Anaesthesia Section DOI : 10.7860/JCDR/2016/17923.7346
Year : 2016 | Month : Mar | Volume : 10 | Issue : 03 Page : UC04 - UC08

The Effect of Gabapentin Plus Celecoxib on Pain and Associated Complications After Laminectomy

Aminolah Vasigh1, Molouk Jaafarpour2, Javaher Khajavikhan3, Ali Khani4

1 Anaesthesiologist, Department of Anaesthesiology, Medicine Faculty, Ilam University of Medical Science, Ilam, IR-Iran.
2 Faculty, Department of Midwifery, Nursing & Midwifery Faculty, Ilam University of Medical Science, Ilam, IR-Iran.
3 Anaesthesiologist, Department of Anaesthesiology, Medicine Faculty, Ilam University of Medical Science, Ilam, IR-Iran.
4 Faculty, Department of Nursing, Nursing & Midwifery Faculty, Ilam University of Medical Science, Ilam, IR-Iran.


NAME, ADDRESS, E-MAIL ID OF THE CORRESPONDING AUTHOR: Dr. Javaher Khajavikhan, Faculty, Department of Anaesthesiology, Medicine Faculty, Ilam University of Medical Science, Ilam, IR-Iran.
E-mail: drjavaherkhajavi@gmail.com
Abstract

Introduction

Prevention and treatment of postoperative pain is a major challenge in postoperative care and well-being of the surgical patient. The multimodal analgesic method has been recommended as an alternative treatment for the management of postoperative pain.

Aim

To assess the comparative effect of gabapentin versus gabapentin plus celecoxib on pain and associated complications after laminectomy.

Materials and Methods

In this randomized double- blind clinical trial, 114 patients scheduled for elective laminectomy received gabapentin (n=38, 900 mg daily), gabapentin plus celecoxib (n=38, 200 mg celecoxib plus 300mg gabapentin twice a day), and placebo (n=38, capsule containing starch). Visual Analog Scale (VAS) was used to determine the severity of pain. Complications after surgery, anxiety scores before surgery and patient’s satisfaction 24 hour after surgery were recorded.

Results

The mean pain sevenity score and morphine consumption in the gabapentin plus celecoxib group were less compared to the placebo and gabapentin group respectively at various intervals (p < 0.001). The mean anxiety score, shivering, nausea, vomiting and pruritus in the gabapentin group were significantly lower compared to the placebo and gabapentin plus celecoxib groups respectively (p < 0.001, p < 0.05). The frequencies of drowsiness (42.1%) in the gabapentin group were significantly high compared to the placebo and gabapentin plus celecoxib group respectively (p <0.001, p< 0.05). In the gabapentin plus celecoxib group patient satisfaction was significantly higher compared to the placebo and gabapentin group (p< 0.05).

Conclusion

Combination of 300 mg gabapentin plus 200 mg celecoxib twice a day is a good alternative in multimodal analgesia, effective in pain control with lesser side effects seen with gabapentin alone.

Introduction

Literature shows that 80% of patients undergoing surgery experience postoperative pain [1,2]. Majority (more than 80%) of these patients reported the intensity as moderate to severe [3]. Pain after surgery with several complications such as decreased wound healing, increased infections, prolonged hospital stays, readmission after discharge, increase morbidity and costs of hospital is a major challenge in postoperative care [1,4]. Therefore management of postsurgical pain plays a critical role in quality of the care plan [57]. Patients who experienced postoperative pain are exposed to decreased pulmonary function and the risk of developing thromboembolism due to immobility and suffer from nausea and vomiting. Also, cardiac workload, systemic vascular resistance, and myocardial oxygen consumption increase due to catecholamine release [8]. Laminectomy following lumbar herniation is one of the most common surgeries with an incidence of 10 to 40% in neurosurgery.

Annually, between 300,000 to 400,000 lumbar surgery was done. This statistics in the UK about 13,000 and over 250 000 in the US. In the United States alone $ 2.5 billion is spent for lumbar surgery. In addition annually, back pain causes loss of about 150 million days of work [911]. Postoperative pain, in these patients can continue for up to 3 days and 13-43% may become chronic [12]. The first choice for the management of postoperative pain is opioid. The use of opioids due to a number of adverse effects such as respiratory depression, nausea, vomiting, excessive sedation, dizziness, drowsiness, pruritus and urinary retention is limited [1,1215].

Recently there has been emphasis on the use of non opioid analgesic drugs [16,17], the use of two or more analgesics and multimodal therapy [1,12]. One of these multimodal analgesia methods is the use of anti-epileptic drugs such as gabapentin [1] and other NSAID’s such as celecoxib. Gabapentin, an anticonvulsant drug that has shown analgesic effect in post-herpetic neuralgia, diabetic neuropathy and neuropathic pain and celecoxib is a COX-2 inhibitor has been demonstrated to have analgesic efficacy after spinal surgery [18].

To understand the importance of economic and physical aspects of postoperative pain, comprehensive studies on the efficacy of gabapentin in laminectomy patients, is necessary. The hypothesis of this study was that after laminectomy, a combination of celecoxib and gabapentin will demonstrate superior analgesic efficacy than either drug alone and cause fewer side effects.

Aim

To assess the comparative effect of gabapentin versus gabapentin plus celecoxib on pain and related complications after laminectomy.

Materials and Methods

This was an experimental study that was carried out at the Imam Khomeini Hospital affiliated with Ilam University of Medical Sciences, Ilam, IR, during the April - September 2015. The sample size was calculated according to information obtained from a pilot study with 10 patients and following formula.

n= (Z1+Z2)2 (2S2) /d2 = 38

Z1 = 95%= 1.96

Z 2 = 80%= 0.84 (test power)

S (an estimate of the standard deviation of VAS in the groups; 1.67 was obtained in a pilot study).

d (The minimum of the mean difference of VAS between the groups which showed a significant difference and was obtained 1.1.)

In a randomized, double-blind clinical trial, 114 patient American society of Anaesthesiologists (ASA) grade I or II, aged 20-60 years, scheduled for elective laminectomy under general anaesthesia were enrolled in this study. Patients were divided into three groups. In each group, there were 38 patients: group A (gabapentin) received 600 mg gabapentin 2 hours before surgery and 300 mg 6 hours after surgery, group B (gabapentin plus celecoxib) received 200 mg celecoxib plus 300mg gabapentin 2 hours before surgery and 6 hours after surgery and group C (placebo) received a placebo capsule orally 2 hours before surgery and 6 hours after surgery.

A simple random sampling design was used [Table/Fig-1]. Sampling with a sealed envelopes technique and coding was done. Coded as: code 1= gabapentin, code 2= gabapentin plus celecoxib, code 3= placebo. Coding and sealed envelopes technique was prepared by a nurse who was not participating in the study. The patients with drug abuse, history of allergic reaction to any of the study drugs, on non-steroidal anti-inflammatory analgesic, pregnancy, cardiovascular, metabolic, respiratory, peptic ulcer and renal failure, or coagulation abnormalities were excluded from the study. Neurosurgeon and anaesthesiologist were same in all patients. Anaesthesia was given with inj. Thiopentone (5 mg/ kg IV) and inj. Atracurium (0.5 mg/ kg IV), and maintained with Isoflurane (1-1.5%) and Nitrous Oxide (50%) in Oxygen. Fentanyl was given in the operation room according to patient need and clinical discretion. Patients were reversed with 0.05 mg/kg Neostigmine combined with 0.02mg/kg Atropine. Standard monitoring included electrocardiogram, noninvasive blood pressure, and pulse oximetry. We used the VAS to determine severity of pain. The pain severity was assessed 2, 4, 6, 8, 12 and 24 hours after surgery. The patient’s mean blood pressure (BP), heart rate (HR), respiratory rate (RR), saturation (SPO2), urine retention, vomiting, shivering, headache, dizziness, nausea, drowsiness, pruritus, discharge time and morphine consumption were recorded. Anxiety scores before surgery and patient’s satisfaction 24 hour after surgery were recorded.

CONSORT diagram of participant in the clinical trial.

Preoperative anxiety was assessed according to a seven-point scale (1 = relaxed, 2 = apprehension, 3 = mild anxiety, 4 = moderate anxiety, 5 = manifest anxiety, 6 = severe anxiety, 7 = very severe anxiety). The patient’s satisfaction with pain management was assessed on a 5-point scale; 0 = poor, 1 = fair average, 2 = moderate, 3 = good and 4 = excellent) during postoperative periods was recorded. Shivering was assessed on a scale with 0 = no shivering observed, 1 = shivering observed [1]. VAS rating is a standard tool for evaluating of pain severity having ratings from 0 to 10. 0 (0 means no pain and 10 means the maximum pain in this scale). To determine the validity of the Questionnaire, content validity was used. The questionnaire was given to 10 faculty members of Ilam University of Medical Sciences and was used after revision. To determine the reliability of questionnaire, Cronbach’s alpha test was used. The reliability of the questionnaire was 0.83. The study was approved by the Institutional Ethics Committee at the Ilam University of Medical Sciences, Ilam, IR, (EC: 94/H/269) and informed consent was obtained from all samples. This study was registered at the Iranian Registry of Clinical Trials (IRCT2015071222870N3).

Statistical Analysis

Collected data were analysed using the statistical software SPSS, Ver.16. (SPSS Inc, Chicago, IL, USA). Descriptive statistics, Chi-square test, one-way ANOVA, LSD and Tukey test and Repeated Measurement were performed to analyse the results. The p<0.05 was considered significant.

Results

Baseline characteristics of the patients are shown in [Table/Fig-2]. Samples characteristics were not different among the groups (p > 0.5). One-way ANOVA test showed that the mean pain sevenity score and morphine consumption in the gabapentin plus celecoxib group were less compared to the placebo and gabapentin group respectively at various intervals (p < 0.001) [Table/Fig-3,4 and 5].

Patient characteristics, duration of anaesthesia and surgery.

CharacteristicsPlacebo(n=38)Gabapentin(n=38)Gabapentin plus Celecoxib(n=38)p-value
Age (year) [mean± sd]50.2±7.249.5±5.949.3±6>0.05
Sex [(M/F) n%][28(73.7%), 10(26.3%)][31(81.6%), 7(18.4%)][25(65.8%), 13(34.3%)]>0.05
Married (n%)34 (89.5%)35 (92.1%)35(92.1%)>0.05
Mean duration of surgery ± SD (hr)2.11 ± 0.232.27 ± 0.282.17± 0.35>0.05
Mean duration of anaesthesia ± SD (hr)2.35 ± 0.142.57 ± 0.182.49± 0.25>0.05
BP (mm/Hg)132± 3.2122±3.6121±3.1>0.05
PR (per/min)72.8± 3.473.6± 5.673.4± 5.4>0.05
Spo295± 3.495± 2.296± 2.7>0.05

Severity of pain, Morphine consumption and Anxiety score in groups.

CharacteristicPlacebo(n=38)Gabapentin(n=38)Gabapentin plus Celecoxib(n=38)p-value
Pain score by VAS at various intervals (hours)M±SDM±SDM±SD
2 h after intervention7.6±14.9±0.74±0.7<0.001
4 h after intervention6.6± 0.93.8± 0.83± 0.9<0.001
6 h after intervention5.4± 0.53.4± 0.52.8± 0.7<0.001
8 h after intervention4.5±0.63± 0.82.6± 0.7<0.001
12 h after intervention2.9±0.71.6± 0.51.5±0.4<0.001
24 h after intervention1.4± 0.40.7± 0.30.6± 0.2<0.001
Morphine consumption (mg)30.1 ± 0.611.9± 4.48.1± 2.7<0.001
Anxiety score3.6± 0.72.4±0.52.5± 0.5<0.001
Patient Satisfaction
Good4(10.5%)19 (50%)22 (57.8%)<0.05
Excellent0 (0)9 (23.6%)11 (28.9%)<0.05

Severity of pain between groups.

Morphine consumption between groups.

According to LSD and Tukey test the mean pain severity in the gabapentin plus celecoxib group were significantly lower compared to the placebo and gabapentin group respectively at various intervals (p <0.001, p<0.05). In 8, 12 and 24 h after the intervention, although the mean pain severity in the gabapentin plus celecoxib group was lower than gabapentin group but there was no statistically significant differences between the two groups (p> 0.05) [Table/Fig-6].

Outcome of severity of pain between groups according to LSD and Tukey test.

Outcome parametersBetween groupp-value
LSDTukey
2 h after InterventionPlaceboGabapentin<0.001<0.001
Gabapentin plus Celecoxib<0.001<0.001
2 h after interventionGabapentin plus CelecoxibGabapentin<0.001<0.001
Placebo<0.001<0.001
4 h after interventionPlaceboGabapentin<0.001<0.001
Gabapentin plus Celecoxib<0.001<0.001
4 h after interventionGabapentin plus CelecoxibGabapentin<0.001<0.001
Placebo<0.001<0.001
6 h after interventionPlaceboGabapentin<0.001<0.001
Gabapentin plus Celecoxib<0.001<0.001
6 h after interventionGabapentin plus CelecoxibGabapentin<0.001<0.001
Placebo<0.001<0.001
8 h after interventionPlaceboGabapentin<0.001<0.001
Gabapentin plus Celecoxib<0.001<0.001
8 h after interventionGabapentin plus CelecoxibGabapentin>0.05>0.05
Placebo<0.001<0.001
12 h after interventionPlaceboGabapentin<0.001<0.001
Gabapentin plus Celecoxib<0.001<0.001
12 h after interventionGabapentin plus CelecoxibGabapentin>0.05>0.05
Placebo<0.001<0.001
24 h after nterventionPlaceboGabapentin<0.001<0.001
Gabapentin plus Celecoxib<0.001<0.001
24 h after interventionGabapentin plus CelecoxibGabapentin>0.05>0.05
Placebo<0.001<0.001

Repeated measurement analysis showed that the mean pain score in the gabapentin group (p< 0.001), placebo group (p< 0.05) and gabapentin plus celecoxib group (p<0.001) were significantly different in various intervals.

The mean anxiety score, shivering, nausea, vomiting and pruritus in the gabapentin group were significantly lower compared to the placebo and gabapentin plus celecoxib group respectively (p < 0.001, p<0.05) [Table/Fig-3,7].

Frequencies of adverse effects between groups.

CharacteristicPlacebo(n%)Gabapentin(n%)Gabapentin plus Celecoxib(n%)p-value
Vomiting15 (39.5%)4 (10.3%)6 (15.8%)<0.05
Shivering16 (42.1%)4 (10.5%)6 (15.8%)<0.05
Headache4 (10.5%)5 (13.2%)6 (15.8%)0.792
Dizziness8 (21.1%)13 (34.2%)13 (34.2%)0.371
Nausea17 (44.7%)5 (12.8%)11 (28.9%)<0.05
Drowsiness2 (5.3%)16 (42.1%)13 (34.2%)<0.001
Pruritus17 (44.7%)7 (18.4%)8 (21.1%)<0.05
Urine Retention9 (23.7%)5 (13.1%)6 (15.8%)0.431

The frequencies of drowsiness (42.1%) in the gabapentin group were significantly high compared to the placebo and gabapentin plus celecoxib group respectively (p<0.001, p< 0.05). No statistically significant difference was observed between the groups in relation to headache, urine retention and dizziness (p> 0.05) [Table/Fig-7]. In the gabapentin plus celecoxib group patient satisfaction was significantly higher compare to the placebo and gabapentin group (p< 0.05) [Table/Fig-3].

Discussion

Postoperative pain, shivering, nausea, vomiting and urine retention are common complication impairing the quality of postoperative recovery, leading to postdischarge readmissions, causing chronic pain after surgery and increasing morbidity and costs [3]. In the past decade, despite our knowledge of pain physiology approximately 80% of patients undergoing surgical procedures experience postoperative pain [18]. Although opioids are the first choice for postoperative pain management they are associated with side effects [19]. Therefore, the multimodal analgesic approach has been recommended as an alternative treatment for the management of postoperative pain [18].

Treatment of postoperative pain and complications such as shivering, nausea and vomiting is a common challenge in postoperative care process and the basic principle in the early mobilization and well-being of the surgical patient [7]. Our results showed that gabapentin with celecoxib significantly reduced pain, overall morphine consumption but preoperative anxiety, pruritus, postoperative shivering, nausea and vomiting were less in the gabapentin alone group. In the gabapentin with celecoxib group patient satisfaction was significantly higher compared to the placebo and gabapentin group. This finding was consistent with the previous studies of the effects of gabapentin on postoperative pain and complications [2023].

Reuben et al., concluded following laminectomy the pregabalin/celecoxib combination was the most effective treatment for reducing pain and patients in these groups had fewer postoperative complications of nausea and vomiting [18]. Syal et al., found that in patients after open cholecystectomy Acetaminphen 1000 mg plus 1200 mg Gabapentin is effective on pain and morphine consumption but increase prevalence of nausea, vomiting and sedation was seen [24]. Ozgencil et al., in a trial of 90 patients after laminectomy found in the gabapentin and pregabalin groups, preoperative anxiety, pruritus, overall morphine consumption, postoperative shivering were significantly lower and patient satisfaction was significantly higher than those in the placebo group [1]. Kumar et al., found that pregabalin after laminectomy significantly decreases pain score compared to the placebo, but the effect was less than to tramadol group. The need for rescue analgesia was less in tramadol group. In pregabalin group the postoperative complications such as nausea, vomiting, and drowsiness were less in comparison to tramadol [8]. Gianesello et al., showed that in spinal surgery pregabalin significantly decreases VAS scores, postoperative incidence of constipation and nausea/vomiting than in the placebo group [12]. Liporaci Juniot in spinal surgery found that gabapentin significantly reduced the pain intensity after surgery [25]. Rahimi et al., concluded that gabapentin 800 mg daily can decreases the pain severity after laminectomy than those in the placebo group and received gabapentin 400 mg daily [26]. Pandey et al., concluded that prophylactic gabapentin in laparoscopic cholecystectomy patients significantly decreases nausea and vomiting and fentanyl consumption [27]. Bafna et al., in patients undergoing elective gynecological surgeries under spinal anaesthesia found that preemptive use of gabapentin and pregabalin significantly reduces the postoperative rescue analgesic requirement and increases the duration of postoperative analgesia [28].

Studies emphasized on the use of nonopioid analgesic drugs and multimodal therapy for preventing pain in the preoperative period. Several benefits of multimodal therapy include improved pain relief, reduction in preoperative stress response, shorter hospital stays, decreased hospital costs, improved patient satisfaction, and a reduction in postoperative morbidity and mortality [12]. The sedation levels in the gabapentin group were significantly higher compare to the placebo and celecoxib group. This finding suggests that gabapentin can raise the sedation levels of patients [1].

Gabapentin, a structural analog of gamma amino butyric acid is an antiepileptic drug that has demonstrated analgesic effect in diabetic neuropathy, post-herpetic neuralgia and neuropathic pain [27,29]. The mechanism of action of gabapentin by binding to the α2δ subunit of voltage dependent calcium channels [30]. Gabapentin has antiallodynic and antihyperalgesic properties that decrease the hyperexcitability of dorsal horn neurons induced by tissue injury. Decrease in central sensitization by an antihyperalgesic drug such as gabapentin can reduce acute postoperative pain. Gabapentin may also prevent opioid tolerance [31]. The anxiolytic effects of gabapentin have been reported in previous study [1]. On the other hand the effect of gabapentin has been reported in the treatment of nausea and vomiting in patients receiving cytotoxic drugs and patients under laparoscopic cholecystectomy. The mechanism of gabapentin in the prevention of emesis due to decreases of tachykinin neurotransmitter activity has been postulated to be useful [27]. The anticonvulsive, anxiolytic and analgesic effects of gabapentin can reduce the incidence of shivering [1].

Recently, celecoxib has been demonstrated to have analgesic efficacy after spinal surgery [32,33]. COX-2 NSAIDs have been demonstrated to have analgesic efficacy during pain at rest and with movement [34]. Meta-analysis studies highlighted the importance using of NSAIDs and COX-2 inhibitors in the multimodal analgesic approach [35]. The cardiovascular side effects of COX-2 inhibitors are widely accepted. Several studies of longterm use of selective COX-2 inhibitors shows an increased risk of incident atrial fibrillation, myocardial infarction, stroke, and heart failure. The limited use of selective COX-2 inhibitors is due to these side effects [3641].

Limitation

The limitations of our study include relatively small sample size and the subjective perception of pain by patients. All patients enrolled in this study were operated upon by a single surgeon and data collected from a single center that was the strength of this study.

Conclusion

To conclude, our findings revealed that after laminectomy, 200 mg celecoxib plus 300mg gabapentin twice a day is the alternative in multimodal analgesia. The adverse effects of gabapentin alone were found to be less. It also decreases the amount of morphine consumption for postoperative pain management as well as increased patient satisfaction in gabapentin plus celecoxib group.

References

[1]Ozgencil E, Yalcin S, Tuna H, Yorukoglu D, Kecik Y, Perioperative administration of gabapentin 1,200 mg day and pregabalin 300 mg day for pain following lumbar laminectomy and discectomy: a randomised, double-blinded, placebocontrolled study Singapore Med J 2011 52(12):883-89.  [Google Scholar]

[2]Apfelbaun JL, Chen C, Mehta SS, Gan TJ, Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged Anaesth Analg 2003 97(2):534-40.  [Google Scholar]

[3]Melemenl A, Staikou C, Fassoulaki A, Gabapentin for acute and chronic post-surgical pain SIGNA VITAE 2007 2(1):42-51.  [Google Scholar]

[4]Orak Y, Gunes Y, Bicer S, Ozcengiz D, The Effect of Gabapentin on Postoperative Pain and Opioid-Related Side Effects in Patients Undergoing Combined Spinal-Epidural Anaesthesia (a Preliminary Study) Clinical and Experimental Medical Sciences 2013 1(6):251-61.  [Google Scholar]

[5]Warner DO, Preventing postoperative pulmonary complications. The role of the anaesthesiologist Anaesthesiology 2000 92(5):1467-72.  [Google Scholar]

[6]Carli F, Zavorsky GS, Optimizing functional exercise capacity in the elderly surgical population Curr Opin Clin Nutr Metab Care 2005 8(1):23-32.  [Google Scholar]

[7]Mathiesen O, Moiniche S, Dahl JB, Gabapentin and postoperative pain: a qualitative and quantitative systematic review, with focus on procedure BMC Anaesthesiology 2007 7(6):2-15.  [Google Scholar]

[8]Kumar KP, Kulkarni DK, Gurajala I, Gopinath R, Pregabalin versus tramadol for postoperative pain management in patients undergoing lumbar laminectomy: a randomized, double-blinded, placebo-controlled study Journal of Pain Research 2013 6:471-78.  [Google Scholar]

[9]Rahimzadeh P, Sharma V, Imani F, Faiz HR, Ghodraty MR, Nikzad-Jamnani AR, Nader ND, Adjuvant Hyaluronidase to Epidural Steroid Improves the Quality of Analgesia in Failed Back Surgery Syndrome: A Prospective Randomized Clinical Trial Pain Physician 2014 17:75-82.  [Google Scholar]

[10]Kim SB, Lee KW, Lee JH, Ah Kim M, Woo An B, The Effect of Hyaluronidase in Interlaminar Lumbar Epidural Injection for Failed Back Surgery Syndrome Ann Rehabil Med 2012 36:466-73.  [Google Scholar]

[11]Porchet F, Vader JP, Larequi-Lauber T, Costanza MC, Burnand B, Dubois RW, The assessment of appropriate indications for laminectomy J Bone Joint Surg [Br] 1999 81-B:234-39.  [Google Scholar]

[12]Gianesello L, Pavoni V, Barboni E, Galeotti I, Nella A, Perioperative Pregabalin for Postoperative Pain Control and Quality of Life After Major Spinal Surgery J Neurosurg Anaesthesiol 2011 0(0):1-6.  [Google Scholar]

[13]Kehlet H, Jensen TS, Woolf CJ, Persistent postsurgical pain: risk factors and prevention Lancet 2006 367:1618-25.  [Google Scholar]

[14]White PF, The role of non-opioid analgesic techniques in the management of pain after ambulatory surgery Anaesth Analg 2002 94:577-85.  [Google Scholar]

[15]Dolin SJ, Cashman JN, Tolerability of acute postoperative pain management: nausea, vomiting, sedation, pruritis and urinary retention. Evidence from puplished data Br J Anaesth 2005 95:584-91.  [Google Scholar]

[16]White PF, Multimodal analgesia: its role in preventing postoperative pain Curr Opin Investig Drugs 2008 9:76-82.  [Google Scholar]

[17]White PF, The changing role of non-opioid analgesic techniques in the management of postoperative pain Anaesth Analg 2005 101:5-22.  [Google Scholar]

[18]Reuben SS, Buvanendran A, Kroin JS, Raghunathan K, The Analgesic Efficacy of Celecoxib, Pregabalin, and Their Combination for Spinal Fusion Surgery Anaesth Analg 2006 103(5):1271-77.  [Google Scholar]

[19]Kehlet H, Wilmore DW, Multimodal strategies to improve surgical outcome Am J Surg 2002 183:630-41.  [Google Scholar]

[20]Dahl JB, Mathiesen O, Miniche S, "Protective premedication": an option with gabapentin and related drugs? A review of gabapentin and pregabalin in the treatment of postoperative pain Acta Anaesthesiol Scand 2004 48:1130-36.  [Google Scholar]

[21]Seib RK, Paul JE, Preoperative gabapentin for postoperative analgesia: a meta-analysis Can J Anaesth 2006 53:461-69.  [Google Scholar]

[22]Hurley RW, Cohen SP, Williams KA, Rowlingson AJ, Wu CL, The analgesic effects of perioperative gabapentin on postoperative pain: a meta-analysis Reg Anaesth Pain Med 2006 31:237-47.  [Google Scholar]

[23]Ho K-Y, Gan TJH, Habib AS, Gabapentin and postoperative pain – a systematic review of randomised controlled trials Pain 2006 126:91-101.  [Google Scholar]

[24]Syal K, Goma M, Dogra RK, Ohri A, Gupta AK, Goel A, Protective Premedication": A Comparative Study of Acetaminophen, Gabapentin and Combination of Acetaminophen with Gabapentin for Postoperative Analgesia J Anaesth Clin Pharmacol 2010 26(4):531-36.  [Google Scholar]

[25]Liporaci Juniot JL, Assesment of preemptive analgesia efficacy in surgical extraction of third molars Rev Baras Anaesthesiol 2012 62(4):502-10.  [Google Scholar]

[26]Rahimi M, Naser Zareh M, Siavashi B, Amiri SR, The Effectiveness of Different Doses of Gabapentin in Controlling Postoperative Pain Journal of Iran Surgery 2014 22(1):44-49.  [Google Scholar]

[27]Pandey CK, Priye S, Ambesh SP, Singh S, Singh U, Singh PK, Prophylactic Gabapentin for prevention of postopretive nausea and vomiting in patients undergoing laparoscopic cholesystectomy . A randomized double blind, placebo controlled study J Postgrad Med 2006 52(2):97-100.  [Google Scholar]

[28]Bafna U, Rajarajeshwaran K, Khandelwal M, Prakash Verma A, A comparison of effect of preemptive use of oral gabapentin and pregabalin for acute postoperative pain after surgery under spinal anaesthesia Journal of Anaesthesiology Clinical Pharmacology 2014 30(3):373-77.  [Google Scholar]

[29]Serpell MG, Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial Pain 2002 99:557-66.  [Google Scholar]

[30]Maneuf YP, Gonzalez MI, Sutton KS, Chung FZ, Pinnock RD, Lee K, Cellular and molecular action of the putative GABA-mimetic, gabapentin Cell Mol Life Sci 2003 60:742-50.  [Google Scholar]

[31]Tiippana E, Hamunen K, Kontinen VK, Kalso E, Do Surgical patients Benefit from Perioperative Gabapentin/Pregabalin? A Systematic Review of Efficacy and Safety Anaesth Analg 2007 104:1545-56.  [Google Scholar]

[32]Reuben SS, Ekman E, The effect of cyclooxygenase-2 inhibition on analgesia and spinal fusion J Bone Joint Surg Am 2005 87:536-42.  [Google Scholar]

[33]Reuben SS, Ekman EF, Raghunathan K, The effect of cyclooxygenase-2 inhibition on acute and chronic pain after spinal-fusion surgery Reg Anaesth Pain Med 2006 31:6-13.  [Google Scholar]

[34]Gilron I, Milne B, Hong M, Cyclooxygenase-2 inhibitors in postoperative pain management. Current evidence and future directions Anaesthesiology 2003 99:1198-208.  [Google Scholar]

[35]Marret E, Kurdi O, Zufferey P, Bonnet F, Effect of nonsteroidal anti-inflammatory drugs on patient-controlled analgesia morphine side effects Anaesthesiology 2005 102:1249-60.  [Google Scholar]

[36]Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery N Engl J Med 2005 352:1081-91.  [Google Scholar]

[37]Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention N Engl J Med 2005 352:1071-80.  [Google Scholar]

[38]Back M, Yin L, Ingelsson E, Cyclooxygenase-2 inhibitors and cardiovascular risk in a nation-wide cohort study after the withdrawal of rofecoxib European Heart Journal 2012 33:1928-33.  [Google Scholar]

[39]Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C, Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials BMJ 2006 332:1302-08.  [Google Scholar]

[40]Ray WA, Varas-Lorenzo C, Chung CP, Castellsague J, Murray KT, Stein CM, Cardiovascular risks of nonsteroidal antiinflammatory drugs in patients after hospitalization for serious coronary heart disease Circ Cardiovasc Qual Outcomes 2009 2:155-63.  [Google Scholar]

[41]Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study Lancet 2005 365:475-81.  [Google Scholar]