A Randomized Controlled Study to Compare Hemodynamic Effects between Clonidine and Pregabalin in Laparoscopic Cholecystectomy.

BACKGROUND: Laparoscopic cholecystectomy (LC) is associated with pneumoperitoneum and hemodynamic disturbances. Pregabalin and Clonidine have been used for anesthetic effects, but a better drug for controlling hemodynamic parameters is being investigated. AIMS: The study was done to assess and compare the efficacy of preoperative single oral dose of pregabalin and clonidine in maintaining the hemodynamic parameters in the LC. SETTINGS AND
DESIGN: The prospective, interventional, randomized, comparative, single-blinded study was conducted in the department of anesthesia and surgery from January 2015 to September 2016 after taking approval from the institutional ethical committee.
MATERIALS AND METHODS: The study included a total of 90 patients, aged between 18 and 56 years of both sexes scheduled for elective LC. Patients were randomized into three groups of 30 each who received oral pregabalin 150 mg, clonidine 200 ug, and placebo. The hemodynamic parameters were recorded at various time intervals along with any adverse events. STATISTICAL ANALYSIS: Quantitative variables were compared using unpaired t-test (when the data sets were not normally distributed) between the two groups. Qualitative variables were compared using Chi-square test/Fisher's exact test. P < 0.05 was considered statistically significant.
RESULTS: There was a significant increase in the heart rate (HR) and systolic, diastolic, and mean blood pressure during laryngoscopy and pneumoperitoneum in the control group as compared to both pregabalin and clonidine. HR was significantly lower in clonidine group after extubation and in postoperative period than both control group and pregabalin group. There was no major difference in the incidence of side effects.
CONCLUSION: Both pregabalin (150 mg) and clonidine (200 ug) were effective in controlling the hemodynamic parameters during LC, with clonidine providing better hemodynamic stability than Pregabalin. Copyright:

INTRODUCTION

Laparoscopic cholecystectomy (LC) has been pursued in comparison to open surgery and has become the gold standard since its first inception in 1987.[1] The advantages offered include small scar, short surgery, and early discharge from the hospital.[2] Though the cost is slightly higher due to the use of specified instruments and the technique, the insurance coverage makes it a relatively affordable surgery. However, pneumoperitoneum is a common side effect of LC, which is required for a proper visualization of the surgical area and certain operative manipulations.

Pneumoperitoneum affects several homeostatic systems leading to alteration in acid-base balance, cardiovascular, pulmonary physiology and stress response such as increase in mean arterial pressure (MAP), decrease in cardiac output, and increase in systemic vascular resistance which causes decreased tissue perfusion.[34] The relative chances of such hemodynamic disturbances during LC are much higher as compared to other types of laparoscopic surgeries due to the unique steep head-up position which is required to be maintained during LC. In addition to the creation of the pneumoperitoneum, endotracheal intubation as required during LC is also an invasive procedure that may cause intense autonomic response. Tachycardia, hypertension, arrhythmias, and myocardial ischemia are induced by intubation.[3]

The primary aim of the anesthetic management during such surgeries is to stabilize the hemodynamic parameters including heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and MAP along with optimal levels of analgesia.[5]

The increasing demand of LC led to surge in the search for pharmacological agents that may help stabilize the HR and BP in response to pneumoperitoneum and intubation. Many drugs including opioids, local anesthetics, adrenergic blocking drugs, and vasodilators have been used to attenuate the response but attained a variable success rate with few disadvantages such as headaches and prolonged anesthesia leading to delayed discharge.[367]

Pregabalin and clonidine are the two drugs which have been studied widely for postoperative analgesia, but there are very few studies that evaluated their use as oral premedication for attenuation of pressor response.[8910]

Clonidine is a selective α2 agonist, which is opioid sparing and decreases HR and blood pressure. It has been used for attenuating vasopressor responses in previous observational studies.[111213] Pregabalin, on the other hand, is a derivative of the neurotransmitter γ aminobutyric acid (GABA) that possess analgesic, anxiolytic, anticonvulsant, and hemodynamic stabilizing properties.[141516] Both drugs can be given orally and are equally good, but the definitive choice among the two remains a matter of choice by the anesthesiologist rather than on evidence-based results.

The present study was thus conducted to study the efficacy of oral premedication with pregabalin or clonidine on changes in HR and mean arterial blood pressure during laryngoscopy and laparoscopy, along with perioperative hemodynamic stability.

MATERIALS AND METHODS

The prospective, interventional, randomized, comparative, single-blinded study was conducted in the department of anesthesia and surgery from January 2015 to September 2016. Approval was taken from the institutional ethical committee. After taking written informed consent from the patients, a total of 90 American Society of Anaesthesiologists (ASA) Grade I or II normotensive patients aged 18–56 years and scheduled for elective surgery under general anesthesia were recruited for the randomized comparative study.

Block randomization with sealed envelope system was chosen to randomize the study patients. Fifteen randomly generated treatment allocations within sealed opaque envelopes assigning A, B, and C in 5 envelopes each were prepared, where A represented oral pregabalin group, B represented oral clonidine group, and C represented control group. Once a patient gave consent to enter a trial, an envelope was opened, and the patient was offered the allocated group. In this technique, patients were randomized in a series of blocks of fifteen. The patient was not aware as to which treatment he/she is getting, making the study single blinded.

The patients were assigned randomly into either of following groups with each group comprising 30 patients:

Group A patients received preoperative oral pregabalin 150 mg 1 h before surgery

Group B patients received preoperative oral clonidine 200 μg 1 h before surgery

Group C patients did not receive any preoperative drug (control group).

The study of Mrinmoy et al.[3] observed that rise in HR, SBP, DBP, and MAP was 81.26 ± 8.40 bpm, 119.6 ± 10.06 mm Hg, 81.26 ± 8.40 mm Hg, and 93.83 ± 8.107 mm Hg, respectively, in the clonidine group. Taking these values as reference and assuming difference of 10% in change in hemodynamic parameters between clonidine and control/pregabalin, the minimum required sample size with 90% power of study and 5% level of significance is 23 patients in each study group. To reduce margin of error, total sample size taken is 90 (30 patients per group).

Formula used is:

For comparing mean of two groups

where Zα is value of Z at two-sided alpha error of 1% and Zβ is value of Z at power of 90% and mean difference is difference in mean values of two groups.

The following eligibility criteria were followed:

Inclusion criteria

Written informed consent by the patient's relative

ASA risk I and II.

Patients aged 18–56 years of either sex

Patients scheduled for elective surgeries under general anesthesia.

Exclusion criteria

Patient refusing to give consent

Allergy to pregabalin, clonidine

Patients with anticipated difficult intubation

Patient having a preexisting neurological disease/seizure disorder or any increased intracranial pressure (hydrocephalus, head injury)

Patients under treatment by steroids, nonsteroidal anti-inflammatory drugs or opioids before surgery

ASA status III, IV, V

Emergency surgeries

Patients with history of asthma, hypertension, diabetes, severe coronary artery disease, myocardial infarction, renal disease, coagulopathy, or bleeding disorder.

On the previous day of surgery, detailed history of the patients was taken; physical examination and routine investigations (complete blood count, renal function test, liver function test, serum electrolytes, chest X-ray, electrocardiogram) were performed. Before 1 h of surgery, Group A patients were given tablet pregabalin 150 mg orally and Group B patients were given tablet clonidine 200 ug orally with a sip of water. Group C patients received none of these. In the operating room, routine monitoring was done. The interventional medications were procured by indenting from the hospital pharmacy and thus were identical. A standard uniform protocol for premedication drugs, induction agents, muscle relaxants, and maintenance of anesthesia were administered in all the patients and the groups.

Patients were induced with fentanyl 3 ug.kg−1 and propofol 2 mg.kg−1; orotracheal intubation was facilitated by vecuronium 0.08 mg.kg−1. Anesthesia was maintained with 100–200 mg.kg−1.min−1 propofol infusion and 66% nitrous oxide in oxygen. At the end of surgery, residual neuromuscular paralysis was antagonized with neostigmine 0.05 mg.kg−1 and glycopyrrolate 0.01 mg.kg−1. On the recovery of the patients, they were extubated and taken to the postanesthesia care unit (PACU). In the PACU, patients received intravenous fentanyl via patient controlled analgesia with patient activated dose of 20 mg, lockout interval of 5 min, with a maximum allowable fentanyl dose being 2 g.kg−1.h−1.

Intraoperatively, HR, MAP, SBP, and DBP levels were monitored and recorded before and after induction, immediately after intubation and 1, 5, and 15 min after laryngoscopy and endotracheal intubation, after insufflation and after 5, 15, 30, and 45 min of insufflation, after exsufflation, at extubation and postop 10 min. Patients were observed for complications and treated as required.

All patients were observed for possible complications or side effects for a minimum period of 24 h postoperatively. Sedation was assessed using the Ramsay Sedation Scale after pretreatment with the study drugs in both the groups. Scoring was done just before induction of anesthesia.

Statistical analysis

Categorical variables were presented in number and percentage (%) and continuous variables were presented as mean ± standard deviation. Quantitative variables were compared using unpaired t-test (when the data sets were not normally distributed) between the two groups. Qualitative variables were compared using Chi-square test/Fisher's exact test. P < 0.05 was considered statistically significant. The data were entered into Microsoft EXCEL spreadsheet and analysis were done using Statistical Package for the Social Sciences (SPSS) version 21.0 IBM, Chicago (USA).

RESULTS

A total of 90 patients were included in the study. Baseline characteristics are given in Table 1. Mean age was 40.8 ± 11.03 years in Group A, 38.4 ± 11.42 years in Group B, and 39.4 ± 12.40 years in Group C. There was no statistically significant difference of age among the 3 groups. Majority of the patients were in ASA Grade 1 in all the groups. The baseline characteristics were comparable among the three groups.

Table 1

Comparison of baseline characteristics between Groups A, B and C

Baseline characteristics	A (n=30)	B (n=30)	C (n=30)	P	95% CI; df
Age (years)
18-30, n(%)	6 (20)	9 (30)	8 (26.67)	0.906	Chi-square test=1.027 (df=4)
31-40, n(%)	9 (30)	9 (30)	8 (26.67)	A versus B: 0.627	A versus B: Chi-square test=0.933 (df=2)
41-56, n(%)	15 (50)	12 (40)	14 (46.67)	A versus C: 0.827B versus C: 0.873	A versus C: Chi-square test=0.379 (df=2)B versus C: Chi-square test=0.271 (df=2)
Mean±SD	40.87±11.04	38.3±11.17	39.4±12.4	0.689	ANOVA; F=0.373; df=87
Median (IQR)	40.5 (32.75-49.75)	37.5 (28.5-48.75)	40 (27.5-50.75)	A versus B: 0.374	A versus B: −3.172-8.305; df=58
Range	23-55	21-56	18-56	A versus C: 0.630 B versus C: 0.719	A versus C: −4.601-7.535; df=58B versus C: −7.199-4.999; df=58
Gender
Female	21 (70)	23 (76.67)	23 (76.67)	0.792	Chi-square test=0.467 (df=2) A versus B: Chi-square test=0.341 (df=1)A versus C: Chi-square test=0.341 (df=1)B versus C: Chi-square test=0 (df=1)
Male	9 (30)	7 (23.33)	7 (23.33)	A versus B: 0.559 A versus C: 0.559B versus C: 1
ASA status, n(%)
I	27 (90)	25 (83.33)	24 (80)	0.553	Chi-square test=1.184 (df=2)
II	3 (10)	5 (16.67)	6 (20)	A versus B: 0.706A versus C: 0.472 B versus C: 0.739	A versus B: Fisher’s exact testA versus C: Fisher’s exact testB versus C: Chi-square test=0.111 (df=1)
Ramsay sedation score, n(%)
1	0	0	30 (100)	<0.0001	Chi-square test=94.737 (df=4)
2	27 (90)	30 (100)	0	A versus B: 0.237	A versus B: Fisher’s exact test
3	3 (10)	0	0	A versus C: <0.0001xs	A versus C: Chi-square test=60 (df=2)
4	0	0	0	B versus C: <0.0001	B versus C: Fisher’s exact test
5	0	0	0
6	0	0	0

SD=Standard deviation, IQR=Interquartile range, ASA=American Society of Anaesthesiologists, CI=Confidence interval

On the Ramsay sedation scale, in Group A, 27 patients scored 2; in Group B, all patients scored 2, and in Group C, all 30 patients scored 1. In our study, all the patients were awake irrespective of the groups when they were brought to the operating room.

The values of HR at preinduction, after giving premedication, and at the time of induction were comparable between three groups with no significant difference. There was statistically significant difference in HR during laryngoscopy and intubation, and up to 5 min after that between Group A and Group B, and Group B and Group C. There was statistically significant difference in HR during insufflation and during intraoperative period between Group A and Group C, Group B and Group C, and Group A and Group B. There was no statistically significant difference in HR at time of exsufflation, extubation and in postoperative period between Group A and Group C whereas HR was significantly lower in Group B when compared with Group C [Table 2].

Table 2

Comparison of heart rate (bpm) between Groups A, B and C

HR (bpm)	A (n=30)	B (n=30)	C (n=30)	P	95% CI; df
Preoperative
Mean±SD	78.9±10.58	83.43±11.67	80.37±10.53	0.266 A versus B: 0.120A versus C: 0.592 B versus C: 0.289	ANOVA; F=1.341; df=87A versus B: −10.292-1.225; df=58 A versus C: −6.923-3.989; df=58B versus C: −2.678-8.812; df=58
Median (IQR)	77.5 (71.25-83.75)	86.5 (73-93)	78.5 (72.5-87.75)
Range	64-113	61-104	61-113
Premedication
Mean±SD	82.03±11.23	80.73±9.72	81.13±11.07	0.890A versus B: 0.633 A versus C: 0.755 B versus C:0.882	ANOVA; F=0.116; df=87 A versus B: −4.128-6.728; df=58A versus C: −4.862-6.662; df=58 B versus C: −5.783-4.983; df=58
Median (IQR)	79.5 (74-85)	82.5 (71.75-88)	82 (74-86.75)
Range	70-120	61-98	61-120
Induction
Mean±SD	85.27±11.65	83.87±9.58	83.73±9.74	0.817 A versus B: 0.613 A versus C: 0.582B versus C: 0.957	ANOVA; F=0.201; df=87 A versus B: −4.111-6.911; df=58A versus C: −4.017-7.083; df=58B versus C: −4.859-5.126; df=58
Median (IQR)	85 (76.25-91.5)	84 (79-88.75)	83.5 (77.25-90)
Range	71-120	65-102	65-102
Laryngoscopy
Mean±SD	99.77±10.82	93.07±9.64	100.47±9.53	0.008A versus B: 0.014A versus C: 0.791B versus C:0.004	ANOVA; F=4.995; df=87 A versus B: 1.404-11.996; df=58 A versus C: −5.968-4.568; df=58 B versus C: −12.353-−2.447; df=58
Median (IQR)	98 (95.25-103)	92.5 (86.5-100)	99.5 (95.25-106)
Range	84-130	71-112	88-130
1 min
Mean±SD	94.47±8.01	89.3±7.95	95.1±9.54	0.018 A versus B: 0.015A versus C: 0.781 B versus C: 0.013	ANOVA; F=4.172; df=87 A versus B: 1.041-9.292; df=58A versus C: −5.185-3.918; df=58B versus C: −10.338-−1.262; df=58
Median (IQR)	96 (90-98.75)	90 (84-94.75)	95 (90-97.75)
Range	82-113	74-102	81-118
5 min
Mean±SD	88.53±8.29	84.47±7.86	89.9±8.81	0.036 A versus B: 0.056 A versus C: 0.538 B versus C: 0.014	ANOVA; F=3.453; df=87A versus B: -0.11-8.243; df=58A versus C: −5.788-3.055; df=58B versus C: −9.749-−1.118; df=58
Median (IQR)	86.5 (84-91.5)	86 (78.5-90)	90 (84-93)
Range	76-111	70-100	76-111
15 min
Mean±SD	85.03±7.57	81.9±8.15	85.83±8.42	0.141 A versus B: 0.128 A versus C: 0.700B versus C: 0.071	ANOVA; F=1.999; df=87 A versus B: −0.932-7.198; df=58 A versus C: −4.938-3.338; df=58 B versus C: −8.214-0.347; df=58
Median (IQR)	82.5 (80-88.75)	84 (74.5-88)	86 (80-89.75)
Range	75-103	68-94	71-108
Insufflation
Mean±SD	99.83±9.88	92.6±10.33	108.3±10.21	<0.0001A versus B: 0.007A versus C: 0.001B versus C: <0.0001	ANOVA; F=18.012; df=87 A versus B: 2.008-12.458; df=58A versus C: −13.658-−3.276; df=5B versus C: −21.008-−10.392; df=58
Median (IQR)	98 (93.25-104.75)	93 (83.5-100.25)	110.5 (100-116.25)
Range	84-122	74-111	89-125
5 min
Mean±SD	96.43±10.81	89.27±10.02	105.07±10.53	<0.0001 A versus B: 0.01A versus C: 0.002B versus C: <0.0001	ANOVA; F=17.168; df=87 A versus B: 1.78-12.553; df=58A versus C: −14.149-−3.118; df=58B versus C: −21.112-−10.488; df=58
Median (IQR)	94.5 (88-102.25)	90 (84-97.25)	105 (97-110)
Range	82-117	70-107	87-127
15 min
Mean±SD	93.6±10.32	85.6±9.05	103.53±8.68	0.141 A versus B: 0.128A versus C: 0.7B versus C: 0.071	ANOVA; F=1.999; df=87 A versus B: −0.932-7.198; df=58A versus C: −4.938-3.338; df=58B versus C: −8.214-0.347; df=58
Median (IQR)	92 (87-98)	86 (80.25-91.5)	103 (97.25-110)
Range	80-116	69-105	88-119
30 min
Mean±SD	90.5±9.91	83.87±9.05	102.1±8.61	<0.0001A versus B: 0.008A versus C: <0.0001 B versus C: <0.0001	ANOVA; F=30.139; df=87 A versus B: 1.728-11.539; df=58A versus C: −16.399-−6.801; df=58B versus C: −22.799-−13.668; df=58
Median (IQR)	89.5 (83.25-94.5)	84 (78.5-88)	101.5 (96.25-109)
Range	78-115	69-104	89-120
45 min
Mean±SD	89.23±9.62	82.4±8.29	98.97±7.78	<0.0001 A versus B: 0.004A versus C: 0.0001B versus C: <0.0001	ANOVA; F=28.129; df=87 A versus B: 2.193-11.473; df=58A versus C: −14.256-−5.211; df=58B versus C: −20.721-−12.412; df=58
Median (IQR)	88 (84-95)	82 (78.25-86.75)	98.5 (92.25-103)
Range	75-108	66-98	86-117
Exsufflation
Mean±SD	83.53±9.03	79.93±7.68	87.27±6.14	0.001 A versus B: 0.101A versus C: 0.066B versus C: 0.0001	ANOVA; F=6.789; df=87 A versus B: −0.733-7.933; df=58A versus C: −7.724-0.257; df=58B versus C: −10.927-−3.74; df=58
Median (IQR)	81.5 (78-87)	80 (72.75-84)	87 (83.25-89.75)
Range	70-109	68-94	76-100
Extubation
Mean±SD	82.87±8.32	77.3±7.32	82.83±6.13	0.004 A versus B: 0.007A versus C: 0.986B versus C: 0.002	ANOVA; F=5.761; df=87 A versus B: 1.516-9.617; df=58A versus C: −3.744-3.81; df=58B versus C: −9.023-−2.043; df=58
Median (IQR)	81 (78-85.75)	77 (70-83)	83.5 (78.25-86.75)
Range	72-107	66-90	70-98
Postoperative 10 min
Mean±SD	79.53±8.41	75.4±7.55	79.6±7.25	0.060 A versus B: 0.049A versus C: 0.973B versus C: 0.031	ANOVA; F=2.892; df=87 A versus B: 0.005-8.262; df=58A versus C: −4.123-3.99; df=58B versus C: −8.024--0.376; df=58
Median (IQR)	78 (74.25-80.75)	74 (70-81)	78.5 (75.25-84.25)
Range	66-104	63-90	68-97

HR=Heart rate, SD=Standard deviation, IQR=Interquartile range, CI=Confidence interval

The values of SBP at preinduction, after giving premedication and at the time of induction were comparable between three groups with no significant difference. There was statistically significant difference in SBP during laryngoscopy and intubation between Group A and Group B and Group B and Group C. There was statistically significant difference in SBP during insufflation and during intraoperative period between Group A and Group C, Group B and Group C and Group A and Group B. There was no statistically significant difference in SBP at time of exsufflation, extubation between Group A and Group C whereas SBP was significantly lower in Group B when compared with Group A and Group C at the time of exsufflation [Table 3].

Table 3

Comparison of systolic blood pressure (mmHg) between Groups A, B and C

SBP (mmHg)	A (n=30)	B (n=30)	C (n=30)	P	95% CI; df
Preoperative
Mean±SD	123.97±11.77	129.3±15.32	124.67±11.16	0.224 A versus B: 0.136A versus C: 0.814 B versus C: 0.185	ANOVA; F=1.518; df=87 A versus B: −12.395-1.728; df=58A versus C: −6.628-5.228; df=58 B versus C: −2.295-11.562; df=58
Median (IQR)	124 (114-132)	129 (121.5-136)	125 (116.75-133)
Range	102-145	93-176	98-143
Premedication
Mean±SD	123.6±13.82	128.67±14.42	123.77±13.65	0.284 A versus B: 0.17A versus C: 0.962 B versus C: 0.181	ANOVA; F=1.274; df=87 A versus B: −12.366-2.232; df=58A versus C: −7.264-6.93; df=58B versus C: −2.357-12.157; df=58
Median (IQR)	126.5 (111-131.5)	129.5 (120-136.75)	122.5 (111.75-133.75)
Range	100-155	97-167	100-155
Induction
Mean±SD	123.37±13.24	121.37±12.92	120.57±10.91	0.667 A versus B: 0.556 A versus C: 0.375 B versus C: 0.796	ANOVA; F=0.406; df=87 A versus B: −4.763-8.763; df=58A versus C: −3.472-9.072; df=58B versus C: −5.381-6.981; df=58
Median (IQR)	123 (112-131.25)	121.5 (111-128.75)	122.5 (112-126)
Range	103-160	88-150	102-145
Laryngoscopy
Mean±SD	142.77±12.44	133.27±15.03	142.3±15.03	0.017A versus B: 0.009A versus C: 0.896B versus C: 0.023	ANOVA; F=4.255; df=87A versus B: 2.369-16.631; df=58A versus C: −6.664-7.598; df=58 B versus C: −16.801-−1.266; df=58
Median (IQR)	141 (136.5-148)	134.5 (123.5-143)	140 (131.5-150.75)
Range	122-180	85-161	111-180
1 min
Mean±SD	138.43±12.89	132.97±14.38	138.23±14.27	0.228A versus B: 0.126A versus C: 0.954B versus C:0.159	ANOVA; F=1.5; df=87 A versus B: −1.59-12.523; df=58 A versus C: −6.829-7.229; df=58 B versus C: −12.67-2.137; df=58
Median (IQR)	136 (130.5-146)	134.5 (126-142)	136 (130-145.25)
Range	113-176	102-164	102-176
5 min
Mean±SD	130.37±11.27	126.63±16.4	128.73±13.31	0.578 A versus B: 0.309A versus C: 0.609B versus C: 0.588	ANOVA; F=0.55; df=87 A versus B: −3.559-11.026; df=58 A versus C: −4.739-8.006; df=58 B versus C: −9.818-5.618; df=58
Median (IQR)	130 (123.25-137.25)	129 (115.25-139.5)	130.5 (122.5-137.5)
Range	105-162	82-155	82-150
15 min
Mean±SD	125.03±9.62	122.97±14.97	125±11.05	0.751 A versus B: 0.527A versus C: 0.990B versus C: 0.551	ANOVA; F=0.287; df=87 A versus B: −4.462-8.595; df=58A versus C: −5.322-5.389; df=58B versus C: −8.834-4.768; df=58
Median (IQR)	127 (119.75-132)	127 (112.5-132)	127 (115.25-133.5)
Range	104-138	78-144	99-143
Insufflation
Mean±SD	143.7±9.98	121.07±12.51	161.73±15.03	<0.0001	ANOVA; F=77.562; df=87
				A versus B: <0.0001 A versus C: <0.0001B versus C: <0.0001	A versus B: 16.786-28.481; df=58A versus C: −24.647-−11.42; df=58B versus C: −47.811-−33.522; df=58
Median (IQR)	142.5 (136.25-148.5)	122.5 (112.75-130)	164 (147.5-170)
Range	129-178	97-142	138-202
5 min
Mean±SD	143.4±8.7	118.67±13.86	161.57±15.76	<0.0001 A versus B: <0.0001A versus C: <0.0001 B versus C: <0.0001	ANOVA; F=80.838; df=87 A versus B: 18.729-30.738; df=58 A versus C: −24.787-−11.546; df=58B versus C: −50.57-−35.23; df=58
Median (IQR)	139.5 (137-150)	120 (112.5-129.5)	165 (148-174.75)
Range	132-167	81-140	122-185
15 min
Mean±SD	141.13±9.59	115.93±14.11	156.7±14.23	0.751 A versus B: 0.527A versus C: 0.99B versus C: 0.551	ANOVA; F=0.287; df=87A versus B: −4.462-8.595; df=58 A versus C: −5.322-5.389; df=58B versus C: −8.834-4.768; df=58
Median (IQR)	141 (134-145.75)	118 (105.25-125.5)	156.5 (145.5-166.75)
Range	127-164	81-138	129-180
30 min
Mean±SD	138.33±9.46	116.3±13.1	150±13.3	<0.0001A versus B: <0.0001A versus C: 0.0002B versus C: <0.0001	ANOVA; F=60.166; df=87A versus B: 16.127-27.94; df=58A versus C: −17.632-−5.701; df=58 B versus C: −40.523-−26.877; df=58
Median (IQR)	138.5 (132.25-142)	115 (108.5-124)	151 (142-158)
Range	120-170	88-144	111-172
45 min
Mean±SD	133.3±10.19	114.27±14.93	145.33±11.32	<0.0001 A versus B: <0.0001 A versus C: 0.0001 B versus C: <0.0001	ANOVA; F=48.564; df=87 A versus B: 12.41-25.657; df=58A versus C: −17.598-−6.469; df=58B versus C: −37.913-−24.22; df=58
Median (IQR)	134 (127.25-138)	112.5 (106.5-127.25)	145 (139-155)
Range	113-165	80-139	118-166
Exsufflation
Mean±SD	125.3±11.13	113.13±15.02	128.1±14.1	0.0001 A versus B: 0.0008 A versus C: 0.396B versus C: 0.0002	ANOVA; F=10.39; df=87 A versus B: 5.321-19.012; df=58 A versus C: −9.366-3.766; df=58 B versus C: −22.496-−7.437; df=58
Median (IQR)	126 (118.5-132)	110.5 (101.25-125.25)	127 (118-139.75)
Range	108-162	89-138	98-154
Extubation
Mean±SD	118.53±11.04	112.97±15.15	119.5±11.42	0.104 A versus B:0.109A versus C: 0.740B versus C: 0.064	ANOVA; F=2.322; df=87 A versus B: −1.285-12.419; df=58A versus C: −6.771-4.838; df=58 B versus C: −13.467-0.4; df=58
Median (IQR)	121.5 (112.25-123.75)	111 (102.5-123)	121.5 (112.25-129.5)
Range	98-148	84-142	98-136
Postoperative 10 min
Mean±SD	115.43±11.67	112.87±14.55	115.07±8.23	0.66 A versus B: 0.453A versus C: 0.888B versus C: 0.474	ANOVA; F=0.417; df=87A versus B: −4.248--9.381; df=58A versus C: −4.852-5.585; df=58B versus C: −8.343-3.943; df=58
Median (IQR)	116 (105-123.5)	113 (103.25-122.75)	114.5 (110-122)
Range	94-139	81-144	96-127

SBP=Systolic blood pressure, SD=Standard deviation, IQR=Interquartile range, CI=Confidence interval

The values of DBP at preinduction, after giving premedication and at the time of induction were comparable between three groups with no significant difference. There was statistically significant difference in DBP during laryngoscopy and intubation between Group A and Group B and Group B and Group C. There was statistically significant difference in DBP during insufflation and during intraoperative period between Group A and Group C, Group B and Group C and Group A and Group B. There was no statistically significant difference in DBP at time of exsufflation, extubation between Group A and Group C whereas DBP was significantly lower in Group B when compared with Group A and Group C at the time of exsufflation and extubation [Table 4].

Table 4

Comparison of diastolic blood pressure (mmHg) between Groups A, B and C

DBP (mmHg)	A (n=30)	B (n=30)	C (n=30)	P	95% CI
Preoperative
Mean±SD	77.57±8.19	78.87±8.77	76.03±7.71	0.414A versus B: 0.555A versus C: 0.458B versus C: 0.189	ANOVA; F=0.89; df=87A versus B: −5.684-3.084; df=58A versus C: −2.577-5.644; df=58 B versus C: −1.434-7.101; df=58
Median (IQR)	78 (72-81)	77.5 (72.5-85.5)	74.5 (71.25-80)
Range	60-96	62-96	64-97
Premedication
Mean±SD	76.33±9.46	78.63±8.74	74.83±8.57	0.257A versus B: 0.332A versus C: 0.522B versus C: 0.094	ANOVA; F=1.377; df=87 A versus B: −7.008-2.408; df=58 A versus C: −3.167-6.167; df=58 B versus C: −0.676-8.276; df=58
Median (IQR)	76.5 (70-82)	76 (72.25-86.25)	74 (69.25-78)
Range	60-102	64-97	64-104
Induction
Mean±SD	79.1±9.93	75.2±10.08	76.57±9.62	0.304 A versus B: 0.136A versus C: 0.319B versus C: 0.593	ANOVA; F=1.205; df=87A versus B: −1.27-9.07; df=58A versus C: −2.517-7.584; df=58 B versus C: −6.458-3.725; df=58
Median (IQR)	77.5 (72.5-83.75)	73.5 (70-81.5)	74.5 (71.25-81)
Range	59-104	58-99	65-102
Laryngoscopy
Mean±SD	92.37±8.87	85.63±11.72	92.9±10.95	0.015 A versus B: 0.014A versus C: 0.836B versus C: 0.016	ANOVA; F=4.396; df=87A versus B: 1.361-12.105; df=58 A versus C: −5.682-4.615; df=58B versus C: −13.128-−1.405; df=58
Median (IQR)	90 (88-95)	86 (80-91.5)	90 (88-99.75)
Range	80-114	49-116	66-114
1 min
Mean±SD	86.47±10.23	82.5±10.83	87.97±10.03	0.114 A versus B: 0.150A versus C: 0.568 B versus C: 0.047	ANOVA;F=2.226; df=87A versus B: −1.478-9.411; df=58A versus C: −6.735-3.735; df=58B versus C: −10.862-−0.071; df=58
Median (IQR)	85 (80.25-91.75)	85 (78.5-89)	88 (84-93.75)
Range	66-110	56-100	56-110
5 min
Mean±SD	79.77±9.92	76.87±11.82	79.47±12.34	0.558A versus B: 0.307 A versus C: 0.917 B versus C: 0.408	ANOVA; F=0.586; df=87 A versus B: −2.738-8.538; df=58A versus C: −5.486-6.086; df=58B versus C: −8.844-3.644; df=58
Median (IQR)	79 (73.25-84)	79 (70-85.5)	81 (76-87)
Range	62-106	42-90	42-106
15 min
Mean±SD	78.63±8.58	74.47±11.19	76.8±10.44	0.284 A versus B: 0.111 A versus C: 0.460B versus C: 0.407	ANOVA; F=1.275; df=87 A versus B: −0.988-9.321; df=58 A versus C: −3.105-6.772; df=58 B versus C: −7.927-3.261; df=58
Median (IQR)	79.5 (74.5-83)	76 (69.5-80.75)	77.5 (73.25-82.5)
Range	55-100	41-92	41-100
Insufflation
Mean±SD	96.2±7.05	73.7±10.61	101.43±8.52	<0.0001A versus B: <0.0001A versus C: 0.012 B versus C: <0.0001	ANOVA; F=83.187; df=87A versus B: 17.845-27.155; df=58A versus C: −9.277-−1.19; df=58B versus C: −32.706-−22.76; df=58
Median (IQR)	97.5 (88.75-99.75)	76 (69.25-80)	99 (98-107.75)
Range	83-111	43-90	79-120
5 min
Mean±SD	95.53±6.04	71.2±10.97	101.3±8.09	<0.0001A versus B: <0.0001A versus C: 0.002B versus C: <0.0001	ANOVA; F=103.39; df=87A versus B: 19.73-28.937; df=58A versus C: −9.456-−2.077; df=58 B versus C: −35.079-−25.121; df=58
Median (IQR)	96 (92.25-98.75)	73 (64.5-77.5)	102 (94.5-107.75)
Range	83-111	44-92	81-116
15 min
Mean±SD	92.4±6.09	69.13±11.49	99.57±7.74	0.284A versus B: 0.111A versus C: 0.46B versus C: 0.407	ANOVA; F=1.275; df=87 A versus B: −0.988-9.321; df=58 A versus C: −3.105-6.772; df=58 B versus C: −7.927-3.261; df=58
Median (IQR)	93 (89-95.75)	70 (64.25-75.5)	98 (95.25-106.75)
Range	82-107	44-90	77-114
30 min
Mean±SD	89.53±4.9	69.7±10	96.87±7.07	<0.0001A versus B: <0.0001A versus C: <0.0001B versus C: <0.0001	ANOVA; F=102.104; df=87A versus B: 15.73-23.937; df=58A versus C: −10.479-−4.187; df=58B versus C: −31.644-−22.69; df=58
Median (IQR)	90 (87-91)	70 (62.5-75.75)	97.5 (93-101.75)
Range	80-102	47-89	75-108
45 min
Mean±SD	85.33±5.33	68.67±11.87	93.93±6.14	<0.0001A versus B: <0.0001 A versus C: <0.0001B versus C: <0.0001	ANOVA; F=71.747; df=87A versus B: 11.865-21.468; df=58 A versus C: −11.569-−5.631; df=58B versus C: −30.186-−20.347; df=58
Median (IQR)	85 (83-87)	72 (60.5-76)	94.5 (90-97.75)
Range	75-101	42-88	76-104
Exsufflation
Mean±SD	79.63±6.33	70.13±10.44	83.3±10.9	<0.0001A versus B: 0.0001A versus C: 0.116 B versus C: <0.0001	ANOVA; F=15.509; df=87A versus B: 5.016-13.984; df=58A versus C: −8.273-0.94; df=58B versus C: −18.683-−7.65; df=58
Median (IQR)	80.5 (75.25-83)	71 (62-76.75)	83 (77-89.5)
Range	66-92	48-92	48-102
Extubation
Mean±SD	75.17±7.51	70.17±10.4	76.83±9.44	0.017A versus B: 0.037A versus C: 0.452B versus C: 0.011	ANOVA; F=4.271; df=87A versus B: 0.312-9.688; df=58A versus C: −6.075-2.742; df=58 B versus C: −11.799-−1.534; df=58
Median (IQR)	76.5 (70-80)	70 (64-78)	77.5 (70.5-82)
Range	60-90	50-90	50-95
Postoperative 10 min
Mean±SD	71.33±9.64	69.5±9.88	71.93±7.05	0.55A versus B: 0.47 A versus C: 0.784B versus C: 0.276	ANOVA; F=0.602; df=87 A versus B: −3.213-6.879; df=58A versus C: −4.965-3.765; df=58B versus C: −6.869-2.002; df=58
Median (IQR)	70.5 (65.25-77.75)	70 (62-78)	72.5 (68-76)
Range	54-92	50-88	55-85

SD=Standard deviation, IQR=Interquartile range, CI=Confidence interval, DBP=Diastolic blood pressure

The values of mean blood pressure at preinduction, after giving premedication and at the time of induction were comparable between three groups with no significant difference. There was statistically significant difference in MBP during laryngoscopy and intubation between Group A and Group B and Group B and Group C. There was statistically significant difference in MBP during insufflation and during intraoperative period between Group A and Group C, Group B and Group C and Group A and Group B. There was no statistically significant difference in MBP at time of exsufflation, extubation and in postoperative period between Group A and Group C whereas MBP was significantly lower in Group B when compared with Group A and Group C at the time of exsufflation and extubation [Table 5].

Table 5

Comparison of mean arterial pressure (mmHg) between Groups A, B and C

MAP (mmHg)	A (n=30)	B (n=30)	C (n=30)	P	95% CI; df
Preoperative
Mean±SD	93.03±8.7	95.68±10.16	92.24±7.97	0.306 A versus B: 0.283A versus C: 0.715B versus C: 0.150	ANOVA; F=1.2; df=87 A versus B: −7.534-2.245; df=58A versus C: −3.524-5.102; df=58B versus C: −1.287-8.154; df=58
Median (IQR)	92 (87.333-97.917)	93.67 (89.917-101.833)	91.5 (86.333-97.083)
Range	76.67-111.33	72.33-116.67	76-111.33
Premedication
Mean±SD	92.09±10.13	95.31±10.15	91.14±9.5	0.239 A versus B: 0.223 A versus C: 0.710B versus C: 0.105	ANOVA; F=1.453; df=87A versus B: −8.461-2.016; df=586A versus C: −4.129-6.017; df=58B versus C: −0.912-9.245; df=58
Median (IQR)	93 (84-97.167)	95.33 (87.417-100.833)	90.83 (83.75-95.833)
Range	76.67-119	75-120.33	76.67-121
Induction
Mean±SD	93.86±9.74	90.59±10.59	91.23±9.34	0.403A versus B: 0.218A versus C: 0.291B versus C: 0.803	ANOVA; F=0.916; df=87A versus B: −1.99-8.524; df=58A versus C: −2.308-7.553; df=58B versus C: −5.804-4.515; df=58
Median (IQR)	93.33 (86.417-98.667)	89.33 (84.833-97.167)	90.67 (83.5-95.75)
Range	76-120	68-114	80.33-116
Laryngoscopy
Mean±SD	109.17±9.37	101.51±12.17	109.37±11.37	0.009A versus B: 0.008A versus C: 0.941B versus C: 0.012	ANOVA; F=4.944; df=87 A versus B: 2.043-13.268; df=58A versus C: −5.584-5.184; df=58 B versus C: −13.942-−−1.769; df=58
Median (IQR)	106.67 (104.083-112.5)	103.67 (94-107.667)	106.67 (104.167-115.167)
Range	94.67-131.33	61-131	81-133.33
1 min
Mean±SD	103.79±9.95	99.32±11.45	104.72±10.64	0.118	ANOVA; F=2.183; df=87
				A versus B: 0.112A versus C: 0.726B versus C:0.063	A versus B: −1.078-10.012; df=58A versus C: −6.257-4.391; df=58 B versus C: −11.113-0.313; df=58
Median (IQR)	102.33 (97.167-108.667)	102.67 (93.833-106.333)	104.33 (100.333-108.583)
Range	88.33-132	71.33-121.33	71.33-132
5 min
Mean±SD	96.63±9.33	93.46±12.77	95.89±11.86	0.531A versus B: 0.275 A versus C: 0.787B versus C: 0.447	ANOVA; F=0.636; df=87 A versus B: −2.601-8.957; df=58A versus C: −4.769-6.258; df=58B versus C: −8.802-3.935; df=58
Median (IQR)	96 (88.833-102.167)	95.67 (89.5-101.917)	97.33 (92.083-101.167)
Range	82.67-117.33	55.33-111	55.33-117.33
15 min
Mean±SD	94.1±7.95	90.63±12.09	92.87±9.89	0.408A versus B: 0.194 A versus C: 0.596B versus C: 0.436	ANOVA; F=0.905; df=87A versus B: −1.82-8.753; df=58A versus C: −3.403-5.869; df=58 B versus C: −7.94-3.473; df=58
Median (IQR)	95 (90.417-98.083)	91.67 (87.583-97.167)	93.33 (89-98.083)
Range	75-112	53.33-109.33	60.33-112
Insufflation
Mean±SD	112.03±6.73	89.49±10.73	121.53±10.11	<0.0001 A versus B: <0.0001A versus C: 0.0001B versus C: <0.0001	ANOVA; F=92.83; df=87 A versus B: 17.916-27.173; df=58
Median (IQR)	111.5 (107.333-115.5)	90.33 (84.917-95.917)	120.5 (114.667-129.333)
Range	100.33-132	61-107.33	98.67-147.33
					A versus C: −13.953-−5.047; df=58B versus C: −37.432-−26.657; df=58
5 min
Mean±SD	111.49±6.17	87.02±11.47	121.39±9.49	<0.0001 A versus B: <0.0001A versus C: <0.0001 B versus C: <0.0001	ANOVA; F=108.42; df=87 A versus B: 19.675-29.258; df=58A versus C: −14.053-−5.747; df=58B versus C: −39.808-−−28.925; df=58
Median (IQR)	110.67 (107.583-114.667)	87.5 (81.917-93.667)	123.83 (114.5-128.333)
Range	101.33-129.67	56.33-108	94.67-135.67
15 min
Mean±SD	108.64±6.19	84.73±11.86	118.61±8.78	0.408 A versus B: 0.194A versus C: 0.596B versus C: 0.436	ANOVA; F=0.905; df=87 A versus B: −1.82-8.753; df=58A versus C: −3.403-5.869; df=58B versus C: −7.94-3.473; df=58
Median (IQR)	108.67 (104.75-111.917)	85 (78.417-90.667)	119.33 (113.583-124)
Range	97-126	56.33-106	94.33-136
30 min
Mean±SD	105.8±5.87	85.23±10.74	114.58±8.17	<0.0001A versus B: <0.0001A versus C: <0.0001B versus C: <0.0001	ANOVA; F=94.27; df=87 A versus B: 16.065-25.068; df=58A versus C: −12.454-−5.101; df=58B versus C: −34.276-−24.413; df=58
Median (IQR)	105.33 (103.75-108.25)	84.83 (77.333-91.167)	115.83 (109.667-120.25)
Range	96.33-124.67	60.67-107.33	92.33-127
45 min
Mean±SD	101.32±6.39	83.87±12.57	111.07±6.71	<0.0001 A versus B: <0.0001 A versus C: <0.0001B versus C: <0.0001	ANOVA; F=70.102; df=87 A versus B: 12.264-22.647; df=58A versus C: −13.13-−6.359; df=58B versus C: −32.441-−21.959; df=58
Median (IQR)	101.5 (98.167-103.5)	84 (77-93)	112.33 (106.667-115.333)
Range	88-122.33	57.33-105	94-121.33
Exsufflation
Mean±SD	94.86±6.83	84.47±11.39	98.23±11.05	<0.0001 A versus B: 0.0001 A versus C: 0.160B versus C: <0.0001	ANOVA; F=15.529; df=87A versus B: 5.513-15.264; df=58A versus C: −8.144-1.389; df=58B versus C: −19.565-−7.969; df=58
Median (IQR)	95.83 (89.25-99.333)	83.17 (76.75-93.25)	96.5 (92-107.833)
Range	84.67-115.33	64.67-107	64.67-114.33
Extubation
Mean±SD	89.62±7.94	84.43±11.32	91.06±8.55	0.019 A versus B: 0.044A versus C: 0.503B versus C: 0.013	ANOVA; F=4.133; df=87A versus B: 0.136-10.242; df=58A versus C: −5.698-2.831; df=58B versus C: −11.808-−1.437; df=58
Median (IQR)	90.17 (84.083-95.167)	83.67 (78.167-93)	90.33 (86-96.25)
Range	74.67-109.33	63.67-107.33	67.33-107.33
Postoperative 10 min
Mean±SD	86.03±9.49	83.96±10.64	86.31±5.57	0.531A versus B: 0.428A versus C: 0.890B versus C: 0.288	ANOVA; F=0.636; df=87A versus B: −3.133-7.289; df=58A versus C: −4.321-3.766; df=58B versus C: −6.775-2.064; df=58
Median (IQR)	86 (78.833-93.333)	83.83 (78.75-90)	86.5 (83.667-89.75)
Range	70.33-107.67	60.33-104.67	71-96.33

DISCUSSION

The hemodynamic responses to laryngoscopy and laparoscopy, comprising of elevation in HR and rise in systolic and DBP, are well known. It has become imperative to develop a novel technique/drug to prevent these potentially hazardous responses.[3]

The drugs for controlling these hemodynamic responses aim to stabilize HR and blood pressure during laryngoscopy and laparoscopy. Safety of such drugs is also a prime concern.

In the present study, we found that both pregabalin or clonidine are effective in maintaining the hemodynamic stability during laryngoscopy and LC with minimal side effects, with clonidine providing a better hemodynamic stability than Pregabalin.

All patients selected in the study belonged to the age between 18 and 55 years. The mean age of patients in group A, B, and C were 40.8 years, 38.4 years, and 39.4 years, respectively. There was no statistically significant difference of age among the three groups (P > 0.05). In all the three groups, the majority of the patients belonged to the age group 41–56 years. The three groups were evenly matched with respect to age. This has helped us to judge the clinical significance of our study as the distribution, metabolism, excretion and action of the drug are undoubtedly varied in different age groups. Therefore, clinically insignificant variation in age simply helped to alleviate these confounding factors. All of the three groups were statistically similar with regard to the sex distribution of the patients. Hence, gender was not the confounding factor in the analysis of results.

In this study, all three groups had a majority of patients in the ASA Grade 1. Patients with ASA Grade 3 and Grade 4 were excluded from the study. The groups were similar in terms of ASA grade also. Therefore, our study was conducted mostly on fit patients having no systemic illness, and there was no systemic disease significantly altering the drug metabolism in patients selected for the study.

All patients in control Group C were anxious before induction, while patients in the pregabalin Group A and the clonidine Group B were sedated and showed decrease in anxiety as compared to control Group C. Preoperative anxiolysis and sedation were higher in oral pregabalin Group A as compared with clonidine Group B.

The mean baseline pulse rate, SBP, DBP, and MBP were similar in all the groups. The comparability of the baseline characteristics in a randomized controlled trial ensures that the outcome is purely linked to the intervention and is not a chance effect as was seen in our study.

On monitoring the stages of preparation, intubation and surgery, we found that the hemodynamic variability was more pronounced during laryngoscopy and intubation among the control population, with a higher HR, SBP, DBP, and MBP as compared to both intervention groups which returned to normal within 15 min. The second variability was noted during insufflation of CO2 gas and throughout the period of pneumoperitoneum. Although the intra-abdominal pressure is continuously monitored during the insufflation and is tried to be kept as low as possible; still the rise in HR and BP becomes unavoidable. The rise in the hemodynamic parameters was significantly attenuated in the clonidine group than pregabalin and control group. Clonidine provided better hemodynamic stability with least rise in HR and blood pressures during various procedures involved in the surgery and even at extubation and in the postoperative period as compared to both the control group and pregabalin group. Our findings are in line with various previous studies who compared clonidine and pregabalin or control population and found a significantly better hemodynamic stabilization with Clonidine.[910] Even, the time periods at which the HR and BP were significantly different among the intervention groups were mostly similar. Gupta et al.,[17] reported hemodynamic variability after laryngoscopy with maximal rise after 1 min of laryngoscopy in the control population. They reported a statistically significant attenuation of HR and BM in premedicated groups (P < 0.0001), with clonidine showing better stabilization than pregabalin. In a study by Parveen et al.,[10] at all the observation periods, HR and BP of clonidine group was lower than that of pregabalin group.

The successful attenuation of the stress response with clonidine and pregabalin at the major events of laryngoscopy, intubation, insufflation and extubation, minimizes the risk of an adverse cardiac event during the routine surgery of LC especially in elderly and hemodynamically compromised patients. As clonidine showed a better response than pregabalin; it holds a clinical relevance for its use in routine practice as it provided the better efficacy and minimal side effects.

The administration of clonidine must be cautioned for dosage as it shown varied response at different doses (2–5 ug/kg) as shown in different studies.[111213] Higher dose of clonidine (5 ug/kg) is usually required for potentiation of postoperative analgesia by intrathecal morphine whereas a small oral dose of clonidine decreased the incidence of perioperative myocardial ischemic episodes without affecting hemodynamic stability. Mrinmoy et al. stressed on a dose of 150 ug as a good standard dose for reducing hemodynamic changes during the operation.[3]

Another clinical relevance of the use of clonidine would be the decreased need for isoflurane and antihypertensives such as esmolol during the surgery as clonidine serves with a multipurpose function due to its varied mechanisms of sympathetic antagonist and antihypertensive. In addition, it also helps prevent certain other complication during the surgery such as perioperative shivering by inhibiting cold thermoregulatory response, and nausea/vomiting by increasing gastrointestinal motility by decreasing sympathetic outflow and increasing parasympathetic out-flow from the central nervous system. This antiemetic property needs clarification of the mechanism from the future studies.

The study holds strength in being a randomized controlled trial comparing two drugs at a time and the results hold clinical significance to propose the routine use of clonidine in a common surgery (LC).

The study suffers from the limitation in not comparing the different doses of clonidine. And in the newer setups, conventional 4-port LC is being replaced by 3-port and single port LC; thus, the use of clonidine also needs to be explored in the modified versions of LC which was not done in the current study.

CONCLUSION

Oral premedication with pregabalin (150 mg) and clonidine (200 mcg) are effective in attenuation of the sympathomimetic response to laryngoscopy and laparoscopy with clonidine providing better hemodynamic stability than Pregabalin.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.