Large Doses of Methylprednisolone Combined With Gabapentin in Total Knee Arthroplasty

The Impact of Pre-emptive Large Doses of Methylprednisolone Combined With Gabapentin on Pain Treatment and Convalescence After Total Knee Arthroplasty in Elderly: A Double-blind Randomized Study

The aim of the study was to assess whether administration of gabapentin and methylprednisolone as "pre-emptive analgesia" in a group of patients above 65 years of age would be effective in complex pain management therapy following total knee arthroplasty (TKA). For the study investigators will qualify one hundred seventy, above 65 years old patients. The participants will be double-blind randomized into two groups: the study and controls The study group will receive as "pre-emptive" analgesia a single dose of 300 mg oral gabapentin and 125 mg intravenous methylprednisolone, while the others placebo. Perioperatively, all the patients will receive opioid and nonopioid analgesic agents calculated for 1 kg of body weight. Investigators will measure the levels of inflammatory markers (leukocytosis, C-reactive protein - CRP), pain intensity level at rest (numerical rating scale - NRS), the life parameters and all complications.

Study Overview

• Status: Completed
• Conditions: Pain, Postoperative; Knee Osteoarthritis; Arthroplasty Complications; Perioperative Complication
• Intervention / Treatment: Drug: Gabapentin 300mg; Drug: Methylprednisolone 125 mg; Drug: Tablet; Drug: Normal Saline 10 mL Injection

Detailed Description

The aim of the study was to assess whether administration of gabapentin and methylprednisolone as "pre-emptive analgesia" in a group of patients above 65 years of age would be effective in complex pain management therapy following total knee arthroplasty (TKA).170 patients operated on due to unilateral TKA will be double-blinded randomized into two groups: the study and the controls. Exclusion criteria are: clinical situation that 1/ restricted glucocorticoid administration: diabetes type 1 and 2, CRP levels above normal values (≥5 mg/l), chronic steroid treatment, peptic ulcers treated in the past 30 days and 2/and the chronic pain in the course of gonarthrosis, high intensity requiring use opioids.

The participants of the study will be subjected to the standardized procedure of subarachnoid anesthesia with subsequent unilateral femoral nerve block at the operated side, followed by the surgical procedure - unilateral TKA. The study group will receive as "pre-emptive" analgesia a single dose of 300 mg oral gabapentin and 125 mg intravenous methylprednisolone, while the others placebo. Prior to anesthesia induction, the patients receive: anti-infection prophylactics intravenous cephazolin 2.0 g, for hemostasis control - tranexamic acid 1.0 g, an anti-emetic agent - ondansetron 8 mg. Fluid supply (crystalloids) will be standardized: 12 ml/kg in the first hour of surgery and 6 ml/kg in the following hours, packed red blood cells if blood loss exceeded 600 ml and hemoglobin concentration <10g/l during the time of operation. Pain management will be carried out based on the results of the NRS scales at rest. Every 6 hours NRS will be checked and intravenous PCA (patient-controlled analgesia) oxycodone hydrochloride, if pain was ≥4 points NRS or intravenous paracetamol, metamizole, if the pain was 2 - 4 NRS points will be administered, all pain medications will be calculated for 1 kg of body weight. In keeping with the ERAS (Enhanced Recovery After Surgery) protocol, on the day of surgery the patients will receive orally fluids and meals, will be mobilized and rehabilitated.

The study was approved by the institutional review board (nr 1072.6120.11.2020). Oral and written informed consent to participate in the study will be collected from all participants of the study. The statistical analysis of the groups will be performed to asess the demographic dates, life parameters, general condition in keeping with the ASA (American Society of Anesthesiology), POSSUM (Physiologic and Operative Severity Score for the enUmeration of Mortality and Morbidity) score, total dose of analgesic medications administered parenterally calculated for 1 kg of body mass in response to value of NRS at rest on day 0, time of administration the first dose, and duration of peripheral nerve block. On the day of surgery and on subsequent days, determinations will be made of glycemia levels and inflammatory markers: C-reactive protein (CRP) and leukocytosis levels.

• Study Type: Interventional
• Enrollment (Actual): 160
• Phase: Phase 4

Contacts and Locations

Study Locations

• Poland
  • Malopolska
    • Krakow, Malopolska, Poland, 30688
      • University Hospital in Krakow

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• patients over 65 years old operated on unilateral total knee arthroplasty

Exclusion Criteria:

• diabetes type 1 and 2,
• CRP levels above normal values (≥5 mg/l),
• chronic steroid treatment,
• peptic ulcers treated in the past 30 days,
• chronic pain in the course of gonarthrosis,

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Study Group; The study group will receive as "pre-emptive" analgesia a single dose of 300 mg oral gabapentin and 125 mg intravenous methylprednisolone.	Drug: Gabapentin 300mg; The study group will receive as "pre-emptive" analgesia a single dose of 300 mg oral gabapentin and 125 mg intravenous methylprednisolone.; Drug: Methylprednisolone 125 mg; The study group will receive as "pre-emptive" analgesia a single dose of 300 mg oral gabapentin and 125 mg intravenous methylprednisolone.
Placebo Comparator: Controls group; The controls group will receive placebo orally - a tablet without any pharmacological properties, intravenously - saline solution.	Drug: Tablet; The controls group will receive placebo orally - a tablet without any pharmacological properties, intravenously - normal saline solution; Drug: Normal Saline 10 mL Injection; The controls group will receive placebo orally - a tablet without any pharmacological properties, intravenously - normal saline solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain intensity assessed by NRS	The level of postoperative pain measured in the numerical rating scale (NRS) at rest (minimum 0 - no pain, maximum 10 - the maximum of pain).	change in every 6 hours on day 0
the dose of parenteral analgesics agents	Dose of oxycodone hydrochloride in mg/kg body weight, paracetamol in mg/kg body weight, metamizole in g/kg body weight	24 hours
C-reactive protein (CRP) level	C-reactive protein (CRP) level measured in mg/l	change in 0,1,2,3 days after surgery
Leukocytosis level	Leukocytosis level measured in µL	change in 0,1,2,3 days after surgery
Adverse effects	The occurrence of adverse effects that would delay early rehabilitation, possible complication development, perioperative mortality to the POSSUM scale, comorbidities	0 day after surgery
Adverse effects	The occurrence of adverse effects that would delay early rehabilitation, possible complication development, perioperative mortality to the POSSUM scale, comorbidities	1 day after surgery
Adverse effects	The occurrence of adverse effects that would delay early rehabilitation, possible complication development, perioperative mortality to the POSSUM scale, comorbidities	2 day after surgery
Adverse effects	The occurrence of adverse effects that would delay early rehabilitation, possible complication development, perioperative mortality to the POSSUM scale, comorbidities	3 day after surgery
Adverse effects	The occurrence of adverse effects that would delay early rehabilitation, possible complication development, perioperative mortality to the POSSUM scale, comorbidities	14 day after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of femoral nerve blockade	The time of femoral nerve block	on the day of surgery
Blood glucose level	The level of glucose in blood in mmol/l	change in 0,1,2,3 days after surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean age	Mean age in years	the day of surgery
Mean hospitalization time	Mean hospitalization time in days	from admission to hospital till 14 days after surgery
Mean postoperative hospitalization time	Mean postoperative hospitalization time in days	change from 0 till 14 days after surgery
Postoperative Mean Arterial Pressure (MAP)	Postoperative Mean Arterial Pressure (MAP) measured in mmHg	change in 0,1,2,3 days after surgery
Postoperative pulse	Postoperative pulse (x/min)) measured in x/min	change in 0,1,2,3 days after surgery
Postoperative saturation (Sp02) of the arterial blood	Postoperative saturation (Sp02) of the arterial blood measured in %	change in 0,1,2,3 days after surgery
Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) morbidity	Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) morbidity measured in %	the day of the surgery
Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) mortality	Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) mortality measured in %	the day of the surgery
Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) physiological score	Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) physiological score measured in points (minimum 12, maximum 96)	the day of the surgery
American Society of Anesthesiology Score (ASA)	American Society of Anesthesiology Score (ASA), grade I-IV	the day of the surgery

Collaborators and Investigators

• Sponsor: Jagiellonian University

Publications and helpful links

General Publications

• Lamplot JD, Wagner ER, Manning DW. Multimodal pain management in total knee arthroplasty: a prospective randomized controlled trial. J Arthroplasty. 2014 Feb;29(2):329-34. doi: 10.1016/j.arth.2013.06.005. Epub 2013 Jul 11.
• Gerbershagen HJ, Aduckathil S, van Wijck AJ, Peelen LM, Kalkman CJ, Meissner W. Pain intensity on the first day after surgery: a prospective cohort study comparing 179 surgical procedures. Anesthesiology. 2013 Apr;118(4):934-44. doi: 10.1097/ALN.0b013e31828866b3.
• Kehlet H, Lindberg-Larsen V. High-dose glucocorticoid before hip and knee arthroplasty: To use or not to use-that's the question. Acta Orthop. 2018 Oct;89(5):477-479. doi: 10.1080/17453674.2018.1475177. Epub 2018 May 21. No abstract available.
• Luna IE, Kehlet H, Petersen MA, Aasvang EK. Clinical, nociceptive and psychological profiling to predict acute pain after total knee arthroplasty. Acta Anaesthesiol Scand. 2017 Jul;61(6):676-687. doi: 10.1111/aas.12899. Epub 2017 May 16.
• Jorgensen CC, Pitter FT, Kehlet H; Lundbeck Foundation Center for Fast-track Hip and Knee Replacement Collaborative Group. Safety aspects of preoperative high-dose glucocorticoid in primary total knee replacement. Br J Anaesth. 2017 Aug 1;119(2):267-275. doi: 10.1093/bja/aex190.
• Hartman J, Khanna V, Habib A, Farrokhyar F, Memon M, Adili A. Perioperative systemic glucocorticoids in total hip and knee arthroplasty: A systematic review of outcomes. J Orthop. 2017 Apr 12;14(2):294-301. doi: 10.1016/j.jor.2017.03.012. eCollection 2017 Jun.
• Lindberg-Larsen V, Ostrowski SR, Lindberg-Larsen M, Rovsing ML, Johansson PI, Kehlet H. The effect of pre-operative methylprednisolone on early endothelial damage after total knee arthroplasty: a randomised, double-blind, placebo-controlled trial. Anaesthesia. 2017 Oct;72(10):1217-1224. doi: 10.1111/anae.13983. Epub 2017 Jul 26.
• Gadek A, Liszka H, Zajac M. The effect of pre-operative high doses of methylprednisolone on pain management and convalescence after total hip replacement in elderly: a double-blind randomized study. Int Orthop. 2021 Apr;45(4):857-863. doi: 10.1007/s00264-020-04802-8. Epub 2020 Sep 17.
• 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 Jan;30(1):38-42. doi: 10.1016/j.arth.2014.04.004. Epub 2014 Apr 13.
• Lubis AMT, Rawung RBV, Tantri AR. Preemptive Analgesia in Total Knee Arthroplasty: Comparing the Effects of Single Dose Combining Celecoxib with Pregabalin and Repetition Dose Combining Celecoxib with Pregabalin: Double-Blind Controlled Clinical Trial. Pain Res Treat. 2018 Aug 7;2018:3807217. doi: 10.1155/2018/3807217. eCollection 2018.
• Osinski T, Bekka S, Regnaux JP, Fletcher D, Martinez V. Functional recovery after knee arthroplasty with regional analgesia: A systematic review and meta-analysis of randomised controlled trials. Eur J Anaesthesiol. 2019 Jun;36(6):418-426. doi: 10.1097/EJA.0000000000000983.
• Berg U, BuLow E, Sundberg M, Rolfson O. No increase in readmissions or adverse events after implementation of fast-track program in total hip and knee replacement at 8 Swedish hospitals: An observational before-and-after study of 14,148 total joint replacements 2011-2015. Acta Orthop. 2018 Oct;89(5):522-527. doi: 10.1080/17453674.2018.1492507. Epub 2018 Jul 9.
• Pamilo KJ, Torkki P, Peltola M, Pesola M, Remes V, Paloneva J. Fast-tracking for total knee replacement reduces use of institutional care without compromising quality. Acta Orthop. 2018 Apr;89(2):184-189. doi: 10.1080/17453674.2017.1399643. Epub 2017 Nov 21.
• Shen S, Gao Z, Liu J. The efficacy and safety of methylprednisolone for pain control after total knee arthroplasty: A meta-analysis of randomized controlled trials. Int J Surg. 2018 Sep;57:91-100. doi: 10.1016/j.ijsu.2018.07.009. Epub 2018 Aug 16.
• Lei Y, Xie J, Xu B, Xie X, Huang Q, Pei F. The efficacy and safety of multiple-dose intravenous tranexamic acid on blood loss following total knee arthroplasty: a randomized controlled trial. Int Orthop. 2017 Oct;41(10):2053-2059. doi: 10.1007/s00264-017-3519-x. Epub 2017 May 31.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2019
• Primary Completion (Actual): January 1, 2020
• Study Completion (Actual): May 1, 2020

Study Registration Dates

• First Submitted: November 21, 2020
• First Submitted That Met QC Criteria: November 28, 2020
• First Posted (Actual): December 4, 2020

Study Record Updates

• Last Update Posted (Actual): December 4, 2020
• Last Update Submitted That Met QC Criteria: November 28, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: total knee arthroplasty; methylprednisolone; pain intensity; gabapentin; pre-emptive analgesia; opioid dose; infection rate
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Pain, Postoperative; Osteoarthritis, Knee; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Tranquilizing Agents; Psychotropic Drugs; Anti-Anxiety Agents; Anticonvulsants; Antimanic Agents; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Gabapentin
• Other Study ID Numbers: 1072.6120.11.2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No