Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 
  • Users Online:658
  • Home
  • Print this page
  • Email this page


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 33  |  Issue : 1  |  Page : 35-38

To compare the efficacy of preemptive oral pregabalin versus oral pregabalin with intravenous ketamine as premedication on early postoperative pain


1 Department of Anaesthesia, Batra Hospital and Medical Research Centre, New Delhi, Delhi, India
2 Department of Medicine, Batra Hospital and Medical Research Centre, New Delhi, Delhi, India

Date of Web Publication9-Apr-2019

Correspondence Address:
Dr. Shivi
Flat Number 90, I Block, Naraina Vihar, New Delhi - 110 068
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpn.ijpn_7_19

Rights and Permissions
  Abstract 

Background and Objectives: Using opioid alone for postoperative pain relief is usually inadequate, and higher doses can cause a multitude of complications. A drug, which has anxiolytic property without the adverse effects of traditional analgesics mentioned, may be an attractive choice for postoperative analgesia. This study was done to compare analgesic efficacy of different nonopioid drugs on early postoperative pain and thus opioid-sparing effect. Materials and Methods: It was a randomized controlled trial. Sixty patients scheduled to undergo elective abdominal surgery under general anesthesia were assessed in the study. Primary Objective: The primary objective of this study was to observe the effect of preemptive pregabalin and pregabalin with intravenous (IV) ketamine on Cumulative analgesic requirement postoperatively. Secondary Objective: The secondary objective of this study was to observe the effect of preemptive pregabalin and pregabalin with IV ketamine on (1) analgesia and (2) adverse effects. Patients were randomly divided into two groups each containing 30 patients. Group P received 150 mg of oral pregabalin, 2 h before induction of anesthesia. Group PK received 150 mg of oral pregabalin, 2 h before induction of anesthesia, and injection ketamine 0.15 mg/kg intravenously just before induction of anesthesia. Heart rate and mean blood pressure (MBP) were observed and recorded at different time intervals during surgery. Heart rate, MBP, time to first analgesic demand, visual analog scale (VAS) score, total postoperative analgesic requirement, sedation score, and side effects were recorded in postoperative period. Results: In Group P, the mean total analgesia requirement in postoperative period was 44.47 ± 5.06 mg, whereas in Group PK, it was 41.8 ± 2.34 mg (P = 0.006). VAS score and time to first analgesic demand were insignificantly higher in Group P. No statistically significant difference was found in side effect profile among the two groups. Conclusion: From our study, it could be concluded that a combination of oral pregabalin and IV ketamine when administered preoperatively can decrease opioid consumption while providing good pain control.

Keywords: Ketamine, multimodal analgesia, opioid sparing, preemptive, pregabalin


How to cite this article:
Shivi, Bhardwaj S. To compare the efficacy of preemptive oral pregabalin versus oral pregabalin with intravenous ketamine as premedication on early postoperative pain. Indian J Pain 2019;33:35-8

How to cite this URL:
Shivi, Bhardwaj S. To compare the efficacy of preemptive oral pregabalin versus oral pregabalin with intravenous ketamine as premedication on early postoperative pain. Indian J Pain [serial online] 2019 [cited 2019 Jun 19];33:35-8. Available from: http://www.indianjpain.org/text.asp?2019/33/1/35/255716




  Introduction Top


Opioids have traditionally been the cornerstone for pharmacotherapy in the management of postoperative pain. However, we often face the situations where monotherapy using opioid alone is inadequate.[1],[2],[3] Administration of high doses of opioids can result in higher incidence of complications such as respiratory depression, sedation, vomiting, constipation, pruritus, immune dysfunction, and urinary retention.[4]

We, therefore, in our study, wanted to explore the opioid-sparing effect of a combination of nonopioid drugs with different mechanisms of action, all having established effect on postoperative pain, and hypothesized that this “protective” package of nontraditional analgesics and antihyperalgesic drugs would demonstrate additive and prolonged postoperative analgesia and, consequently, significantly reduced intraoperative and postoperative opioid requirements and pain scores.


  Materials and Methods Top


This study was a prospective, randomized, double-blinded study conducted after obtaining Institutional Ethical Committee clearance and the patient's consent. We enrolled 100 patients with the American Society of Anesthesiologists (ASA) Grades 1 and 2, aged between 18 and 60 years, scheduled to undergo elective abdominal surgery under general anesthesia. Those who did not give consent, of age <18 years or >60 years, of ASA Grades 3–5, suffering from central nervous system disorders, having chronic pain conditions, and had taken analgesics in the past 48 h were excluded from this study.

Patients were randomly divided into two groups (Group P and Group PK) using computer-generated random sequence of numbers with each group containing 30 patients. The patients in both groups received 150 mg of oral pregabalin 2 h before induction of anesthesia. Two syringes were prepared by an anesthesiologist not involved in the evaluation of the patients. According to the randomization assignment, these syringes were filled with ketamine solution (5 mg/ml) or saline 0.9%. Investigators involved in patient management or data collection were unaware of the group assignment. Patients in Group PK received injection ketamine (0.15 mg/Kg), whereas Group P received injection normal saline just before induction of anesthesia.

At the time of preanesthetic checkup, the patients were acquainted with the visual analog scale (VAS) for pain scoring. A standard 10-cm VAS was used, which has end points labeled “no pain” and “worst possible pain.”

All the patients were kept fasting for 6 h for solids and 2 h for clear fluids before surgery, and they received general anesthesia following a standardized protocol. Induction was carried with injection propofol 2.0 mg/kg body weight and injection fentanyl 2.0 μg/kg body weight intravenous (IV). After giving injection vecuronium bromide 0.1 mg/kg body weight IV and ventilating the patient with oxygen and nitrous oxide for 3 min, intubation was facilitated with cuffed oral endotracheal tube of the appropriate size for airway management, and anesthesia was maintained with isoflurane and nitrous oxide in oxygen with controlled ventilation using circle system to keep end-tidal carbon dioxide between 35 and 40 mmHg. Additional fentanyl was given as deemed necessary by the attending anesthesiologist. At the end of surgery, the patients were extubated on the table following reversal of neuromuscular blockade.

Vitals such as heart rate and mean blood pressure (MBP) were recorded before induction, after induction, after intubation, after surgical incision, and after extubation. After surgery, heart rate and MBP were observed and recorded every hour for the first 6 h and then at 12 h and 24 h postoperatively in the ward. Furthermore, the time to first analgesic demand, VAS score, and total postoperative analgesic requirement were recorded.

Pain was assessed by VAS. Patients were asked to place a mark from 0 to 10 to describe the intensity of pain with 0 taken as no pain and 10 as worst possible pain.

Patient-controlled analgesia (PCA) was provided as rescue analgesia. Morphine in dose of 0.03 mg/kg was used in IV PCA pump with no basal flow. Whenever required, patient can self administered a bolus of 0.5 ml. A next bolus dose can only be administered after a lockout time of 15 minutes.

Sedation was assessed at 1, 15, 30, and 60–120 min postoperatively using Ramsay Sedation Score. Side effects such as respiratory depression (respiratory rate <8/min or arterial oxygen saturation <90%), nausea, vomiting, lightheadedness, dizziness, vertigo, and diplopia were also recorded.

Primary objective

The primary objective of this study is to observe the effect of preemptive pregabalin and pregabalin with IV ketamine on cumulative analgesic requirement postoperatively.

Secondary objective

The secondary objective of this study is to observe the effect of preemptive pregabalin and pregabalin with IV ketamine on:

  1. Analgesia
  2. Adverse effects.


Sample size calculation was based on mean morphine consumption. A clinically significant morphine-sparing effect was considered to be 15 mg over 24 h. According to the previous data (mean [standard deviation (SD)]: 38(19) mg)[5] and for α-risk of 0.05 with a power of 80%, 26 patients per group were necessary. To account for dropouts, we planned to include 30 patients per group. The descriptive statistics for quantitative variables is presented in mean and SD. For qualitative variables, the data are presented in terms of frequencies along with respective percentages under different categories. The Chi-square test was used to compare the categorical variables. The unpaired t-test was used to compare the continuous variables between the groups across the time periods. The repeated measure of analysis of variance was used to compare the changes in the continuous variables over the time periods with interaction of time and groups. P < 0.05 was considered significant. All the analyses were carried out on SPSS 16.0 version (IBM, Inc., Chicago, IL, USA).


  Results Top


A total of 60 patients scheduled to undergo abdominal surgery were included in this study [Figure 1]. The two groups were comparable on demographic data [Table 1]. Mean heart rate intraoperatively was found to be lower in Group PK as compared to Group P at different time intervals with significant difference before induction (mean: 85.37 ± 11.86 vs. 92.33 ± 11.21, P = 0.02), after surgical incision (mean: 73.43 ± 5.74 vs. 79.07 ± 4.57, P = 0.0001), and after extubation (mean: 80.43 ± 5.96 vs. 85.60 ± 6.33, P = 0.002). MBP intraoperatively in Group PK was found to be lower at all time intervals as compared to Group P. The MBP after surgical incision was found to be significantly lower in Group PK than Group P (mean: 75.07 ± 6.22 vs. 78.30 ± 6.20, P = 0.04). In Group P, the mean total analgesia requirement in postoperative period was 44.47 ± 5.06 mg, whereas in Group PK, it was 41.8 ± 2.34 mg, which was statistically significant (P = 0.006) [Table 2] and [Figure 2].
Figure 1: Flowchart showing movement of patients through the study

Click here to view
Table 1: Comparison of demographic details

Click here to view
Table 2: Comparison of total postoperative analgesia requirement (mg) between the groups

Click here to view
Figure 2: Comparison of total postoperative analgesia requirement (mg) between the groups

Click here to view


The time to first analgesic demand was found to be insignificantly (P = 0.91) higher in Group P (17.81 ± 3.95) than Group PK (17.69 ± 4.63) [Table 3]. Mean VAS score in Group P was observed to be higher in initial postoperative hours as compared to Group PK, while in later, postoperative hours mean VAS score was found to be higher in Group PK. There was no statistically significant difference in VAS score at all the time periods between the groups. There was no significant difference in side effects between the groups at all the time periods.
Table 3: Comparison of time to first analgesic demand (h) between the groups

Click here to view



  Discussion Top


Despite the considerable advances which have been made in the management of perioperative pain, a significant proportion of surgical patients still suffer from inadequate pain control. A multimodal analgesic regimen should be adjusted keeping the needs of the individual patient in consideration such as their preexisting medical conditions, types of surgery, and previous experiences related to both acute and chronic pain management. There is a lack of consensus with regard to the ideal opioid-sparing multimodal analgesia regimen.

Pregabalin binds to the α-2-δ subunit of voltage-gated calcium channels, reducing the release of several excitatory neurotransmitters and blocking the development of hyperalgesia and central sensitization.[6],[7] Ketamine produces antinociceptive actions via inhibition of NMDA receptors and activation of descending inhibitory monoaminergic pain pathways. NMDA receptor-mediated spinal reflexes are intimately involved as the pharmacological basis for windup, which contributes to neuropathic pain. Ketamine prevents this pain associated with windup.[8],[9] Various studies are done to show the opioid-sparing action of pregabalin and ketamine when given preemptively but fewer data available on combination of these two drugs. In search of an ideal multimodal analgesic combination for abdominal surgeries, we conducted this study comparing analgesic efficacy of pregabalin alone with pregabalin along with ketamine when given preemptively.

We found that the mean heart rate in Group P (pregabalin alone) was higher than Group PK (pregabalin + ketamine) at all intervals; statistically significant difference was found before induction (0.02), after surgical incision (0.0001), and after extubation (0.002). Similarly, the MBP in Group PK was found to be lower at all time intervals as compared to Group P. The MBP after surgical incision was found to be significantly lower in Group PK than Group P (P = 0.04). Hence, in our study, we found better hemodynamic stability when we used a combination of pregabalin and ketamine (Group PK) against pregabalin alone (Group P) in the intraoperative period. This difference may be explained by better analgesic effect of combination of pregabalin with ketamine as compared to pregabalin alone.

Martinez et al.[5] in a randomized, double-blind, controlled study compared the efficacy of pregabalin alone, ketamine alone, and their combination on postoperative pain when given preemptively. They found that the combination of pregabalin and ketamine in patients undergoing total hip arthroplasty did not provide when compared to pregabalin better pain control alone. The pain scores at rest and on movement were found to be similar in this study at all time intervals among both the groups. Our study corroborated with the results of Martinez et al., as the mean VAS scores at all time intervals postoperatively were not significantly different among Group P and Group PK. Although in our study it was observed that time to first analgesic demand was greater in pregabalin–ketamine combination group (Group PK) as compared to pregabalin-alone group (Group P), the difference was not statistically significant.

Martinez et al.[5] found that the mean (SD) total 48-h morphine use was reduced in the combined ketamine and pregabalin group (38(19) mg), as compared to ketamine-alone group (52(22) mg) and pregabalin-alone group (44(20) mg). Similarly, in our study, we found that that total postoperative analgesia requirement was significantly (P = 0.006) lower in pregabalin–ketamine combination group (Group PK, 41.8 ± 2.34 mg), as compared to pregabalin-alone group (Group P, 44.47 ± 5.06 mg). No statistically significant difference was found in side effects profile among the two groups.

Limitation of our study was that the bioavailability of drugs used was not ascertained, and there can be a large variation of bioavailability of orally administered drugs. Furthermore, patient variability in pain threshold was not taken into consideration. Although our sample size was adequate, to make conclusive recommendations, larger multicenter trials to further evaluate the efficacy of opioid-sparing effect of pregabalin and ketamine when used as a combination in abdominal surgeries are warranted in the future.


  Conclusion Top


The combination of oral pregabalin and IV ketamine when given preemptively reduces opioid consumption in postoperative period in patients undergoing abdominal surgeries.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kehlet H. Postoperative opioid sparing to hasten recovery: What are the issues? Anesthesiology 2005;102:1083-5.  Back to cited text no. 1
    
2.
Kehlet H, Dahl JB. The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg 1993;77:1048-56.  Back to cited text no. 2
    
3.
White PF, Kehlet H, Neal JM, Schricker T, Carr DB, Carli F, et al. The role of the anesthesiologist in fast-track surgery: From multimodal analgesia to perioperative medical care. Anesth Analg 2007;104:1380-96.  Back to cited text no. 3
    
4.
Dolin SJ, Cashman JN. Tolerability of acute postoperative pain management: Nausea, vomiting, sedation, pruritus, and urinary retention. Evidence from published data. Br J Anaesth 2005;95:584-91.  Back to cited text no. 4
    
5.
Martinez V, Cymerman A, Ben Ammar S, Fiaud JF, Rapon C, Poindessous F, et al. The analgesic efficiency of combined pregabalin and ketamine for total hip arthroplasty: A randomised, double-blind, controlled study. Anaesthesia 2014;69:46-52.  Back to cited text no. 5
    
6.
Shneker BF, McAuley JW. Pregabalin: A new neuromodulator with broad therapeutic indications. Ann Pharmacother 2005;39:2029-37.  Back to cited text no. 6
    
7.
Chizh BA, Göhring M, Tröster A, Quartey GK, Schmelz M, Koppert W, et al. Effects of oral pregabalin and aprepitant on pain and central sensitization in the electrical hyperalgesia model in human volunteers. Br J Anaesth 2007;98:246-54.  Back to cited text no. 7
    
8.
Roytblat L, Korotkoruchko A, Katz J, Glazer M, Greemberg L, Fisher A, et al. Postoperative pain: The effect of low-dose ketamine in addition to general anesthesia. Anesth Analg 1993;77:1161-5.  Back to cited text no. 8
    
9.
Lin HQ, Jia DL. Effect of preemptive ketamine administration on postoperative visceral pain after gynecological laparoscopic surgery. J Huazhong Univ Sci Technolog Med Sci 2016;36:584-7.  Back to cited text no. 9
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Materials and Me...
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed423    
    Printed16    
    Emailed0    
    PDF Downloaded28    
    Comments [Add]    

Recommend this journal