebo tablet. The reduction of postoperative pain and the best quality of patient recovery will be evaluated using the Visual Analogue Pain Scale (VAS) and the McGill Pain Questionnaire. Also, it will be evaluated the consumption of opioids as a rescue analgesic medication and the presence of adverse effects such as nausea and vomiting.

Detailed description:
The sample population of this study is 102 female patients (50 already included in the study), who have undergone abdominal hysterectomy surgery for benign conditions, with or without joint oophorectomy / salpingectomy. The patients received spinal anesthesia, at hospital "Santa Casa de Alfenas" - Minas Gerais / Brazil ("Casa de Caridade Nossa Senhora do Perpétuo Socorro"). All surgeries were performed by the same team of surgeons.

All patients were evaluated and followed from the preoperative period, up to 24 hours postoperatively, passing through the intraoperative period. During all stages, patients were assisted by a properly trained multi-professional team, consisting of a doctor, nurse and nursing technician.

For the patient to be included in the study, she must have understood and agreed with the informed consent form that was explained in detail to all possible candidates in the preoperative period.

This is a double blind randomized study. The patients were randomly allocated to 02 groups, in which Group 1 received medication A (designated in the study as medication 1), whereas Group 2 received medication B (designated in the study as medication 2).

Study participants and researchers were blinded as to the use of drug / placebo to avoid measurement bias. To carry out the blinding process, an external researcher was assigned to randomize the groups and prepare the pills in opaque and closed envelopes characterized only by a control identification (A or B), which is known only to this researcher. Patients in both groups received identical sealed envelopes, 02h before the start of the anesthetic procedure, only identified as medication A or B, which contained two pills in each envelope. A second researcher is responsible for collecting data and monitoring the patient from the intraoperative period up to 24 hours after discharge from the post-anesthetic recovery room (PARR).

In the operating room, venoclysis was performed with jelco No. 18 or No. 20, and an infusion of 08 ml.kg-1 of crystalloid solution (lactated ringer). The patients were properly monitored with pulse oximetry, cardioscope, and non-invasive blood pressure monitor. After monitoring, patients were premedicated with intravenous (IV) midazolam at a dosage of 0.03 mg.kg1.

To perform spinal anesthesia, the patients were seated on the surgical stretcher by the nursing team. Asepsis and antisepsis were performed at the puncture site with alcoholic chlorhexidine solution. After placement of sterile drapes, local anesthesia was performed with 2.0% lidocaine without vasoconstrictor. The first attempt at subarachnoid puncture was performed, using the median technique, between the intervertebral levels L3-L4 or L4-L5 or L5-S1, with a 25 gauge Quincke needle for subarachnoid anesthesia. If there was a technical difficulty in the puncture, the paramedian puncture technique was chosen. The confirmation of the correct puncture was based on the aspiration of cerebrospinal fluid. Anesthesia was performed with the local anesthetic 0.5% bupivacaine at a dosage of 0.3 mg.kg-1, injected from a 5 ml disposable syringe. After anesthesia, the patients were placed in the supine position, and the correct level of anesthesia was proven with thermal sensitivity tests using cotton soaked with alcoholic solution. After the anesthesia reached the sensory level of the T4 thoracic vertebra, the surgical team was allowed to start the procedure. Prior to the beginning of the surgical incision, a delayed bladder probe was performed in all patients according to the surgeon's indication.

Hemodynamic changes in blood pressure were controlled with the use of vasoactive medications such as ephedrine or metaraminol. For prophylaxis of postoperative nausea and vomiting (PONV) ondansetron was administered at a dosage of 4 mg intravenously (IV) 30 minutes before the end of surgery. Tenoxicam was prescribed for all patients at a dosage of 20 mg IV at regular intervals every 12 hours for the purpose of anti-inflammatory and analgesic action. For analgesic relief, dipyrone IV was also prescribed at a dosage of 50 mg.kg-1 at regular intervals every 6 hours. During the surgery, and also at the end of the surgery, the patients were evaluated for the degree of sedation using the Ramsay sedation scale as a basis.

At the end of the surgery, the patients were referred to the post-anaesthesia care unit, where they were monitored again, and went through the pain assessment process using the visual analog scale (VAS) in relation to pain at rest and "movement" (the patient was asked to perform the forced cough movement), through a direct question with scale demonstration. Pains characterized as mild (0 - 2 VAS) received no medication other than those already prescribed; pain characterized as moderate (3 - 7 EVA) received IV morphine at a dosage of 0.025 mg.kg-1; and severe pain (8 - 10 VAS) received IV morphine at a dose of 0.05 mg.kg-1 every 01 h until analgesic control.

To consider themselves able to be discharged from the post-anaesthesia care unit for clinical follow-up in wards, patients should reach a score ≥ 9 on the modified Aldrete Scale and have VAS pain scores ≤ 2.

In the infirmary, patients were tested at regular intervals for pain intensity, by of a team of nurses trained and qualified to do so. The patients had pain classified as moderate (VAS ≥ 2 \<8) or severe (VAS ≥ 8), receiving drugs with morphine IV in the dose of 1 mg and 2 mg respectively, according to the medical prescription.

24 h after discharge from the post-anaesthesia care unit, in the ward, all the patient was assessed by the same examiner who performed an assessment at the post-anaesthesia care unit, who stratified the patient again from the EVA and assessed using the McGill questionnaire.

During the entire hospitalization period, the use of central nervous system (CNS) depressant drugs (example: ketamine, droperidol, promethazine) and / or analgesic drugs that do not contain any study protocol was avoided. If some patients were medicated with these drugs, they were excluded from the study.

The data related to surgery (pre, trans and postoperative) were collected for statistical analysis, according to Annex II, in which a total duration of surgery in minutes; the total intravenous medication infused; the values of mean arterial pressure and heart rate in the pre, intra and postoperative period; a presence or not, as well as a quantity, of PONV in the post-anaesthesia care unit and after 24h; presence or not of dizziness as a possible side effect; among others.

All data selected through the study will be digitized and analyzed using the Statistic® 7.0 software. The data will be compared using repeated measures ANOVA, followed by Newman-Keuls post-hoc, being considered for p \<0.05.

Arms: arm 1: Patients were randomly allocated to Group P(0) - Placebo by a double blind randomized study. Group P(0) received two placebo tablets as medication, 02h before the start of the anesthesic-surgical procedure in identical sealed envelops, only identified as medication A or B arm 2: Patients were randomly allocated to Group P(1) - Pregabalin 300mg by a double blind randomized study. Group P(1) received two tablets of pregabalin 150mg, 02h before the start of the anesthesic-surgical procedure in identical sealed envelops, only identified as medication A or B
Interventions: intervention 1: Pregabalin 300mg intervention 2: Placebo
Intervention descriptions: intervention 1: Group P1 will receive a 300 mg tablet of pregabalin, 02h before the surgical procedure intervention 2: Group P0 will receive a placebo tablet, 02h before the surgical procedure

Protocol documents:
Prot_SAP_000.pdf: 
 
Use of oral pregabalina as preemptive analgesia in abdominal 
hysterectomy: evaluation of postoperative pain in a 
randomized clinical trial. 
 
 
 
Register Clinical Trials (clinicaltrials.gov): NCT04495374 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
January, 20, 2021 
 


METHODS 
Study design 
This study is revealed to be an experimental, randomized, double-blind, controlled 
placebo controlled clinical trial. The trial included only female patients, who would 
undergo abdominal hysterectomy surgery under spinal anesthesia, where after 
randomization as patients they were allocated into two groups, the placebo controlled 
group (P0) and the pregabalin 300 mg group (P1).  
The entire study had been carried out a research protocol in accordance with the 
recommendations of the Consolidated Standards of Reporting Trials (CONSORT). The 
revised CONSORT statement in 2010, consists of a list of 25 items in a table that 
configure a checklist with guidelines for the development of randomized clinical trials 
with parallel groups, this statement also contains a flowchart to guide the experimental 
design of the study.  
Study location and period  
All procedures, procedures and data collections for this study were carried out at 
Santa Casa de Alfenas - MG (Casa de Caridade Nossa Senhora do Perpétuo Socorro). 
The inclusion of patients in the study and the collection of data from September 2019 to 
September 2020.  
Sample population  
Initially the sample size was out of base from a pilot study carried out with 10 
patients, where establishing a 95% confidence level and a power above 80% using non-
parametric tests (Mann-Whitney test) for primary study outcomes, to decide to make an 
initial allocation of 51 patients in each study group, totaling 102 patients. These 10 
patients in the pilot study were also included in the final version of the study.  
Prepared to an atypical health scenario issued by the pandemic of COVID-19, 
during the year of 2020, in the month of September of that same year to choose to carry 
out new statistical analyzes with a population included so far in the study. From these 
new analyzes, the results obtained were statistic for the primary outcomes and due to 
difficulties imposed by the pandemic caused by the coronavirus, it was decided to 
interrupt the data collection at this time, totaling a total of 55 patients included in the 
study.  


The inclusion criteria are detailed below, where all are mandatory, and also the 
criteria and exclusion used to define the sample population.  
Inclusion criteria: (1) Female patients; (2) Age between 20 and 65 years; (3) 
Patients who will undergo elective abdominal hysterectomy surgery due to benign 
pathologies; (4) Be classified as physical status by the Society of Anesthesiologists (ASA) 
as ASA I (healthy individual) or ASA II (patient with mild and controlled systemic 
disease);  
Exclusion criteria: (1) Allergy or known intolerance to pregabalin or opioids; (2) 
Patients with chronic pain or fibromyalgia; (3) Patients on chronic use of opioids; (4) 
carriers of malignant neoplasms; (5) Pregnant women; (6) People with active 
uncontrolled cardiovascular disease; (7) Patients with kidney and / or liver disease; (8) 
Patients who have spinal deformities that make spinal anesthesia impossible; (9) Presence 
of coagulation disorders or anticoagulant therapy that cannot be suspended for surgery; 
(10) Presence of active sepsis;  
After accepting to participate in the study and signing the informed consent form, 
the sociodemographic data of all patients were collected through a questionnaire, for 
further analysis. 
Groups and interventions  
As this is a randomized clinical trial, this study was made up of two groups. The 
group P0, the group designated as placebo controlled, and the group P1, consisted of 
patients participating in the intervention group.  
Group P0: Received two placebo tablets composed of starch and aerosil (colloidal 
silicon dioxide).  
Group P1: They received two tablets identical to the tablets in group P0, but in 
this case, the tablets were each composed of pregabalin in the 150mg dosage, totaling a 
total dosage of 300mg of pregabalin.  
All tablets were made in the same pharmacy handling, under conditions provided 
for in good manufacturing practices, to avoid bias.  
 
 


Blinding  
In order to avoid measurement bias, after elaboration, the tablets were placed in 
opaque and sealed envelopes, being identified only as formula A or formula B. An 
external researcher, who was not involved in randomization or data collection, was 
responsible by blinding, being the only researcher to know the composition of each 
formula. At the end of the study, this researcher informed the rest of the team of the 
composition of each formula, with Formula A consisting of two tablets of 150 mg of 
pregabalin each, and Formula B consisting of two placebo tablets.  
Since the patients included in the study, the researcher responsible for medication 
randomization and administration, and also the researcher responsible for monitoring and 
collecting data, did not have knowledge about the composition of the interventions 
(formula A and formula B).  
Randomization  
After determining the sample population and preparing interventions in sealed and 
opaque envelopes, the randomization procedure had been carried out. To carry out the 
random allocation process, an external researcher was responsible for administering to 
the patient a sealed, opaque envelope containing the intervention (placebo or pregabalin 
300mg) over a period of 02 hours prior to the start of the anesthetic-surgical procedure, 
with randomization it was simple, carried out by entering the study, where the first patient 
to be admitted to the study received formula A intervention, and the second received 
formula B, and so on. Another researcher was responsible for the patient's perioperative 
follow-up and data collection. 
Experimental draw  
A total of 58 patients were selected for the research. After randomization, 30 
patients were allocated to the P0 group (placebo), but during the follow-up two were 
excluded, one due to the use of subarachnoid morphine and the other due to the use of 
analgesic medications (tramadol) in the immediate postoperative period, which was not 
included in the study protocol. In the P1 group (pregabalin 300mg), 28 patients were 
allocated, in which one patient had to be excluded due to the use of subarachnoid 
morphine during anesthesia. Thus, the analyzes were performed with a total of 28 patients 
in the P0 group and a total of 27 patients in the P1 group. 


Evaluation procedures and measures  
After the patient inclusion process, blinding and random allocation to groups were 
carried out. The patients participating in the P0 group received a sealed envelope 
containing two placebo tablets, while patients belonging to the P1 group received an 
identical envelope containing two tablets of 150mg pregabalin each, all tablets were 
administered within two hours prior to the start of surgery. , in the nursing room where 
the patients were hospitalized. 
 In the operating room, venoclysis was performed with jelco No. 18 or No. 20, and 
an infusion of 08 ml.kg-1 of crystalloid solution (lactated ringer). The patients were 
properly monitored with pulse oximetry, cardioscope, and non-invasive blood pressure 
monitor. After monitoring, patients were premedicated with intravenous (IV) midazolam 
at a dosage of 0.03 mg.kg-1  
To perform spinal anesthesia, the patients were seated on the surgical stretcher by 
the nursing team. Asepsis and antisepsis were performed at the puncture site with 
alcoholic chlorhexidine solution. After placement of sterile drapes, local anesthesia was 
performed with 2.0% lidocaine without vasoconstrictor. The first attempt at subarachnoid 
puncture was performed, using the median technique, between the intervertebral levels 
L3-L4 or L4-L5 or L5-S1, with a 25G Quincke needle for subarachnoid anesthesia. In 
case of technical difficulty in the puncture, the paramedian puncture technique was 
chosen. The confirmation of the correct puncture was based on the aspiration of 
cerebrospinal fluid. Anesthesia was performed with the local anesthetic 0.5% bupivacaine 
at a dosage of 0.3 mg.kg-1, injected from a 5 ml disposable syringe. After anesthesia, the 
patients were placed in the supine position, and the correct level of anesthesia was proven 
with thermal sensitivity tests using cotton soaked with alcoholic solution. After the 
anesthesia reached the sensory level of the T4 thoracic vertebra, the surgical team was 
allowed to start the procedure. Prior to the beginning of the surgical incision, a delayed 
bladder probe was performed in all patients according to the surgeon's indication. All 
surgeries were performed by the same team of surgeons.  
Hemodynamic changes in blood pressure were controlled with the use of 
vasoactive medications such as ephedrine or metaraminol. For prophylaxis of 
postoperative nausea and vomiting (PONV) ondansetron was administered at a dosage of 
4 mg intravenously (IV) 30 minutes before the end of surgery. It was prescribed for all 


tenoxicam patients at a dosage of 20 mg IV at regular intervals every 12 hours for the 
purpose of anti-inflammatory and analgesic action. For analgesic relief, dipyrone IV was 
also prescribed at a dosage of 50 mg.kg-1 at regular intervals every 6 hours. During the 
surgery, and also at the end of the surgery, the patients were evaluated for the degree of 
sedation using the Ramsay sedation scale as a basis.  
At the end of the surgery, the patients were referred to the PACU, where they were 
monitored again, and went through the pain assessment process using the visual analog 
scale (VAS) in relation to pain at rest and “movement” (the patient was asked to perform 
the forced cough movement), through a direct question with scale demonstration. Pain 
characterized as mild (0 - 2 VAS) received no medication, in addition to those already 
prescribed; pain characterized as moderate (3 - 7 EVA) received IV morphine at a dosage 
of 0.025 mg.kg-1; and severe pain (8 - 10 VAS) received IV morphine at a dosage of 0.05 
mg.kg-1 every 01 h until analgesic control. To be considered able to be discharged from 
the PACU for clinical follow-up in wards, patients should reach a score ≥ 9 on the 
modified Aldrete Scale (Table 3) and have VAS pain scores ≤ 2. 
Upon arriving at the infirmary, patients were periodically evaluated at regular 
intervals in relation to the intensity of pain, with the help of a team of properly trained 
and qualified nurses. For patients who presented moderate-intensity pain (VAS ≥ 2 <8) 
or pain classified as severe (VAS ≥ 8), IV morphine was administered at a dose of 1 mg 
and 2 mg, respectively, according to a medical prescription. All analgesic medications 
used were recorded in the patient's medical record. 24 h after discharge from the PACU, 
in the ward, the patient was evaluated by the same examiner who performed the 
evaluation in the PACU, who again performed the stratification of pain by VAS and an 
evaluation with the McGill questionnaire.  
During the entire hospitalization period of the study patients, the use of CNS 
depressant drugs (example: ketamine, droperidol, promethazine) and / or analgesic drugs 
that are not included in the study protocol was avoided. If any of the patients were 
medicated with such drugs, they would be excluded from the study to avoid bias in the 
statistical analysis. The data related to surgery (pre, trans and postoperative) were 
collected for statistical analysis, according to Annex II, in which, for example, the total 
duration of surgery in minutes was described; the total of intravenous fluids infused; the 
values of mean arterial pressure and heart rate in the pre, intra and postoperative period; 


the presence or not, as well as the quantity, of PONV in the PACU and after 24h; presence 
or not of dizziness as a possible side effect, among others. 
Outcomes  
The primary outcome was the assessment of postoperative pain using two 
different scales, the traditional visual analog scale (VAS) and the McGill Pain 
Questionnaire. The secondary outcome was the comparative analysis between the groups 
of opioid consumption in the postoperative period, evaluating both the total dosage of 
opioids used, as well as the time between the end of surgery and the request for the first 
analgesic rescue dose.  
Other outcomes that were analyzed, apart from the variation in patients' 
hemodynamic data during the surgical times (pre, intra and immediate postoperative 
period), the degree of sedation was also evaluated using the Ramsay scale, and the 
presence of side effects such as nausea and vomiting, itching and dizziness. Other 
independent variables were analyzed, such as age, weight, body mass index, education 
level, profession, family income.  
Ethical aspects and records  
This study with the objective of preserving the patients' physical and 
psychological integrity followed the statements enunciated by the Declaration of 
Helsinki. All patients previously admitted to the study were clarified about the 
methodological process, the randomization and blinding process, the guarantee of 
confidentiality, about possible side effects of the interventions and also about the risks 
and benefits of participating in the study and the consent costs for participation in it. After 
clarifying any doubts and consenting to the patients' participation, the free and informed 
consent form (ICF) was signed, to which one of the copies was delivered to the patient 
and another copy was filed with the study researchers.  
According to Resolution No. 466 of December 12, 2012, of the National Health 
Council, which addresses the guidelines and regulatory standards for research involving 
human beings, this study was approved by the Research Ethics Committee (CEP) of 
UNIFAL- MG under opinion number 3,334,050 on June 17, 2019 (ANNEX IV). This 
research was also recorded in the North American database for the registration of clinical 
trials, Clinical Trials (clinicaltrials.gov), under the protocol NCT04495374.  


Statistical analysis  
Descriptive analysis (median, mean and standard deviation) was performed for 
continuous variables that followed a standard distribution, and these were expressed in a 
table.  
When analyzing parametric variables, the t test was used, and in comparisons 
between groups, the t test was used for independent samples, and in the analysis of data 
at different points in time between patients in the same group, we chose to use the test. t 
paired.  
When evaluating non-parametric variables, the Mann-Whitney test was chosen. 
To compare numerical measurements between the times in each group, the Wilcoxon test 
was used for the related samples. To assess qualitative variables, Pearson's chi-square test 
or Fisher's exact test was chosen.  
All data obtained were digitized and analyzed using the Statistic® 7.0 software, 
with a significance level of 5% (p <0.05). For the elaboration of statistical graphs, the 
program used was the GraphPad Prism version 5.00 (Trial) of 2007.