Comparing the prophylactic effects of oral gabapentin, pregabalin, and celecoxib on postoperative pain management in orthopedic surgery of the lower extremity: A double-blind randomized controlled trial
Dorna Kheirabadi1, Mohammad Reza Safavi2, Marzieh Taghvaei3, Mohammad Reza Habibzadeh4, Azim Honarmand2
1 Anesthesiology and Critical Care Research Center, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
2 Department of Anesthesiology and Critical Care, Anesthesiology and Critical Care Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
3 Department of Anesthesiology and Critical Care, Anesthesiology and Critical Care Research Center, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
4 Department of Anesthesiology and Critical Care, Anesthesiology and Critical Care Research Center, Fellowship in Critical Care Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
|Date of Submission||30-Apr-2019|
|Date of Decision||20-Jul-2019|
|Date of Acceptance||23-Oct-2019|
|Date of Web Publication||20-Jan-2020|
Dr. Dorna Kheirabadi
Anesthesiology and Critical Care Research Center, School of Medicine, Isfahan University of Medical Sciences, Isfahan
Source of Support: None, Conflict of Interest: None
Background: Lower extremity pain after orthopedic surgery is so frequent that has led to many treatment modalities. This study aims to compare the prophylactic effects of oral gabapentin, pregabalin, and celecoxib on reducing postsurgical pain of the lower extremity orthopedic surgery. Materials and Methods: In a double-blind randomized controlled trial, 120 patients were randomly divided into four groups using block design randomization. 1 h before spinal anesthesia, the studied groups received 300 mg oral gabapentin; 75 mg oral pregabalin; 200 mg oral celecoxib; and starch as placebo. The severity of postoperative pain (using visual analog scale), mean arterial pressure, heart rate, opioid consumption dose, and drug side effects were recorded for six times (each 60 min up to two times and then every 6 h for the next four times). Chi-square, one-way analysis of variance (ANOVA), and ANOVA repeated measure tests were used for statistical analysis. Results: Significant reduction of pain severity was observed only at the first time measurement between pregabalin and placebo groups (P: 0.014). Patients in the pregabalin group required lower dose of opioid compared to placebo group during admission in surgical ward. There were no significant differences concerning pain reduction, opioid administration, and side effects between pregabalin, gabapentin, and celecoxib groups. Conclusion: Taking 75 mg oral pregabalin before lower extremity orthopedic surgery can attenuate postoperative pain, especially during the 1st h postoperation as well as less opioid consumption and much more patients' satisfaction.
Keywords: Celecoxib, gabapentin, postsurgical pain, pregabalin
|How to cite this article:|
Kheirabadi D, Safavi MR, Taghvaei M, Habibzadeh MR, Honarmand A. Comparing the prophylactic effects of oral gabapentin, pregabalin, and celecoxib on postoperative pain management in orthopedic surgery of the lower extremity: A double-blind randomized controlled trial. J Res Med Sci 2020;25:9
|How to cite this URL:|
Kheirabadi D, Safavi MR, Taghvaei M, Habibzadeh MR, Honarmand A. Comparing the prophylactic effects of oral gabapentin, pregabalin, and celecoxib on postoperative pain management in orthopedic surgery of the lower extremity: A double-blind randomized controlled trial. J Res Med Sci [serial online] 2020 [cited 2020 Oct 21];25:9. Available from: https://www.jmsjournal.net/text.asp?2020/25/1/9/276171
| Introduction|| |
Postoperative pain differs from other types of pain because it rises during a short time after operation but can be controlled more easily than chronic pain. Orthopedic surgeries cause excessive pain after a few days. Optimal postoperative pain control leads to faster recovery, reduction of complications, and patient satisfaction improvement.
Oral multimodal analgesia for hip and knee arthroplasty is increasingly used as a part of enhanced recovery protocols. It was designed for early postoperative pain relief and early discharge besides reducing undesirable side effects related to single-agent opioid administration. Acute pain management after orthopedic surgery can be challenging. Postorthopedic surgery pain has different pathophysiology versus the pain associated with other surgical procedures. This is happened due to various nerve damages during different surgeries. Hence, postoperative pain control is a significant issue that requires multiple approaches to be solved. Poor postoperative pain control can lead to complications such as delayed hospital discharge, long-term use of opioids, pulmonary edema and atelectasis, hypoxemia and cardiovascular diseases. Pain can also restrict patients' movement and result in more risk of thromboembolism and less gastrointestinal (GI) and genitourinary tract motility., Poor pain control in orthopedic surgeries prevents the patient to participate in rehabilitation schedules that contributes to prolonged recovery time, reduction of limb force, joint stiffness, joint pain, and more local pain. Chronic pain can destroy the quality of patients' life. Postsurgical pain management can bring mortality, admission time in hospital, and treatment costs down. Although opioids are commonly used for lessening postsurgical pain, their use is accompanied by some limitations. Previous findings have shown that multimodal analgesia (combination of different methods of pain control) both intra- and post-operative ones are more effective. Gabapentin and pregabalin have several pharmacological mechanisms including contrasting with L-amino acid transporters and prevention of Ca 2+ transmission through high-voltage gated channels, which cause less release of neurotransmitters and synaptic excitability., Reduction of Ca 2+ influx guides to fewer release of stimulating amino-acids and substance-p and results in neuronal suppression. Gabapentin, the analog of gamma-aminobutyric acid, is an antiepileptic drug which is used for pain control nowadays.
Previous studies showed that gabapentin controls limb's phantom pain effectively. Pregabalin attaches to its neuronal calcium channels and affects the neurotransmitter release. It is beneficial for controlling fibromyalgia, neural cord pain, and postsurgical pain and has a suitable pharmacokinetic profile with no dose-dependent absorption.
Studies on patients undergoing orthopedic surgery showed that pregabalin decreases pain score in these patients compared to placebo. Gabapentin and pregabalin were effective in neuropathic pain control like postsurgical pain.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly considered for postsurgical pain without having opioid-related side effects. NSAIDs are potential analgesics without making sedation that is commonly seen with opioids' consumption. NSAIDs have shown a reduction in morphine use by 27% during the first 24 h after operation.
Celecoxib inhibits cyclooxygenase, especially COX-2 and reduces the prostaglandins production. This drug has renal and cardiovascular complications. It is used for osteoarthritis and gout treatments and has analgesic effects after operation. Research showed that oral celecoxib reduced postsurgical pain as effective as 600 mg aspirin or 1000 mg paracetamol.
Due to lack of studies comparing different abovementioned modalities with respect to postorthopedic surgery pain of lower extremity, we compared the prophylactic effects of oral gabapentin, pregabalin, and celecoxib on postoperative pain reduction with placebo in these kinds of surgeries.
| Subjects and Methods|| |
This study was approved by the Isfahan University of Medical Sciences' Institutional Review Board, registered in the WHO clinical trial registration site (IRCT20180722040557N1) and received written informed consent from all individuals involved in the trial.
A double-blind randomized controlled trial was performed to compare the prophylactic effects of oral gabapentin, pregabalin, celecoxib, and placebo on controlling postorthopedic surgery pain of the lower extremity under spinal anesthesia in Al Zahra and Kashani Hospitals, Isfahan, Iran, from August 15, 2018, to October 9, 2018.
Inclusion criteria were candidates for elective lower limb orthopedic surgery, lack of contraindications for spinal anesthesia, increased intracranial pressure, coagulation disorders and restriction for sitting position, patient's consent to spinal anesthesia, age range of 16–78 years, absence of uncontrolled systemic diseases including hypertension, ischemic heart disease, heart failure, etc., and the American Society of Anesthesiologists (ASA) physical status classes I and II.
Exclusion criteria include patient's refusal to participation, failure of spinal anesthesia (more than twice), requirement to the different anesthetic method, and prolonged surgical time.
After receiving the ethic committee approval, 120 candidates for lower limb orthopedic surgery, who met the above inclusion criteria, were selected and received written consent. After that, they were assigned to four groups using block design randomization: numbers from 1 to 30 were allocated to the first group, numbers from 31 to 60 were put in the second group, numbers from 61 to 90 were allocated to the third group, and finally, numbers from 91 to 120 were assigned to the fourth group. Patients were blind to their medications intentionally to design a double-blind study. A person, who did not have any role in data collecting, put drugs into the same capsules with different codes. Starch was used as placebo. An anesthesiologist, who gave the drugs, was also blind to the capsules' content.
Two trained personnel collected all data separately to increase the accuracy of data collection. The data of 20 cases were excluded from the analysis due to the mismatch of pain severity reported to data collectors. Hence, the final analysis was done with a data pool of 100 cases [Figure 1].
One hour before spinal anesthesia induction, one of the following three medications was given to separate groups: 300 mg gabapentin (Abidi company, Iran) for the first group, 75 mg pregabalin (ACTOVERCO company, Iran) for the second group, and 200 mg celecoxib (Daroupakhsh company, Iran) for the third group. 2 g starch was used as placebo for the fourth group.
All of the patients in the operating room underwent a standard heart rate (HR), SPO2 saturation, and blood pressure monitoring. Before spinal anesthesia, all of the patients received 10–15 cc/kg isotonic saline and then spinal anesthesia was performed by a 23–25-gauge needle on L3–L4 and L4–L5 levels using the midline approach. Bevel of needle was inserted vertically in dura mater to minimize the transverse incision of dura. Once the needle touched the subarachnoid space, it was turned for 90° counterclockwise. Barbotage technique was used to confirm the needle's position in the subarachnoid space. We tried spinal anesthesia no more than twice for each patient so after two failings, the patient was excluded from our study. Bupivacaine 0.5% or marcaine (2.5–3 cc) was injected within 10 min for local anesthesia. After that, the patient's bed was set to prevent high spinal cord position and reduce the risk of saddle anesthesia. The pinprick test was applied to check the sensory block level and assure analgesia at the T10 level, which was suitable area for surgical incision. Patients underwent noninvasive blood pressure, electrocardiogram, and pulse oximetry monitoring in a standard way. Whenever the patient's blood pressure dropped >:30% from the basic level, intravenous (IV) ephedrine 5 mg was injected. For controlling bradycardia (HR < 50/min), IV atropine 0.5 mg and for nausea/vomiting reduction, IV ondansetron 4 mg were considered. Mean arterial pressure (MAP) and HR were recorded before anesthesia. Then, pain score using visual analog scale, MAP, HR, patient's opioid consuming dose (based on patient's requirement), and probable drug-induced side effects including chill, headache, nausea, vomiting, dizziness, and fever were documented six times. Two measurements were done in the recovery room (every 60 min for 2 h), and four measurements were done in the surgical ward (every 6 h up to 24 h).
The age, weight, gender, preanesthesia MAP and HR, anesthesia time, and ASA physical status were documented for each patient.
Collected data were analyzed using Chi-square test (for qualitative data), one-way analysis of variance (ANOVA), ANOVA-repeated measure, and post hoc tests using SPSS version 20 (SPSS Inc., Chicago, IL, USA). P < 0.05 was considered as significant for confidence interval of 95%.
| Results|| |
This study evaluated 120 patients fallen into four equal groups. Six patients in the placebo group, eight patients in the gabapentin group, four patients in the pregabalin group, and two patients in the celecoxib group were excluded due to data mismatching of collectors. Finally, the analysis was conducted with 100 patients.
There were no significant differences between groups regarding age, weight, gender, ASA class, preanesthesia MAP and HR, and mean anesthesia time [Table 1].
Significant differences concerning pain score were only observed at the first time measurement between pregabalin and placebo groups using post hoc tests (P = 0.014).
Significant differences between placebo group and others were not found at other times.
In addition, gabapentin, pregabalin, and celecoxib drugs did not make significant differences at all times regarding pain severity. Pregabalin group had significantly less opioid consumption during hospitalization in surgical ward than placebo one [Table 2].
|Table 2: Pain score and pethidine consumption dose shown for each group at different times|
Click here to view
Post hoc tests revealed that MAP for pregabalin group was significantly less than MAP for placebo one at time 1 (P = 0.04) and time 6 (P = 0.02). Moreover, MAP for celecoxib group was significantly less than control group at time 2 (P = 0.03).
There were not any significant differences between groups regarding HR by pair at all times [Table 3].
Placebo, gabapentin, pregabalin, and celecoxib groups had 19, 16, 15, and 15 cases who sustained probable side effects, respectively (79.1%, 72.7%, 57.7%, and 53.5%, respectively).
The most frequent side effects in placebo, gabapentin, pregabalin, and celecoxib groups defined as chill (29%), headache (31%), chill (19%), and vomiting (21%), respectively. Having mentioned that, though, there was no significant difference between these groups (P = 0.28).
Evaluations found that the highest mean for consuming dose of ephedrine was 13.33 ± 5.77 mg and related to placebo group. However, only one patient in the celecoxib group and one patient in pregabalin had needed ephedrine. Hence, no significant differences for ephedrine consumption were observed between groups (P = 0.66). Atropine was required only for two patients (in pregabalin and celecoxib groups) with no significant differences between groups (P = 0.5).
Pregabalin group had announced significantly higher levels of satisfaction compared to others [Table 4].
| Discussion|| |
Postoperative pain is a widespread and challenging complication in patients undergoing surgical procedures, especially orthopedic surgeries which can lead to long-term opioid use and diseases. Due to the wrenching and destructive effects of postoperative pain, many researchers have struggled through variety of methods to control it but there is no consensus on a standard method for postsurgical pain control.
We found that pregabalin group experienced significantly less pain severity at the recovery time compared to the control group, but other drugs (gabapentin and celecoxib) did not significantly reduce the pain during recovery time. Significant reduction in pain score was not found between four groups during patients' follow-up at surgical ward. Pregabalin group significantly needed least pethidine dose during admission in surgical ward while the placebo group required the most amount of it. Hence, pregabalin is highly recommended before orthopedic surgery of lower extremity.
Previous findings claimed that postoperative consumption of parecoxib sodium had opioid-sparing and pain reduction effects after total knee arthroplasty surgery. Another study on patients undergoing spinal surgery revealed that the preoperative administration of pregabalin significantly reduced pain scores and enhanced functional outcome compared to placebo. A systematic review, that evaluated oral celecoxib effects, realized that it had a significant effect on postsurgical pain reduction without any significant side effects. Another study in the same patients showed that COX-2 selective inhibitors decreased postoral surgery pain as same as traditional NSAIDs besides clinical advantages in relation to GI safety.
Analgesic studies has shown that oral celecoxib with equivalent dose to 600 mg aspirin or 1000 mg paracetamol can be effective in postoperative pain reduction. A study on patients undergoing spinal surgery showed that use of 400 mg oral celecoxib could significantly reduce postoperative pain.
Li et al. claimed supporting evidences for perioperative administration of oral pregabalin because of its postoperative pain relief effects in a safe way.
Pourfakhr et al. declared that consuming 75 mg oral pregabalin before anesthesia induction can effectively control pain after septorhinoplasty procedure with rare complications.
Amjad study on patients who underwent open cholecystectomy revealed that preoperative administration of 150 mg oral pregabalin had no more pain relief effects in comparison with 200 mg oral celecoxib while prevalence of side effects was more for pregabalin group.
A meta-analysis study assessed effects of pregabalin on attenuating postoperative pain following thoracotomy and it found that pregabalin can prevent postoperative pain and cause less neuropathic pain and opioid consumption.
Anand study evaluated analgesic effects of pregabalin after laparoscopic cholecystectomy and claimed that preoperative administration of 150 mg pregabalin orally can control postoperative pain noticeably and reduce opioid requirements as well as reduce nausea and vomiting besides higher satisfaction level of patients.
This study was performed with some limitations for instance groups' matching based on the type of surgery.
| Conclusion|| |
Taking 75 mg oral pregabalin before lower extremity orthopedic surgery can attenuate postoperative pain, especially during the 1st h postoperation as well as less opioid consumption, less MAP, no more side effects, and much more patients' satisfaction.
It is recommended to be administered before these surgical procedures. Concerning the restrictions of the current study and impact of multimodal analgesia regimen on frequency of short-term and long-term opioid use, more studies are required to be done.
We would like to thank the patients and authorities of Al-Zahra and Kashani University Hospitals, Isfahan, Iran, for their cooperation with this study. The ethic committee approval number of this study is 396335 received from Isfahan University of Medical Sciences' Institutional Review Board. We are sincerely thankful to Dr. Amir Mohammad Nourbakhsh for language editing.
Financial support and sponsorship
This study was supported by a research grant from the fluid research fund of the Vice-Chancellor for Research of Isfahan University of Medical Sciences.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Nasir M, Latif K, Ahmad MJ. Pre-emptive pain control: Comparison of ketorolac and diclofenac sodium. Prof Med J 2007;14:591-7.
Rose MA, Kam PC. Gabapentin: Pharmacology and its use in pain management. Anaesthesia 2002;57:451-62.
Kurd MF, Kreitz T, Schroeder G, Vaccaro AR. The role of multimodal analgesia in spine surgery. J Am Acad Orthop Surg 2017;25:260-8.
Golladay GJ, Balch KR, Dalury DF, Satpathy J, Jiranek WA. Oral multimodal analgesia for total joint arthroplasty. J Arthroplasty 2017;32:S69-73.
Khurana G, Jindal P, Sharma JP, Bansal KK. Postoperative pain and long-term functional outcome after administration of gabapentin and pregabalin in patients undergoing spinal surgery. Spine (Phila Pa 1976) 2014;39:E363-8.
Wu CL, Raja SN. Treatment of acute postoperative pain. Lancet 2011;377:2215-25.
Pflug AE, Murphy TM, Butler SH, Tucker GT. The effects of postoperative peridural analgesia on pulmonary therapy and pulmonary complications. Anesthesiology 1974;41:8-17.
Reuben SS, Sklar J. Pain management in patients who undergo outpatient arthroscopic surgery of the knee. J Bone Joint Surg Am 2000;82:1754-66.
Reuben SS, Buvanendran A. Preventing the development of chronic pain after orthopaedic surgery with preventive multimodal analgesic techniques. J Bone Joint Surg Am 2007;89:1343-58.
Marret E, Kurdi O, Zufferey P, Bonnet F. Effects of nonsteroidal antiinflammatory drugs on patient-controlled analgesia morphine side effects: Meta-analysis of randomized controlled trials. Anesthesiology 2005;102:1249-60.
Kehlet H, Wilmore DW. Multimodal strategies to improve surgical outcome. Am J Surg 2002;183:630-41.
Fink K, Meder W, Dooley DJ, Göthert M. Inhibition of neuronal Ca (2+) influx by gabapentin and subsequent reduction of neurotransmitter release from rat neocortical slices. Br J Pharmacol 2000;130:900-6.
Oka M, Itoh Y, Wada M, Yamamoto A, Fujita T. Gabapentin blocks L-type and P/Q-type ca2+ channels involved in depolarization-stimulated nitric oxide synthase activity in primary cultures of neurons from mouse cerebral cortex. Pharm Res 2003;20:897-9.
Gilron I. Gabapentin and pregabalin for chronic neuropathic and early postsurgical pain: Current evidence and future directions. Curr Opin Anaesthesiol 2007;20:456-72.
Myrick H, Anton R, Voronin K, Wang W, Henderson S. A double-blind evaluation of gabapentin on alcohol effects and drinking in a clinical laboratory paradigm. Alcohol Clin Exp Res 2007;31:221-7.
Tiippana EM, Hamunen K, Kontinen VK, Kalso E. Do surgical patients benefit from perioperative gabapentin/pregabalin? A systematic review of efficacy and safety. Anesth Analg 2007;104:1545-56, table of contents.
Luo ZD, Calcutt NA, Higuera ES, Valder CR, Song YH, Svensson CI, et al
. Injury type-specific calcium channel alpha 2 delta-1 subunit up-regulation in rat neuropathic pain models correlates with antiallodynic effects of gabapentin. J Pharmacol Exp Ther 2002;303:1199-205.
Hubbard RC, Naumann TM, Traylor L, Dhadda S. Parecoxib sodium has opioid-sparing effects in patients undergoing total knee arthroplasty under spinal anaesthesia. Br J Anaesth 2003;90:166-72.
Chen LC, Elliott RA, Ashcroft DM. Systematic review of the analgesic efficacy and tolerability of COX-2 inhibitors in post-operative pain control. J Clin Pharm Ther 2004;29:215-29.
McQuay HJ, Moore RA. Dose-response in direct comparisons of different doses of aspirin, ibuprofen and paracetamol (acetaminophen) in analgesic studies. Br J Clin Pharmacol 2007;63:271-8.
Derry S, Moore RA. Single dose oral celecoxib for acute postoperative pain in adults. Cochrane Database Syst Rev 2013;10:CD004233.
Cicconetti A, Bartoli A, Ripari F, Ripari A. COX-2 selective inhibitors: A literature review of analgesic efficacy and safety in oral-maxillofacial surgery. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;97:139-46.
Huang YM, Wang CM, Wang CT, Lin WP, Horng LC, Jiang CC. Perioperative celecoxib administration for pain management after total knee arthroplasty a randomized, controlled study. BMC Musculoskelet Disord 2008;9:77.
Li S, Zhang W, Cheng S, Li Y. Does pregabalin effectively and safely relieve postoperative pain in patients undergoing pulmonary resections?. Interactive cardiovascular and thoracic surgery. 2019 Jun 10.
Pourfakhr P, Khajavi MR, Jalali A, Memari F, Etezadi F, Roochi MM, et al
. Low-dose preoperative pregabalin improves postoperative pain management in septorhinoplasty surgery: A double-blind randomized clinical trial. Eur Arch Otorhinolaryngol 2019;276:2243-9.
Ali A, Babar KM. Comparison of preoperative dose of pregabalin with celecoxib for attenuation of postoperative pain after open cholecystectomy. Anaesth Pain Intensive Care 2019;3:137-41.
Yu Y, Liu N, Zeng Q, Duan J, Bao Q, Lei M, et al
. The efficacy of pregabalin for the management of acute and chronic postoperative pain in thoracotomy: A meta-analysis with trial sequential analysis of randomized-controlled trials. J Pain Res 2019;12:159-70.
Anand LK, Sandhu M, Singh J, Mitra S. Evaluation of analgesic efficacy of pregabalin for postoperative pain relief after laparoscopic cholecystectomy: A double blind study. Anaesthe Pain Intensive Care 2019;19:174-080.
[Table 1], [Table 2], [Table 3], [Table 4]