Perioperative gabapentinoid use lowers short-term opioid consumption following lower limb arthroplasty: Systematic review and meta-analysis

Ryan Campbell, MD; Jacqueline Nguyen Khuong, MD; Zhengyang Liu, BBiomed; Carla Borg, MD; Sarah Jackson, BBiomed; Dhruvesh M. Ramson, MBBS (Hons); Juliana Kok, MD; Ned Douglas, MD; Jahan C. Penny-Dimri, MBBS (Hons); Luke A. Perry, MBBS (Hons)

doi:10.5055/jom.2021.0635

Authors

Ryan Campbell, MD
Jacqueline Nguyen Khuong, MD
Zhengyang Liu, BBiomed
Carla Borg, MD
Sarah Jackson, BBiomed
Dhruvesh M. Ramson, MBBS (Hons)
Juliana Kok, MD
Ned Douglas, MD
Jahan C. Penny-Dimri, MBBS (Hons)
Luke A. Perry, MBBS (Hons)

DOI:

https://doi.org/10.5055/jom.2021.0635

Keywords:

total knee arthroplasty, total hip arthroplasty, gabapentin, pregabalin, perioperative medicine, analgesia

Abstract

Background: The management of post-operative pain and high levels of acute and chronic opioid use following total knee arthroplasty (TKA) and total hip arthroplasty (THA) remain challenges to the perioperative team. We performed a systematic review and meta-analysis to determine the opioid sparing effects, analgesic effects, and safety profile of perioperative gabapentinoid usage in lower limb arthroplasty.

Methods: We searched multiple databases from inception until May 2019 and included randomized controlled trials (RCT) on perioperative gabapentinoids in lower limb arthroplasty. The primary outcome was cumulative opioid consumption (oral morphine equivalents) at 24 and 48 hours, and the secondary outcomes were pain scores, time to hospital discharge, and adverse events including nausea, vomiting, pruritus, and sedation. Methodological quality was assessed using the Cochrane tool. The grading of recommendations assessment, development, and evaluation methodology for the certainty of evidence was also used.

Results: We included 19 RCT involving 2,455 patients undergoing lower limb arthroplasty. The overall methodological quality of included studies was good. Gabapentinoid use was associated with a significant reduction in opioid consumption at 24 hour (mean difference (MD) 22.81 mg [95 percent Confidence Interval (CI) 13.64-31.98]) and 48 hour (MD 44.03 mg [95 percent CI 16.92-71.14]). We found no meaningful difference in pain scores at rest between gabapentinoid and placebo groups at 24 or 48 hours. Gabapentinoid use reduced the risk of postoperative nausea (risk ratio (RR) 0.69 [95 percent CI 0.57-0.82]), vomiting (RR 0.65 [95 percent CI 0.47-0.91]), and pruritus (RR 0.60 [0.37-0.98]), but not sedation (RR 1.25 [0.76-2.06]). There was no effect on time to discharge from hospital (MD—0.05 days [95 percent CI −0.31 to 0.20].

Conclusions: The addition of gabapentinoids to perioperative multimodal analgesia decreases opioid consumption following lower limb arthroplasty, while also lowering rates of nausea, vomiting, and pruritus. Further study is required to evaluate the effect of gabapentinoid use on long-term opioid use and dependence.

Author Biographies

Ryan Campbell, MD

Department of Medicine, University of New South Wales, South Wales, Australia

Jacqueline Nguyen Khuong, MD

Department of Anaesthesia, Royal Melbourne Hospital, Parkville, Australia; Melbourne Medical School, University of Melbourne, Parkville Australia

Zhengyang Liu, BBiomed

Department of Anaesthesia, Royal Melbourne Hospital, Parkville, Australia; Melbourne Medical School, University of Melbourne, Parkville Australia

Carla Borg, MD

Department of Medicine, Monash University, Australia

Sarah Jackson, BBiomed

Department of Anaesthesia, Royal Melbourne Hospital, Parkville, Australia; Melbourne Medical School, University of Melbourne, Parkville Australia

Dhruvesh M. Ramson, MBBS (Hons)

Department of Surgery, Monash University, Clayton Australia

Juliana Kok, MD

Department of Anaesthesia, Royal Melbourne Hospital, Parkville, Australia

Ned Douglas, MD

Department of Anaesthesia, Royal Melbourne Hospital, Parkville, Australia

Jahan C. Penny-Dimri, MBBS (Hons)

Department of Surgery, Monash University, Clayton Australia

Luke A. Perry, MBBS (Hons)

Department of Anaesthesia, Royal Melbourne Hospital, Parkville, Australia

References

Bashinskaya B, Zimmerman RM, Walcott BP, et al.: Arthroplasty utilization in the United States is predicted by age-specific population groups. ISRN Orthop. 2012; 2012.

Pang WW, Hsu TC, Tung CC, et al.: Is total knee replacement more painful than total hip replacement? Acta Anaesthesiol Sin. 2000; 38(3): 143-148.

Allen HW, Liu SS, Ware PD, et al.: Peripheral nerve blocks improve analgesia after total knee replacement surgery. Anesth Analg. 1998; 87(1): 93-97.

Gaffney CJ, Pelt CE, Gililland JM, et al.: Perioperative pain management in hip and knee arthroplasty. Orthop Clin North Am. 2017; 48(4): 407-419.

Pepper AM, Mercuri JJ, Behery OA, et al.: Total hip and knee arthroplasty perioperative pain management: What should be in the cocktail. JBJS Rev. 2018; 6(12): e5.

Chincholkar M: Analgesic mechanisms of gabapentinoids and effects in experimental pain models: A narrative review. Br J Anaesth. 2018; 120(6): 1315-1334.

Hamilton TW, Strickland LH, Pandit HG: A meta-analysis on the use of gabapentinoids for the treatment of acute post-operative pain following total knee arthroplasty. J Bone Jt Surg Am Vol. 2016; 98(16): 1340-1350.

Mishra R, Tripathi M, Chandola HC: Comparative clinical study of gabapentin and pregabalin for post-operative analgesia in laparoscopic cholecystectomy. Anesth Essays Res. 2016; 10(2): 201-206.

Qadeer M, Waqas M, Rashid MJ, et al.: Preventive gabapentin versus pregabalin to decrease post-operative pain after lumbar microdiscectomy: A randomized controlled trial. Asian Spine J. 2017; 11(1): 93-98.

Robertson K, Marshman LAG, Plummer D, et al.: Effect of gabapentin vs pregabalin on pain intensity in adults with chronic sciatica: A randomized clinical trial. JAMA Neurol. 2019; 76(1): 28-34.

Schmidt PC, Ruchelli G, Mackey SC, et al.: Perioperative gabapentinoids: Choice of agent, dose, timing, and effects on chronic postsurgical pain. Anesthesiol: J Am Soc Anesthesiol. 2013; 119(5): 1215-1221.

Buvanendran A, Kroin JS, Della Valle CJ, et al.: Perioperative oral pregabalin reduces chronic pain after total knee arthroplasty: A prospective, randomized, controlled trial. Anesth Analg. 2010; 110(1): 199-207.

Clarke H, Page GM, McCartney CJ, et al.: Pregabalin reduces post-operative opioid consumption and pain for 1 week after hospital discharge, but does not affect function at 6 weeks or 3 months after total hip arthroplasty. Br J Anaesth. 2015; 115(6): 903-911.

Clarke H, Pereira S, Kennedy D, et al.: Adding gabapentin to a multimodal regimen does not reduce acute pain, opioid consumption or chronic pain after total hip arthroplasty. Acta Anaesthesiol Scand. 2009; 53(8): 1073-1083.

Clarke H, Pereira S, Kennedy D, et al.: Gabapentin decreases morphine consumption and improves functional recovery following total knee arthroplasty. Pain Res Manag. 2009; 14(3): 217-222.

Clarke HA, Katz J, McCartney CJ, et al.: Perioperative gabapentin reduces 24 h opioid consumption and improves in-hospital rehabilitation but not post-discharge outcomes after total knee arthroplasty with peripheral nerve block. Br J Anaesth. 2014; 113(5): 855-864.

Jain P, Jolly A, Bholla V, et al.: Evaluation of efficacy of oral pregabalin in reducing post-operative pain in patients undergoing total knee arthroplasty. Indian J Orthop. 2012; 46(6): 646-652.

Lee C, Lee J, Lee G, et al.: Pregabalin and dexmedetomidine combined for pain after total knee arthroplasty or total hip arthroplasty performed under spinal anesthesia. Orthopedics. 2018; 41(6): 365-370.

Lee JK, Chung KS, Choi CH: The effect of a single dose of preemptive pregabalin administered with COX-2 inhibitor: A trial in total knee arthroplasty. J Arthroplasty. 2015; 30(1): 38-42.

Leung JM, Sands LP, Chen N, et al.: Perioperative gabapentin does not reduce post-operative delirium in older surgical patients: A randomized clinical trial. Anesthesiology. 2017; 127(4): 633-644.

Lunn TH, Husted H, Laursen MB, et al.: Analgesic and sedative effects of perioperative gabapentin in total knee arthroplasty: A randomized, double-blind, placebo-controlled dosefinding study. Pain. 2015; 156(12): 2438-2448.

Martinez V, Cymerman A, Ben Ammar S, et al.: The analgesic efficiency of combined pregabalin and ketamine for total hip arthroplasty: A randomised, double-blind, controlled study. Anaesthesia. 2014; 69(1): 46-52.

Mathiesen O, Jacobsen LS, Holm HE, et al.: Pregabalin and dexamethasone for post-operative pain control: A randomized controlled study in hip arthroplasty. Br J Anaesth. 2008; 101(4): 535-541.

Paul JE, Nantha-Aree M, Buckley N, et al.: Gabapentin does not improve multimodal analgesia outcomes for total knee arthroplasty: A randomized controlled trial. Can J Anaesth. 2013; 60(5): 423-431.

Paul JE, Nantha-Aree M, Buckley N, et al.: Randomized controlled trial of gabapentin as an adjunct to perioperative analgesia in total hip arthroplasty patients. Can J Anaesth. 2015; 62(5): 476-484.

Rasmussen ML, Mathiesen O, Dierking G, et al.: Multimodal analgesia with gabapentin, ketamine and dexamethasone in combination with paracetamol and ketorolac after hip arthroplasty: a preliminary study. Eur J Anaesthesiol. 2010; 27(4): 324-330.

Niruthisard AE, Bunburaphong P, Chinda P, et al.: Preoperative pregabalin and/or celecoxib for pain management after total knee arthroplasty under intrathecal morphine: A randomized controlled trial. Asian Biomed. 2013; 7: 579-585.

Singla NK, Chelly JE, Lionberger DR, et al.: Pregabalin for the treatment of post-operative pain: Results from three controlled trials using different surgical models. J Pain Res. 2015; 8: 9-20.

YaDeau JT, Lin Y, Mayman DJ, et al.: Pregabalin and pain after total knee arthroplasty: A double-blind, randomized, placebo-controlled, multidose trial. Br J Anaesth. 2015; 115(2): 285-293.

Yik JH, Tham WYW, Tay KH, et al.: Perioperative pregabalin does not reduce opioid requirements in total knee arthroplasty. Knee Surg Sports Traumatol Arthrosc. 2019; 27(7): 2104-2110.

Higgins JP, Altman DG, Gotzsche PC, et al.: The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011; 343: d5928.

Medicine AaNZCoA-FoP: Opioid dose equivalence. 2019. Available at https://fpm.anzca.edu.au/documents/opioid-doseequivalence.pdf. Accessed December 18, 2020.

Viechtbauer W: Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010; 36(3): 1-48.

Lam DM, Choi SW, Wong SS, et al.: Efficacy of pregabalin in acute post-operative pain under different surgical categories: A meta-analysis. Medicine (Baltimore). 2015; 94(46): e1944.

Dong J, Li W, Wang Y: The effect of pregabalin on acute post-operative pain in patients undergoing total knee arthroplasty: A meta-analysis. Int J Surg. 2016; 34: 148-160.

Han C, Kuang MJ, Ma JX, et al.: Is pregabalin effective and safe in total knee arthroplasty? A PRISMA-compliant meta-analysis of randomized-controlled trials. Medicine (Baltimore). 2017; 96(26): e6947.

Han C, Li XD, Jiang HQ, et al.: The use of gabapentin in the management of post-operative pain after total hip arthroplasty: a meta-analysis of randomised controlled trials. J Orthop Surg Res. 2016; 11(1): 79.

Li F, Ma J, Kuang M, et al.: The efficacy of pregabalin for the management of post-operative pain in primary total knee and hip arthroplasty: A meta-analysis. J Orthop Surg Res. 2017; 12(1): 49.

Mao Y, Wu L, Ding W: The efficacy of preoperative administration of gabapentin/pregabalin in improving pain after total hip arthroplasty: A meta-analysis. BMC Musculoskeletal Disorders. 2016; 17(1): 373.

Verret M, Lauzier F, Zarychanski R, et al.: Perioperative use of gabapentinoids for the management of post-operative acute pain: A systematic review and meta-analysis. Anesthesiology. 2020; 133(2): 265-279.

Kjaer Petersen K, Lunn TH, Husted H, et al.: The influence of pre- and perioperative administration of gabapentin on pain 3-4 years after total knee arthroplasty. Scand J Pain. 2018; 18(2): 237-245.

Liu B, Liu R, Wang L: A meta-analysis of the preoperative use of gabapentinoids for the treatment of acute post-operative pain following spinal surgery. Medicine (Baltimore). 2017; 96(37): e8031.

Grant MC, Lee H, Page AJ, et al.: The effect of preoperative gabapentin on post-operative nausea and vomiting: A metaanalysis. Anesth Analg. 2016; 122(4): 976-985.

Guttuso T, Jr.: Gabapentin's anti-nausea and anti-emetic effects: A review. Exp Brain Res. 2014; 232(8): 2535-2539.

Administration USFaD: FDA in Brief: FDA requires new warnings for gabapentinoids about risk of respiratory depression. 2019. Available at https://www.fda.gov/news-events/fdabrief/fda-brief-fda-requires-new-warnings-gabapentinoidsabout-risk-respiratory-depression. Accessed December 18, 2020.

Myhre M, Diep LM, Stubhaug A: Pregabalin has analgesic, ventilatory, and cognitive effects in combination with remifentanil. Anesthesiology. 2016; 124(1): 141-149.

Piovezan RD, Kase C, Moizinho R, et al.: Gabapentin acutely increases the apnea-hypopnea index in older men: Data from a randomized, double-blind, placebo-controlled study. J Sleep Res. 2017; 26(2): 166-170.

Weingarten TN, Jacob AK, Njathi CW, et al.: Multimodal analgesic protocol and postanesthesia respiratory depression during phase i recovery after total joint arthroplasty. Reg Anesth Pain Med. 2015; 40(4): 330-336.

Cavalcante AN, Sprung J, Schroeder DR, et al.: Multimodal analgesic therapy with gabapentin and its association with postoperative respiratory depression. Anesth Analg. 2017; 125(1): 141-146.

Savelloni J, Gunter H, Lee KC, et al.: Risk of respiratory depression with opioids and concomitant gabapentinoids. J Pain Res. 2017; 10: 2635-2641.

Deljou A, Hedrick SJ, Portner ER, et al.: Pattern of perioperative gabapentinoid use and risk for post-operative naloxone administration. Br J Anaesth. 2018; 120(4): 798-806.

Ohnuma T, Krishnamoorthy V, Ellis AR, et al.: Association 'between gabapentinoids on the day of colorectal surgery and adverse post-operative respiratory outcomes. Ann Surg. 2019; 270(6): e65-e67.

van Haagen MHM, Verburg H, Hesseling B, et al.: Optimizing the dose of local infiltration analgesia and gabapentin for total knee arthroplasty, a randomized single blind trial in 128 patients. Knee. 2018; 25(1): 153-160.