Safety and Efficacy of Pre-emptive Tapentadol vs Pregabalin in Post Operative Pain Following Surgery

Safety and Efficacy of Pre-emptive Tapentadol vs Pregabalin in Post Operative Pain Following Unilateral Total Knee Arthroplasty- A Randomised, Double Blind, Active Control, Clinical Trial

Preemptive analgesia is a treatment modality which starts even before the surgery, so that the central sensitization is prevented due to incisional injury at the time of surgery, so it covers the period of surgery and initial post-operative period preventing the development of central sensitization.

Gabapentinoid compounds are gabapentin and pregabalin which have been extensively used in seizure disorder patient. Role of gabapentinoid compounds in the management of pain, as a pre-emptive analgesia is yet to be completely evaluated in post operative pain. Opioids have always been the preferred drugs to manage post operative pain. Since opioids have major side effects of nausea vomiting associated with its treatment their use comes with management of these side effects.

Currently, diagnostic and therapeutic approaches to manage pain experienced by individuals are limited especially because there's a lack of bio-markers predictive of therapeutic outcome. In search of an objective method for pain measurement, as pain has always been subjective and it is perceived by different people differently the study will also include finding the use of COX(cyclo-oxygenase)-2 as a bio-marker of pain in post-operative patients.

Although several randomized clinical trials and met-analyses have been conducted comparing the safety and efficacy of tapentadol or pregabalin in post-operative pain, there is no head to head clinical trial conducted comparing the preemptive use of two drugs for postoperative pain following total knee arthroplasty (TKA). Hence the present study is planned.

Study Overview

• Status: Completed
• Conditions: Osteoarthritis, Knee
• Intervention / Treatment: Drug: Pregabalin 150mg; Drug: Tapentadol 100 MG Oral Tablet

Detailed Description

MATERIALS AND METHODS

After approval of the institutional Ethics committee board, written informed consent will be taken from all the eligible and willing patients.

A. Study design: Randomized double blind active controlled parallel group noninferiority clinical trial.

B. Randomization: A variable block randomization. The allocation ratio will be 1:1 ratio between two interventions arms i.e. tapentadol 100 mg(milligram) and pregabalin 150 mg(milligram) orally.

C. Allocation concealment: This study will be participant and investigator blinded. Allocation concealment will be done by sequentially numbered sealed drug pouches.

D. Study site: Department of Pharmacology and Orthopedics of AIIMS, Bhubaneswar.

Selection Criteria

A. Inclusion criteria

1. Patients both males and females undergoing total knee arthroplasty surgery.
2. Patients are capable of providing an informed consent.
3. Age group between 18-75 years.

B. Exclusion criteria

1. Patients with asthma, COPD(Chronic obstructive pulmonary disease) or any other respiratory disease.
2. Persistent nausea and vomiting at time of randomization
3. Epilepsy.
4. Treated with mono amine oxidase inhibitors, tricyclic antidepressants, serotonin norepinephrine re-uptake inhibitors, gabapentinoids.
5. Patient with known neurological/ neuropsychiatric disorders.
6. Drug or alcohol abuse history
7. Opioid tolerance or opioid dependence.
8. Known history of opioid allergy or pregabalin allergy.
9. Renal disease (creatinine >1.5mg/dl)
10. Liver disease (total bilirubin >1.5mg/dl)
11. Pregnancy and lactation.
12. Cardiovascular insufficiency.
13. Patient with potential serotonin syndrome.
14. Patient with history of constipation and prone to paralytic ileus.

Study procedure, tools & evaluation

1. Consent: Patients will be explained the benefit and harm of joining the study and freedom of withdrawing from the study any moment they would like to. A full voluntary written informed consent will be obtained from each patient. Study will be conducted following the principles of Helsinki after getting written permission of the institutional ethics committee. Before enrolment of first patient in this study registration for clinical trial will be done.
2. All the patients will be screened before enrollment after eliciting detailed history they will undergo complete medical and laboratory examinations.
3. A total of 90 patients of either sex will be selected randomly and will be assigned to receive 100 mg of Tapentadol or 150mg Pregabalin orally 1hr before surgery in a double-blind manner. The patient will be assessed for pain at 0,6,12, and 24hrs, post operatively by visual analogue scale score(VAS) (0-100). Pain measurements will also be done on TOTPAR scale at 0,6,12,24 hours. Total rescue analgesic consumption also will be assessed at 24hrs post operatively. All treatment emergent adverse events will be documented. The time to 1st patient request for supplemental analgesia also will be recorded.
4. A blood sample will be obtained from each of the patients twice once at 0 hrs. and again at 6hrs post operatively to evaluate concentration of COX-2 levels by ELISA with commercially available ELISA kits.

• Study Type: Interventional
• Enrollment (Actual): 95
• Phase: Phase 4

Contacts and Locations

Study Locations

• India
  • Odisha
    • Bhubaneswar, Odisha, India, 751019
      • All India Institute of Medical Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 1. Patients both males and females undergoing total knee arthroplasty surgery. 2. Patients are capable of providing an informed consent. 3. Age group between 18-75 years.

Exclusion Criteria:

• 1.Patients with asthma, COPD or any other respiratory disease. 2. Persistent nausea and vomiting at time of randomization 3. Epilepsy. 4. Treated with mono amine oxidase inhibitors, tricyclic antidepressants, serotonin norepinephrine re-uptake inhibitors, gabapentinoids.

  5. Patient with known neurological/ neuropsychiatric disorders. 6. Drug or alcohol abuse history 7. Opioid tolerance or opioid dependence. 8. Known history of opioid allergy or pregabalin allergy. 9. Renal disease (creatinine >1.5mg/dl) 10. Liver disease (total bilirubin >1.5mg/dl) 11. Pregnancy and lactation. 12. Cardiovascular insufficiency. 13. Patient with potential serotonin syndrome. 14. Patient with history of constipation and prone to paralytic ileus.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Pregabalin; Pregabalin 150mg oral tablets before one hour before undergoing unilateral total knee arthroplasty	Drug: Pregabalin 150mg; This arm will receive drugs one hour before undergoing unilateral total knee arthroplasty. Interventions pregabalin 150mg oral tablets.
Experimental: Tapentadol; tapentadol 100mg oral tablets before one hour before undergoing unilateral total knee arthroplasty	Drug: Tapentadol 100 MG Oral Tablet; This arm will receive drugs one hour before undergoing unilateral total knee arthroplasty. Interventions tapentadol 100mg oral tablets.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy and safety of pregabalin and tapentadol by measuring the mean difference in the mean VAS score.	Visual analogue scale (VAS) from 0 to 100 mm score at 0,6,12,24 hrs. post operatively in both the groups.	Evaluated over 24hrs post unilateral total knee arthroplasty

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparing differences in TOTPAR scale through different time points of 24 hours Comparing differences in TOTPAR (none, mild, moderate and severe) scale through different time points of 24 hours	Scoring on TOTPAR scale at 0,6,12,24 hrs. post operatively in both the groups	Recorded over 24hrs post unilateral total knee arthroplasty
Measuring the rescue analgesic requirement in both the groups	Mean difference in total analgesic consumption in both the groups post operatively	Recorded over 24hrs post unilateral total knee arthroplasty
Monitoring adverse events in both the groups including post-operative nausea vomiting (PONV)	Frequency of nausea and vomiting in both the groups.	Recorded over 24hrs post unilateral total knee arthroplasty
Percentage of adverse events in a 4-point verbal scale.	On a scale (None, Mild, Moderate, Severe) in both the groups.	Recorded over 24hrs post unilateral total knee arthroplasty
Estimation of COX-2 at 0hrs and 6hrs post operatively in both the groups by ELISA.	Estimated in both the groups by ELISA.	In two blood samples one at 0hrs and 6hrs post operatively
Reduction of VAS and nausea/vomiting	Reduction of VAS to 3 at the end of 6 hours and 12 hours without nausea and vomiting	Evaluated at the end of 6 hours and 12 hours without nausea and vomiting

Collaborators and Investigators

• Sponsor: All India Institute of Medical Sciences, Bhubaneswar
• Investigators: Principal Investigator: Debasish Hota, MD;DM, AIIMS Bhubaneswar

Publications and helpful links

General Publications

• Dahl JB, Moiniche S. Pre-emptive analgesia. Br Med Bull. 2004 Dec 13;71:13-27. doi: 10.1093/bmb/ldh030. Print 2004.
• American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012 Feb;116(2):248-73. doi: 10.1097/ALN.0b013e31823c1030. No abstract available.
• Jain P, Jolly A, Bholla V, Adatia S, Sood J. Evaluation of efficacy of oral pregabalin in reducing postoperative pain in patients undergoing total knee arthroplasty. Indian J Orthop. 2012 Nov;46(6):646-52. doi: 10.4103/0019-5413.104196.
• Noah NM, Mwilu SK, Sadik OA, Fatah AA, Arcilesi RD. Immunosensors for quantifying cyclooxygenase 2 pain biomarkers. Clin Chim Acta. 2011 Jul 15;412(15-16):1391-8. doi: 10.1016/j.cca.2011.04.017. Epub 2011 Apr 17.
• Brennan F, Carr DB, Cousins M. Pain management: a fundamental human right. Anesth Analg. 2007 Jul;105(1):205-21. doi: 10.1213/01.ane.0000268145.52345.55.
• Kissin I. Preemptive analgesia. Anesthesiology. 2000 Oct;93(4):1138-43. doi: 10.1097/00000542-200010000-00040. No abstract available.
• Garimella V, Cellini C. Postoperative pain control. Clin Colon Rectal Surg. 2013 Sep;26(3):191-6. doi: 10.1055/s-0033-1351138.
• Pogatzki-Zahn EM, Segelcke D, Schug SA. Postoperative pain-from mechanisms to treatment. Pain Rep. 2017 Mar 15;2(2):e588. doi: 10.1097/PR9.0000000000000588. eCollection 2017 Mar.
• Harsoor S. Emerging concepts in post-operative pain management. Indian J Anaesth. 2011 Mar;55(2):101-3. doi: 10.4103/0019-5049.79872. No abstract available.
• Meacham K, Shepherd A, Mohapatra DP, Haroutounian S. Neuropathic Pain: Central vs. Peripheral Mechanisms. Curr Pain Headache Rep. 2017 Jun;21(6):28. doi: 10.1007/s11916-017-0629-5.
• Rosero EB, Joshi GP. Preemptive, preventive, multimodal analgesia: what do they really mean? Plast Reconstr Surg. 2014 Oct;134(4 Suppl 2):85S-93S. doi: 10.1097/PRS.0000000000000671.
• Woolf CJ, Chong MS. Preemptive analgesia--treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg. 1993 Aug;77(2):362-79. doi: 10.1213/00000539-199377020-00026. No abstract available.
• Silverman RB. From basic science to blockbuster drug: the discovery of Lyrica. Angew Chem Int Ed Engl. 2008;47(19):3500-4. doi: 10.1002/anie.200704280. No abstract available.
• Wang YM, Xia M, Shan N, Yuan P, Wang DL, Shao JH, Ma HW, Wang LL, Zhang Y. Pregabalin can decrease acute pain and postoperative nausea and vomiting in hysterectomy: A meta-analysis. Medicine (Baltimore). 2017 Aug;96(31):e7714. doi: 10.1097/MD.0000000000007714.
• Hartrick C, Van Hove I, Stegmann JU, Oh C, Upmalis D. Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebo-controlled study. Clin Ther. 2009 Feb;31(2):260-71. doi: 10.1016/j.clinthera.2009.02.009.
• Pergolizzi J, Alon E, Baron R, Bonezzi C, Dobrogowski J, Galvez R, Jensen T, Kress HG, Marcus MA, Morlion B, Perrot S, Treede RD. Tapentadol in the management of chronic low back pain: a novel approach to a complex condition? J Pain Res. 2011;4:203-10. doi: 10.2147/JPR.S19625. Epub 2011 Jul 21.
• Brune K, Patrignani P. New insights into the use of currently available non-steroidal anti-inflammatory drugs. J Pain Res. 2015 Feb 20;8:105-18. doi: 10.2147/JPR.S75160. eCollection 2015.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2018
• Primary Completion (Actual): March 24, 2020
• Study Completion (Actual): May 19, 2020

Study Registration Dates

• First Submitted: July 19, 2018
• First Submitted That Met QC Criteria: July 26, 2018
• First Posted (Actual): July 27, 2018

Study Record Updates

• Last Update Posted (Actual): June 25, 2020
• Last Update Submitted That Met QC Criteria: June 24, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: OA knee,pre-emptive analgesia,TKA,Opioids,gabapentinoids
• 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; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Anti-Anxiety Agents; Anticonvulsants; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Adrenergic Uptake Inhibitors; Pregabalin; Tapentadol
• Other Study ID Numbers: IEC/AIIMSBBSR/PGTH/18/12

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
• product manufactured in and exported from the U.S.: No