|Year : 2014 | Volume
| Issue : 3 | Page : 155-159
Prospective, randomised, double blinded controlled trial of gabapentin and pregabalin as pre emptive analgesia in patients undergoing lower abdominal and limb surgery under spinal anaesthesia
Induja Rajendran1, Asha Basavareddy2, Bikash Ranjan Meher3, Srikanth Srinivasan4
1 Third Year MBBS Student, Sri Venkateshwaraa Medical College and Hospital, Pondicherry, India
2 Department of Pharmacology, Sri Devaraj Urs Medical College, Tamaka, Kolar, Karnataka, India
3 Department of Pharmacology, Sri Venkateshwaraa Medical College and Hospital, Pondicherry, India
4 Department of Community Medicine, Sri Venkateshwaraa Medical College and Hospital, Pondicherry, India
|Date of Web Publication||11-Aug-2014|
Associate Professor, Department of Pharmacology, Sri Devaraj Urs Medical College, Tamak, Kolar - 563 101, Karnataka
Source of Support: None, Conflict of Interest: None
Introduction: Postoperative pain management of high quality is important and in majority of post surgical cases pain is not treated adequately. We have evaluated the efficacy and safety of pregabalin and gabapentine as preemptive analgesic for post operative pain management in patients undergoing lower abdominal and lower limb surgery under spinal anesthesia. Materials and Methods: In a randomized double blind study, 90 patients were divided into three groups. Group G received tab gabapentin 900 mg, Group P received tab pregabalin 300 mg and Group C received placebo tablet orally 1 hour prior to surgery. All patients underwent surgery under spinal anesthesia using 0.5% Bupivacaine. Assessment of postoperative pain was made with visual Analogue Scale (VAS) score at 1, 2, 4, 6, 8, 12, 18, and 24 hours post operatively. Injection tramadol 100 mg was given as rescue analgesic intramuscularly when VAS score was > 7 in all the groups. Time to first rescue analgesics and number of rescue analgesics received were noted in all groups. The occurrences of side effects were noted in all groups. Results: The tramadol as rescue analgesia consumption was less in pregabalin and gabapentin groups compared to control and was statistically significant (P < 0.001). Initial VAS scores were lower in pregabalin (3.2 ± 0.4) and gabapentin (3.63 ± 0.32) groups compared to control (6.60 ± 0.77) and was statistically significant (P < 0.001). Time to first rescue analgesia was significantly longer for pregabalin (24.6 hours) followed by gabapentin (20.76 hours) and control (4.93 hours) groups. Conclusion: Pregabalin 300 mg single dose given 1 hour prior to surgery is superior to 900 mg gabapentin and placebo in attenuating post operative in patients undergoing lower abdominal and lower limb surgery. Both drugs are better than placebo.
Keywords: Analgesia, gabapentin, pain, preemptive, pregabalin
|How to cite this article:|
Rajendran I, Basavareddy A, Meher BR, Srinivasan S. Prospective, randomised, double blinded controlled trial of gabapentin and pregabalin as pre emptive analgesia in patients undergoing lower abdominal and limb surgery under spinal anaesthesia. Indian J Pain 2014;28:155-9
|How to cite this URL:|
Rajendran I, Basavareddy A, Meher BR, Srinivasan S. Prospective, randomised, double blinded controlled trial of gabapentin and pregabalin as pre emptive analgesia in patients undergoing lower abdominal and limb surgery under spinal anaesthesia. Indian J Pain [serial online] 2014 [cited 2020 Jul 10];28:155-9. Available from: http://www.indianjpain.org/text.asp?2014/28/3/155/138450
| Introduction|| |
Postoperative pain management of high quality is utmost important but still remains a challenge.  Among all the surgical procedures, it is thought that pain is inadequately treated in almost 50% cases.  Central neural hyperexcitability is one of the factor that aggravate post operative pain, recent studies have suggested that some drugs can prevent or attenuate the central neural hyperexicitability. , gabapentine and pregabalin were originally developed to treat spastic conditions and as adjuvant for the management of resistant epilepsy.  Gabapentin is a lipophilic structural analogue of gamma-aminobutyric acid (GABA) and is N-methyl-D-aspartate receptor (NMDA) antagonist which binds to voltage dependent L-type of calcium channels.  Pregabalin is an anticonvulsant drug used for neuropathic pain which causes influx of calcium and release GABA.  Pregabalin is more lipid soluble and has better pharmacokinetic profile with fewer drug interactions in comparison to its developmental predecessor gabapentin. 
Gabapentin has been found to be useful in postoperative pain after breast surgery  , spinal surgery,  and laproscopic cholecystectomy.  Similarly pregabalin is claimed to be useful in preventing acute nociceptive pain of surgery, to reduce opioid consumption post operatively. , Pregabalin may be useful in amelioration of postoperative anxiety as its effectiveness in treating generalized anxiety disorder has been proved in several clinical trials. ,, None of these studies compare pregabalin 300 mg and gabapentin 900 mg in surgeries under spinal anesthesia. The present study was therefore designed to evaluate and compare the role of preoperative single dose of pregabalin with gabapentin for attenuating postoperative pain, rescue analgesic requirement and safety profile in patients undergoing surgeries under spinal anesthesia.
| Materials and Methods|| |
This study was registered with clinical trial registry of India with trial registry number CTRI/2014/03/004509. After getting written informed consent from each participant 90 subjects (males and females) in the age-group of 18-70years with ASA grade I and II undergoing surgeries under spinal anesthesia using 0.5% bupivacaine were included in the study. Patients aged more than 70 years having contraindications to the use of pregabalin, gabapentin or current use of gabapentinoids, taking analgesics for chronic pain, sedation, epileptics, impaired renal functions, and body weight > 20% of the ideal body weight were excluded.
Study design and outcome
This was prospective, randomized, double blind, placebo controlled, comparative clinical study. Patients meeting inclusion criteria during preanesthetic evaluation were randomly assigned into three groups of 30 each with the help of a computer-generated table of random numbers, to receive either pregabalin 300 mg, gabapentin 900 mg or matching placebo. The study medications looked identical and were packed and sealed in opaque covers labeled with investigators name, project title and randomization number. Each patient received appropriate randomized number and allocated to their group according to the number. No anesthetist or assessor was aware of the group assignment until the entire 90 patients were included and the assessment was completed. These 90 patients were divided into Group P - receiving pregabalin 300 mg; Group G - receiving gabapentin 900 mg; and group C - receiving matching placebo. The study drug was administered orally 1 hour prior to surgery. No other sedative preanesthetic medication was administered. Patients were familiarized with the use of a 10 cm linear Visual Analogue Scale (VAS) for pain, which ranges from 0 (no pain) to 10 (worst imaginable pain). In the operation theatre, pulse oximeter, heart rate, noninvasive blood pressure and electrocardiogram (ECG) were monitored. Anesthesia was standardized in all patients, 10 ml/kg ringer lactate was preloaded in all patients before giving spinal anesthesia for various surgical procedures. Spinal anesthesia was instituted wit 15 mg of 0.5% bupivacaine. Intravenous (IV) fluids were continued intraoperativey. After surgery all patients were transferred to surgical intensive care unit (SICU). In SICU pain was assessed immediately by VAS and thereafter assessed at every 2 hours for 24 hrs assessment was done by a trained nurse and medical student. If VAS score was more than 7, patient received injection tramadol 100 mg intramuscularly and was noted. Time for first dose of rescue analgesia and total dose of rescue of rescue analgesia in 72 hours was recorded and considered as primary outcome.
Any complications like dizziness, somnolence, post operative nausea, vomiting (PONV), confusion, urinary retention of adverse events were recorded in 72 hours of postoperative period. The severity of PONV was graded on a four-point ordinal scale (0 = no nausea, 1 = mild nausea, 2 = moderate nausea, 3 = severe nausea with vomiting). The Ramsay sedation scale (awake levels were 1 = anxious, agitated; 2 = oriented, co operative, tranquil; 3 = responds to command; asleep levels were dependent on patients response to a light glabellar tap or loud auditory stimulus; 4 = brisk response; 5 = sluggish response; and 6 = no response) was used to assess sedation score in all groups. The data were unblinded at the end of the study.
Data were analyzed using SPSS version 16. Sample size was calculated keeping power of 80% and α value to 0.05 for comparing two means (gabapentin and pregabalin) with anticipated standard deviation being 3.1 and difference between the means as 2.5. The calculated sample size for each group came up to 24. We have taken 30 patients in each group keeping dropouts into consideration. One way analysis of variance (ANOVA) was used for comparing total analgesic consumption over 72 hours and time interval to first analgesic. Post hock Bonferroni test was used for intergroup comparison. Non parametric Krushal Wallis test was used for comparing sedation scores over 24 hours. The chi-square test was used to find association between side effects and study drug. Descriptive variables expressed as mean ± SD.
| Results|| |
This study was conducted at Sri Venkateshwaraa Medical College Hospital and Research Center, Pondicherry, India. The numbers of patients screened were 96, out of whom 90 were enrolled in the study and all patients completed the study. The groups were comparable with respect to age, weight, sex, ASA grade I/II, and duration of surgery [Table 1]. Patient distribution according to the type of surgery is comparable in all groups [Table 2]. The time to first analgesic and total consumption of tramadol as rescue analgesic are shown in [Table 3]. The difference in time to first rescue analgesia was significant in group P (P < 0.001) and group G (P < 0.001) compared to group C. Two patients in group P did not require rescue analgesic. The total consumption of tramadol in 72 hours was 386.5 ± 20.12 for control, 90.65 ± 9.25 with pregabalin and 200.77 ± 16.77 with gabapentin. The VAS scores postoperatively at regular intervals of all the groups are depicted in [Table 4]. There is significant difference (P < 0.001) between all groups from first hour to 8 hour. The VAS scores of gabapentin (P = 0.206) at 12 hour was not significantly reduced compared to control. The total VAS scores of pregabalin and gabapentin were significantly (P < 0.001) less compared to control. The total VAS score of pregabalin was significantly less (P = 0.023) compared to gabapentin. The sedation scores at different time interval are shown in [Table 5]. The incidence and severity of PONV, incidence of headache, dizziness, and urinary retention are presented in [Table 6]. Respiratory depression was not observed in any patient.
|Table 1: Patient Demographic and intraoperative variables (Values expressed as mean ± SD, numbers)|
Click here to view
|Table 3: Comparison of Post operative analgesia (values in mean ± SD and number)|
Click here to view
| Discussion|| |
In the present study we have observed that preoperative single dose of pregabalin (300 mg) resulted in significant reduction in postoperative analgesic requirement compared to gabapentin (900 mg) and placebo in infraumbilical surgeries under spinal anesthesia. The VAS scores were significantly reduced in the initial hours of recovery. The antinociceptive and antihyperalgesic properties of gabapentin and pregablin have been demonstrated in experimental animal models of neuropathic and inflammatory pain.  The central nervous system (CNS) is well-protected from harmfull effect of noxious stimuli and hyperalgesia by administering preincisional analgesia. Several studies have reported the effectiveness of gabapentin and pregabalin in neuropathic pain, acute postoperative pain by reducing postoperative analgesic requirement with better patient satisfaction  in surgeries like vaginal hysterectomy  , thyroid surgery  and also in epidural analgesia. 
The mechanism of action of pregabalin and gabapentin are same as they both are GABA analogues. Pregabalin is required in lesser dose and is associated with few dose related adverse effects compared to gabapentin as it has better pharmacokinetic profile.  Most of the previous studies have reported 1200 mg of gabapentin. ,,,, One study by Ghai A et al., have used gabapentin 900 mg for pain management after abdominal hysterectomy.  As there was paucity of studies using gabapentin 900 mg and no study had been reported in lower abdominal and lower limb surgeries under spinal anesthesia, we designed this controlled clinical study to compare gabapentin 900 mg with pregabalin 300 mg. In this study we have also calculated the total analgesic consumption for 72 hours, which is significantly less (P < 0.001) with pregabalin compared to gabapentin and control.
Many studies reported ineffectiveness of pregabalin in the dose of 50 mg  , 100 mg in gynecological surgeries  and 150 mg in day care laproscopic surgeries.  In contrast to the above studies Agarwal A et al., showed 150 mg pregabalin was effective in attenuating postoperative pain after laproscopic cholecystectomy  and laproscopic hysterectomy.  There was decrease in pain scores in our study with pregabalin and gabapentin which is consistent with previous studies. ,, There was significant difference in score for initial 12 hours which is much longer than the plasma t1/2 of Pregabalin (6-8 hours). Time to first analgesic was significantly longer with pregabalin due to its quicker and consistent action compared to gabapentin. The incidence of side-effects were comparable in all the groups except for sedation which is an expected, harmless side effect.
Limitations of our study are only single dose of gabapentin and pregabalin are used which does not infer the long term benefits to the patient. Study with different doses needs to be conducted for both gabapentin and pregabalin to arrive at an appropriate analgesic dose. More studies are to be conducted to compare the pre and post operative analgesic effects of gabapentin and pregabalin.
In conclusion, preemptive pregabalin 300 mg reduced the analgesic requirement compared to gabapentin 900 mg and placebo in lower abdominal and lower limb surgeries. The side effect profile was comparable in all the groups. We suggest use of pregabalin 300 mg in treating post operative pain after lower abdominal and lower limb surgeries under spinal anesthesia.
| Acknowledgment|| |
The authors acknowledge Dr Deepali Mukherjee, Professor and Head, Dept. of Pharmacology for all the support for conducting this study.
| References|| |
|1.||Woolf CJ, Chong MS. Preemptive analgesia - Treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg 1993;77:362-79. |
|2.||Gottschalk A, Smith DS. New concepts in acute pain therapy: Preemptive analgesia. Am Fam Physician 2001;63:1979-84. |
|3.||Woolf CJ. Evidence for a central component of postinjury pain hypersensitivity. Nature 1983;306:686-8. |
|4.||Wall PD. The prevention of postoperative pain. Pain 1988;33:289-90. |
|5.||Bryans JS, Wustrow DJ. 3 substitute GABA analogues with central nervous system activity: A review. Med Res Rev 1999;19:149-77. |
|6.||Rock DM, Kelly KM, Macdonald RL. Gabapentin actions on ligand- and voltage-gated responses in cultured rodent neurons. Epilepsy Res 1993;16:89-98. |
|7.||Benkert, Otto, Hippius, Hanns. Kompendium Der Psychiatrischen Pharmacotherapia, 6 th ed. Springer; 2006. |
|8.||Ben ME. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia 2004;45:13-8. |
|9.||Fassoulaki A, Patris K, Sarantopoulos C, Hogan Q. The analgesic effect of Gabapentin and mexiletine after breast surgery for cancer. Anesth Analg 2002;95:985-91. |
|10.||Turan A, Karamanlioglu B, Memis D, Hamamcioglu MK, Tükenmez B, Pamukçu Z, et al. Analgesic effects of Gabapentin after spnal surgery. Anaesthesiology 2004;100:935-8. |
|11.||Pandey CK, Priye S, Singh S, Singh U, Singh RB, Singh PK. Preemptive use of gabapentin significantly decreases postoperative pain and rescue analgesic requirements in laparoscopic cholecystectomy. Can J Anaesth 2004;51: 358-63. |
|12.||Hill CM, Balkenohl M, Thomas DW, Walker R, Mathe H, Murray G. Pregabalin in patients with postoperative dental pain. Eur J Pain 2001;5:119-24. |
|13.||Hurley RW, Chatterjea D, Feng MH, Tayolor CP, Hammond DL. Gabapentin and pregabalin can interact synergistically with naproxen to produce antihyperalgesia. Anesthesiology 2002;97:1263-73. |
|14.||Pande AC, Feltner DE, Jefferson JW, Davidson JR, Pollack M, Stein MB, et al. Efficacy of the novel anxiolytic Pregabalin in social anxiety disorder: A placebo- controlled, multicenter study. J Clin Psychopharmacol 2004;24:141-9. |
|15.||Feltner DE, Crockatt JG, Dubovsky SJ, Cohn CK, Shrivastava RK, Targum SD, et al. A randomized, double blind, placebo controlled, fixed dose, multicenter study of Pregabalin in patients with generalized anxiety disorder. J Clin Psychopharmacol 2003;23:240-9. |
|16.||Pande AC, Gockott JG, Feltner DE, Janney CA, Smith WT, Weisler R, et al. Pregabalin in generalized anxiety disorder: A placebo-controlled trial. Am J Psychiatry 2003;160:533-40. |
|17.||Tiippana EM, Hamunen K, Kontinen VK, Kalso E. Do surgical patients benefit from preoperative gabapentin/pregabalin? A systematic review of efficacy and safety. Anaesth Analg 2007;104:1545-56. |
|18.||Rorarius MG, Mennander S, Souminen P, Rintala S, Puura A, Pirhonen R, et al. Gabapentin for the prevention of post operative pain after vaginal hysterectomy. Pain 2004;110:175-81. |
|19.||Al-Mujadi H, A-Rfai AR, Katzarov MG, Dehrab NA, Batra YK, Al-Qattan AR. Preemptive Gabapentin reduces postoperative pain and opioid demand following thyroid surgery. Can J Anesth 2006;53:268-73. |
|20.||Turan A, Kaya G, Karamanlioglu B, Pamukcu Z, Apfel CC. effect of oral Gabapentin on post operative epidural analgesia. Br J Anaesth 2006;96:242-6. |
|21.||Saraswat V, Arora V. Preemptive gabapentin vs pregabalin for acute postoperative pain after surgery under spinal anaesthesia. Indian J Anaesth 2008;52:829-34. |
|22.||Ghai A, Gupta M, Hooda S, Singla D, Wadhera R. A randomized controlled trial to compare pregabalin with gabapentin for postoperative pain in abdominal hysterectomy. Saudi J Anaesth 2011;5:252-7. |
|23.||Paech MJ, Gay R, Chua S, Scott K, Christmas T, Doherty DA. A randomized, placebo-controlled trial of preoperative pregabalin for postoperative pain relief after minor gynaecological surgery. Anesth Analg 2007;105:1449-53. |
|24.||Jokela R, Ahonen J, Taligren M, Haanpaa M, Kortilla K. Pretreatment with pregabalin 75 or 150 mg with ibuprofen to control pain after day care gynaecological laproscopic surgery. Br J Anaesth 2008;100:834-40. |
|25.||Agrawal A, Gautam S, Gupta D, Agarwal S, Singh PK, Singh U. Evaluation of a single preoperative dose of Pregabalin for attenuation of post operative pain after laproscopic cholecystectomy. Br J Anaesth 2008;101:700. |
|26.||Jokela R, Ahonen J, Taligren M, Haanpaa M, Kortilla K. A randomized controlled trial of perioperative administration of pregabalin for pain after laparoscopic hysterectomy. Pain 2008;134:106-12. |
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
|This article has been cited by|
||Benefit and harm of pregabalin in acute pain treatment: a systematic review with meta-analyses and trial sequential analyses
| ||M. L. Fabritius,C. Strøm,S. Koyuncu,P. Jæger,P. L. Petersen,A. Geisler,J. Wetterslev,J. B. Dahl,O. Mathiesen |
| ||BJA: British Journal of Anaesthesia. 2017; 119(4): 775 |
|[Pubmed] | [DOI]|
||Gabapentin for post-operative pain management - a systematic review with meta-analyses and trial sequential analyses
| ||M. L. Fabritius,A. Geisler,P. L. Petersen,L. Nikolajsen,M. S. Hansen,V. Kontinen,K. Hamunen,J. B. Dahl,J. Wetterslev,O. Mathiesen |
| ||Acta Anaesthesiologica Scandinavica. 2016; |
|[Pubmed] | [DOI]|
||Efficacy of Pregabalin in Acute Postoperative Pain Under Different Surgical Categories
| ||David M.H. Lam,Siu-Wai Choi,Stanley S.C. Wong,Michael G. Irwin,Chi-Wai Cheung |
| ||Medicine. 2015; 94(46): e1944 |
|[Pubmed] | [DOI]|
||A systematic review and meta-regression analysis of prophylactic gabapentin for postoperative pain
| ||B. Doleman,T. P. Heinink,D. J. Read,R. J. Faleiro,J. N. Lund,J. P. Williams |
| ||Anaesthesia. 2015; 70(10): 1186 |
|[Pubmed] | [DOI]|