Repeat Dose Steroid to Prevent Pain Relapse After Total Knee Arthroplasty in Patients With High Pain Response

Study Overview
=================
Brief Summary
-----------------
The aim of the study is to compare the effect of a repeat moderate dose of glucocorticoids postoperatively after preoperative high dose upon postoperative pain after Total Knee Arthroplasty (TKA) in an High Pain Respondes (HPR) population to a standard single high dose systemic preoperative administration in an HPR population. As a standard procedure, all patients referred to the outpatient clinic due to suspected degenerative knee disease will be asked to fulfill the Pain Catastrophizing Scale (PCS). If TKA is decided, patients with a PCS score above 20 will be treated with intravenously administered Dexamethasone 1 mg/kg as a rounded-up-dose to closest 10 mg according to our guideline for FAST-TRACK TKA. The repeat-dosing group (RDG) will receive a dose of 24 mg dexamethasone tablets at 9-11 pm on the first postoperative day. The control-group (CG) will receive placebo tablets at 9-11 pm on the first postoperative day.

Detailed Description
-----------------
Total hip and knee arthroplasty (THA/TKA) are frequently performed procedures and are expected to increase in numbers along with the growing elderly population the next decade. Total Knee Arthroplasty (TKA) is suitable for FAST-TRACK surgery, and is often performed as outpatient surgery with no hospital overnight stay. Challenges in FAST-TRACK surgery include postoperative pain, nausea and vomiting (PONV), complications due to rescue-analgesics and surgical complications. Pain is a well-known clinical problem, with up to 75% of TKA patients experiencing moderate to severe pain the first day after surgery, and 30-40% still experiencing moderate to severe pain 2 weeks after surgery, potentially delaying ambulation and recovery within the first weeks. The role of severe acute postoperative pain upon the development of chronic pain is debatable, but important. Data from our recently finished study in High Pain Responders (HPR), defined as patients with a score above 20 on the Pain Catastrophizing Scale (PCS), receiving preoperative high dose dexamethasone (Nielsen et al.: IN PREPARATION, clinicaltrials.gov ID NCT03763734, EudraCT 2018-002635-23, VEK H-18034778) found a persistent moderate to severe pain in 40 % of patients, at time 48 hours after surgery, corresponding to the time when the physiological effect of our dexamethasone intervention declines. Moderate to severe pain (Visual analogue scale (VAS >30)) 24 hours postoperatively during a 5-meter walk test was associated with relapse pain at 48 hours. Other studies have made attempts of investigating the effect of a repeated dose of steroids after TKA and Total Hip Arthroplasty (THA), but all have done so with a postoperative injection of low dose steroids. No previous studies have, to our knowledge, investigated the effects of repeat dosing after a preoperative high dose of steroid, and none focused on patients selected by their postoperative pain response. In spite of many studies and systematic reviews on the subject, the optimal timing and dose for steroid-intervention in TKA in different patient groups is still inadequately understood The study conduct with a repeat moderate dose of steroids given as an oral tablet at 9-11 pm on the day after TKA surgery in patients receiving preoperative high dose steroids, who have a high postoperative pain response, in a FAST-TRACK perioperative setting. Oral administration of the repeat dose will allow for possible early discharge in future clinical settings. The hypothesis is that a repeat moderate dose of glucocorticoid will reduce the postoperative pain on postoperative day 2 and cumulated pain day 2-3 after TKA surgery, when compared to single high dose preoperatively.

Official Title
-----------------
Repeat Dose Steroid to Prevent Pain Relapse After Total Knee Arthroplasty in Patients With High Pain Response - A Randomized Double-blind Placebo-controlled Trial

Conditions
-----------------
Post Operative Pain, Acute

Intervention / Treatment
-----------------
* Drug: Dexamethasone 24 mg
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 40 years. Primary unilateral TKA. Ability to participate in the study (understand written and spoken Danish language, self-reported pain and satisfaction). Signed written informed consent form. PCS >20. Moderate to severe postoperative pain (VAS >30) in a 5-meter walk test 22-26 hours after end of surgery. Exclusion Criteria: Ongoing treatment of systemic glucocorticoids or other immunosuppressant treatment apart from inhaled steroids. Insulin-dependent diabetes. Pregnancy or breastfeeding.* Allergies concerning the study-drug. Mental disability that could impair a patient's decision-making capability of giving informed consent and not enabling valid data collection. Patients with known diagnoses of schizophrenia, ongoing psychosis, bipolar disease and/or a history of ongoing anti-psychotic treatment. Patients with modulated pain-reception (experience) based on other diseases or injuries, e.g. spinal cord or brain injury, severe polyneuropathies or neurologic disorders. Peripheral nerve block per- or postoperatively. Pregnancy: No women with suspected or proven pregnancy are eligible for inclusion. The following will be considered as safe contraception: intrauterine device or hormonal contraception. For women aged between 40-50 years, a urine HCG test for pregnancy will be performed.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A double-blind randomization will be carried out, 5:5 block-randomization, half of which will be allocated to the CG and the other half to RDG. Group 1: Postoperative placebo tablet on day 1 after surgery. Group 2: Postoperative dexamethasone 24 mg tablet on day 1 after surgery.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo tablet on day 1 after surgery given as one single dose.<br>Control Group (CG): Intervention: Postoperative oral placebo tablet on day 1 after surgery given as one single dose. | Drug: Placebo<br>* Placebo tablet given on day 1 after surgery.<br>|
| Active Comparator: Dexamethasone 24 mg on day 1 after surgery given as one single dose.<br>Repeat Dose Group (RDG): Intervention: Postoperative oral dexamethasone 24 mg on day 1 after surgery given as one single dose. | Drug: Dexamethasone 24 mg<br>* Dexamethasone 24 mg on day 1 after surgery.<br>* Other names: Dexa-ratiopharm;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postoperative pain after 48 hours / day 2 morning, according to VAS-scale | The amount of patients with moderate postoperative pain in a 5 meter walk test day 2 morgning(48 hours) postoperatively after total knee-arthroplasty. Pain is monitored by the Visual Analog Scale(VAS) 0-100 mm, where 0 is no pain and 100 mm is the worst pain. Moderate pain is considered a VAS >30 mm. | Day 2 morning | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulated pain upon ambulation, according to VAS-scale (0-100mm), in a 5-meter walk test | Pain is monitored by the Visual Analog Scale(VAS) 0-100 mm, where 0 is no pain and 100 mm is the worst pain. Moderate pain is considered a VAS >30 mm | From day 2-3 | 
| Cumulated pain score, according to VAS-scale (0-100mm), at rest, upon ambulation in a 5-meter walk test and at night according to VAS-scale(0-100mm) | Pain is monitored by the Visual Analog Scale(VAS) 0-100 mm, where 0 is no pain and 100 mm is the worst pain. Moderate pain is considered a VAS >30 mm | From day 2-7 | 
| Quality of sleep, lethargy, dizziness, and nausea postoperative registration, according to the VAS-scale(0-100mm) | ain is monitored by the Visual Analog Scale(VAS) 0-100 mm, where 0 is no pain and 100 mm is the worst pain. Moderate pain is considered a VAS >30 mm | From day 2-7 | 
| Cumulative use of rescue analgesics per day. |  | From day 2-7 | 
| Patient satisfaction with analgesic regimen in a ordinal scale from 0 to 10 |  | Day 7 | 
| Number of re-admissions within 30 days, and reasons why (follow-up by EPJ on postoperative day 30) |  | Day 30 | 
| Morbidity and mortality (30-day follow-up by EPJ or telephone). | Number of participant with morbidity and mortality in the first 30 days. Follow-up by EPJ or telephone. | Day 30 | 
| Why still in hospital, an audit into the reasons the patient has not yet been discharged from the ward | An investigation into reason of why our patients remain in the hospital in the days after total Knee Arthroplasty in our Fast-Track center. This is investigated through a questionnaire previously used in a similar investigation in our center. The questionnaire is filled in by our project nurse. the questionnaire is a checkmark schedule with predetermined reasons to stay in hospital like low bloodpressure, sedation, dizzyness, lack of physiotherapy and medical and surgical complications. The outcome assesment will be descriptive. | Day 7 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Dexamethason, repeat, glucocorticoids, TKA surgery, steroids, High Pain Responders, postoperative pain, repeat dosing, FAST-TRACK