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

Study Overview
=================
Brief Summary
-----------------
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.

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 Patients both males and females undergoing total knee arthroplasty surgery. Patients are capable of providing an informed consent. Age group between 18-75 years. B. Exclusion criteria Patients with asthma, COPD(Chronic obstructive pulmonary disease) or any other respiratory disease. Persistent nausea and vomiting at time of randomization Epilepsy. Treated with mono amine oxidase inhibitors, tricyclic antidepressants, serotonin norepinephrine re-uptake inhibitors, gabapentinoids. Patient with known neurological/ neuropsychiatric disorders. Drug or alcohol abuse history Opioid tolerance or opioid dependence. Known history of opioid allergy or pregabalin allergy. Renal disease (creatinine >1.5mg/dl) Liver disease (total bilirubin >1.5mg/dl) Pregnancy and lactation. Cardiovascular insufficiency. Patient with potential serotonin syndrome. Patient with history of constipation and prone to paralytic ileus. Study procedure, tools & evaluation 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. All the patients will be screened before enrollment after eliciting detailed history they will undergo complete medical and laboratory examinations. 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. 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.

Official Title
-----------------
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

Conditions
-----------------
Osteoarthritis, Knee

Intervention / Treatment
-----------------
* Drug: Tapentadol 100 MG Oral Tablet
* Drug: Pregabalin 150mg


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
OA knee,pre-emptive analgesia,TKA,Opioids,gabapentinoids