Efficacy And Safety Of Pregabalin For Pain Following Total Knee Replacement

Study Overview
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Brief Summary
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Pregabalin added to the standard of care with dosing starting preoperatively and continuing for up to 6 weeks post surgery will decrease the intensity of post-operative pain following total knee replacement.

Official Title
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A Multicenter, Double-Blind Randomized, Placebo-Controlled Study Of The Efficacy And Safety Of Pregabalin In The Treatment Of Subjects With Post-Operative Pain Following Total Knee Arthroplasty (TKA)

Conditions
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Osteoarthritis, Postoperative Pain

Intervention / Treatment
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* Drug: pregabalin
* Drug: pregabalin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with osteoarthritis (OA) undergoing elective TKA under regional anesthesia (neuroaxial with or without peripheral nerve block). Subjects able to demonstrate sufficient psychomotor dexterity and cognitive capacity to use Patient Controlled Analgesia/Patient Controlled Epidural Analgesia if used as part of the standard of care. The subject's preoperative health is graded as American Society of Anesthesiology Class 1 to Class 3 Exclusion Criteria: Subjects undergoing revision, unicompartmental, bilateral total knee arthroplasty or subjects with planned second knee total knee arthroplasty at time of present procedure. Subjects with inflammatory arthritides (i.e., rheumatoid arthritis, lupus, ankylosing spondylitis, psoriatic arthritis); Lyme disease. Subjects with fibromyalgia and or other chronic pain syndromes

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: pregabalin<br>* 150 milligram (mg)/ day (double blind)<br>|
| Experimental: 2<br> | Drug: pregabalin<br>* 300 mg/day (double blind)<br>|
| Placebo Comparator: 3<br> | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subject Reported Worst Pain Score in Daily Diaries Using the Worst Pain Item of the Modified Brief Pain Inventory - Short Form (m-BPI-sf) | The mBPI-SF is a self administered questionnaire developed to assess pain severity and pain interference with functional activities during a 24-hour period prior to evaluation. For the Worst Pain item of the m-BPI-sf scale (11 point Likert scale; range: 0 [no pain] to 10 [pain as bad as you can imagine]), subjects were asked to rate their pain by marking an X in one of the ten boxes that best described their pain at its worst in the last 24 hours post surgery and at least 12 hours after discontinuation of the peripheral nerve block or neuroaxial block. | 48 hours after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Total Amount of Opioids Used During the Entire Hospital Stay | Total cumulative dose calculated as mg of oral morphine equivalent and included opioids given by any route (patient controlled analgesia [PCA] pump, parenteral bolus or oral). Results for daily total not including pregabalin (not an opioid). Statistical model included main effect of treatment group and center. 1 subject at 144 h, 300 mg=non-missing data. Due to small sample size (N=1, 300 mg; N=5, other groups) and large opioid consumption for another subject in same center, least squares mean (300 mg, 144 h) is negative. | 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 168 hours, 192 hours, 216 hours | 
| Opioids Used Post Discharge | The amount of opioid use was calculated as mg of oral morphine equivalent and included opioids administered by any route (PCA pump, parenteral bolus, or oral). Weeks 2, 4, and 6 total daily doses were calculated by adding the cumulative doses during the 2 week period prior to the visit and dividing them by the number of days in the period. This outcome measure does not include pregabalin as it is not an opioid. | Week 2, Week 4, Week 6/Early Termination (ET) | 
| Analgesics Used During the Hospital Stay (Acetylsalicylic Acid, Ketorolac, and Paracetamol) | Total dose for in-hospital visits was the total dose for the day. | 24 hours, 48 hours, 72 hours | 
| Analgesics Used Post Discharge (Acetylsalicylic Acid [Week 2] and Paracetamol [Weeks 2, 4, and 6] | Weeks 2, 4, and 6 total daily doses were calculated by adding the cumulative doses during the 2 week period prior to the visit and dividing them by the number of days in the period. | Week 2, Week 4, Week 6/ET | 
| Analgesics Used Post Discharge (Ibuprofen) for the Pregabalin 150 mg and Placebo Treatment Groups | Weeks 2, 4, and 6 total daily doses were calculated by adding the cumulative doses during the 2 week period prior to the visit and dividing them by the number of days in the period. | Week 2, Week 4, Week 6/ET | 
| Analgesics Used Post Discharge (Ibuprofen) for the Pregabalin 300 mg Treatment Group | Weeks 2, 4, and 6 total daily doses were calculated by adding the cumulative doses during the 2 week period prior to the visit and dividing them by the number of days in the period. | Week 2, Week 4, Week 6/ET | 
| Analgesics Used Post Discharge (Acetylsalicylic Acid) for the Pregabalin 150 mg and Placebo Treatment Groups at Week 4 | Week 4 total daily dose was calculated by adding the cumulative doses during the 2 week period prior to the visit and dividing them by the number of days in the period. | Week 4 | 
| Analgesics Used Post Discharge (Acetylsalicylic Acid) for the Pregabalin 300 mg Treatment Group at Week 4 | Week 4 total daily dose was calculated by adding the cumulative doses during the 2 week period prior to the visit and dividing them by the number of days in the period. | Week 4 | 
| Analgesics Used Post Discharge (Acetylsalicylic Acid) for the Pregabalin 150 mg and Placebo Treatment Groups at Week 6/ET | Week 6 total daily dose was calculated by adding the cumulative doses during the 2 week period prior to the visit and dividing them by the number of days in the period. | Week 6/ET | 
| Analgesics Used Post Discharge (Acetylsalicylic Acid) for the Pregabalin 300 mg and Placebo Treatment Groups at Week 6/ET | Week 6 total daily dose was calculated by adding the cumulative doses during the 2 week period prior to the visit and dividing them by the number of days in the period. | Week 6/ET | 
| The Effect of Pregabalin Compared to Placebo on the Occurrence of Opioid-Related Symptoms as Assessed Using the Opioid-Related Symptom Distress Scale (OR-SDS) - Frequency Composite Score | The OR-SDS was used to assess subject-reported levels of frequency concerning 10 symptoms known to be associated with opioid medication usage: fatigue, drowsiness, inability to concentrate, nausea, dizziness, constipation, itching, difficulty with urination, confusion, and retching/vomiting. Symptom frequency was rated as: 1=rarely, 2=occasionally, 3=frequently, or 4=almost constantly. The average score for each symptom was calculated by taking the mean of patient-reported score. Total possible frequency score: 0 (less frequent) to 4 (more frequent). | 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, Discharge, Week 2, Week 4, Week 6/ET | 
| The Effect of Pregabalin Compared to Placebo on the Occurrence of Opioid-Related Symptoms as Assessed Using the OR-SDS - Severity Composite Score | The OR-SDS was used to assess subject-reported levels of severity concerning 10 symptoms known to be associated with opioid medication usage: fatigue, drowsiness, inability to concentrate, nausea, dizziness, constipation, itching, difficulty with urination, confusion, and retching/vomiting. Symptom severity was rated as: 1=slight, 2=moderate, 3=severe, or 4=very severe. The average score for each symptom was calculated by taking the mean of patient-reported score. Total possible severity score: 0 (less severe) to 4 (more severe). | 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, Discharge, Week 2, Week 4, Week 6/ET | 
| The Effect of Pregabalin Compared to Placebo on the Occurrence of Opioid-Related Symptoms as Assessed Using the OR-SDS - Degree of Bother Composite Score | The OR-SDS was used to assess subject-reported level of degree of bother concerning 10 symptoms known to be associated with opioid medication usage: fatigue, drowsiness, inability to concentrate, nausea, dizziness, constipation, itching, difficulty with urination, confusion, and retching/vomiting. Symptom degree of bother was rated as: 1=not at all, 2=a little bit, 3=somewhat, 4=quite a bit, or 5=very much. Average score for each symptom was calculated by taking the mean of patient-reported score. Total possible degree of bother score: 0 (less degree of bother) to 5 (greater degree of bother). | 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, Discharge, Week 2, Week 4, Week 6/ET | 
| The Effect of Pregabalin Compared to Placebo on the Occurrence of Opioid-Related Symptoms as Assessed Using the OR-SDS - Overall Composite Score | The OR-SDS assessed subject-reported levels of frequency, severity and degree of bother for 10 symptoms known to be associated with opioid medication usage: fatigue, drowsiness, inability to concentrate, nausea, dizziness, constipation, itching, difficulty with urination, confusion, retching and vomiting. The overall composite score was the average across frequency, severity, and degree of bother scores. Total possible score: 0 (better) to 4.34 (worse). | 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, Discharge, Week 2, Week 4, Week 6/ET | 
| Total Clinically Meaningful Event (CME) Score | CMEs were defined using OR-SDS (assesses subject-reported levels of severity concerning 10 symptoms associated with opioid medication usage: fatigue, drowsiness, inability to concentrate, nausea, dizziness, constipation, itching, difficulty with urination, confusion and retching/vomiting). CME = any symptom rated as severe or very severe, with the exception of confusion. Confusion was defined as a CME if the severity score was at least moderate. Total score = the sum of CMEs across symptoms. Each CME = 1 point. Total CME score ranges from 0 to 9. | 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, Discharge, Week 2, Week 4, and Week 6/ET | 
| Pain Interference Index Score as Measured by the m-BPI-sf | m-BPI-sf questionnaire (7-items) assessed pain interference with functional activities during the past 24 hours. Pain interference index = average of pain interference question (Q) 5A to 5G. Questions were asked as follows: how, during the past 24 hours, has pain interfered with general activity (Q5A), mood (Q5B), walking ability (Q5C), normal work (outside home and housework) (Q5D), relations with other people (Q5E), sleep (Q5F), enjoyment of life (Q5G). Scale: 0=does not interfere to 10=completely interferes. | Discharge, Week 2, Week 4, Week 6/ET, Month 3, Month 6 | 
| Pain Interference With Relations With People as Measured by the m-BPI-sf | m-BPI-sf questionnaire (7-items) assessed pain interference with functional activities during the past 24 hours. Q5E: Subject response to 'how, during the past 24 hours, pain has interfered with your relations with other people'. Scale: 0 = does not interfere to 10 = completely interferes. | Discharge, Week 2, Week 4, Week 6/ET, Month 3, Month 6 | 
| Pain Interference With Enjoyment of Life as Measured by the m-BPI-sf | m-BPI-sf questionnaire (7-items) assessed pain interference with functional activities during the past 24 hours. Q5G: Subject response to 'how, during the past 24 hours, pain has interfered with your enjoyment of life'. Scale: 0 = does not interfere to 10 = completely interferes. | Discharge, Week 2, Week 4, Week 6/ET, Month 3, Month 6 | 
| Pain Interference With General Activity as Measured by the m-BPI-sf | m-BPI-sf questionnaire (7-items) assessed pain interference with functional activities during the past 24 hours. Q5A: Subject response to 'how, during the past 24 hours, pain has interfered with your general activity. Scale: 0 = does not interfere to 10 = completely interferes. | Discharge, Week 2, Week 4, Week 6/ET, Month 3, Month 6 | 
| Pain Interference With Mood as Measured by the m-BPI-sf | m-BPI-sf questionnaire (7-items) assessed pain interference with functional activities during the past 24 hours. Q5B: Subject response to 'how, during the past 24 hours, pain has interfered with your mood'. Scale: 0 = does not interfere to 10 = completely interferes. | Discharge, Week 2, Week 4, Week 6/ET, Month 3, Month 6 | 
| Pain Interference With Walking Ability as Measured by the m-BPI-sf | m-BPI-sf questionnaire (7-items) assessed pain interference with functional activities during the past 24 hours. Q5C: Subject response to 'how, during the past 24 hours, pain has interfered with your walking ability'. Scale: 0 = does not interfere to 10 = completely interferes. | Discharge, Week 2, Week 4, Week 6/ET, Month 3, Month 6 | 
| Pain Interference With Normal Work as Measured by the m-BPI-sf | m-BPI-sf questionnaire (7-items) assessed pain interference with functional activities during the past 24 hours. Q5D: Subject response to 'how, during the past 24 hours, pain has interfered with your normal work (work outside the home and housework)'. Scale: 0 = does not interfere to 10 = completely interferes. | Discharge, Week 2, Week 4, Week 6/ET, Month 3, Month 6 | 
| Pain Interference With Sleep as Measured by the m-BPI-sf | m-BPI-sf questionnaire (7-items) assessed pain interference with functional activities during the past 24 hours. Q5F: Subject response to 'how, during the past 24 hours, pain has interfered with your sleep'. Scale: 0 = does not interfere to 10 = completely interferes. | Discharge, Week 2, Week 4, Week 6/ET, Month 3, Month 6 | 
| Daily and Weekly Worst Pain During the Hospital Stay and Post Discharge Assessed by the Pain Numerical Rating Scale (NRS) | Subject rated scale for worst pain over the last 24 hours. Scores ranged from 0 (no pain) to 10 (pain as bad as you can imagine). Weekly mean scores were calculated post-discharge. | 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 168 hours, and 192 hours during the hospital stay, Week 2, Week 4, Week 6/ET | 
| Daily and Weekly Average Pain During the Hospital Stay and Post Discharge Assessed by the Pain NRS | Subject rated scale for average pain intensity over the last 24 hours. Scores range from 0 (no pain) to 10 (pain as bad as you can imagine). Weekly mean scores were calculated post-discharge. | 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 168 hours, and 192 hours during the hospital stay, Week 2, Week 4, Week 6/ET | 
| Current Pain During the Hospital Stay Assessed by the Pain NRS | Subject rated scale for average pain intensity over the last 24 hours. Pain was assessed using the question How much pain do you have right now? Scores range from 0 (no pain) to 10 (most possible pain). | 4, 8, 12, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, 104, 112, 120, 128, 136, 144, 152, 160, 168, 176, 184, and 192 hours during the hospital stay | 
| Pain-Related Sleep Interference Post Surgery | The NRS-Sleep: subject rated 11-point numerical rating scale ranging from 0 (did not interfere with sleep) to 10 (completely interfered [unable to sleep due to pain]) rating how pain has interfered with sleep during the past 24 hours. Weekly mean scores were calculated post hospital discharge. | 24 hours, 48 hours, 72 hours, 96 hours 120 hours, 144 hours, 168 hours, and 192 hours post-surgery, Week 2, Week 4, Week 6/ET | 
| Change From Baseline in Visual Analogue Scale for Anxiety (VAS-Anxiety) Score Prior to Surgery | VAS-Anxiety was administered to measure pre-operative anxiety. Score: 0 = no anxiety to 100 = worst imaginable anxiety. | Day 1, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, and 6 hours prior to surgery | 
| Timed Up-and-Go (TUG) | TUG: time taken in seconds to rise from a standard arm chair, walk to a line on the floor 3 meters away, turn, return and sit down again. | 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, Week 2, Week 4, Week 6/ET | 
| Range of Motion (ROM) Assessment of the Active Flexion of the Surgical Knee | The degree of active (patient moving the knee) knee flexion and extension tolerated by each subject was recorded. Active ROM in the sitting position was assessed with a goniometer. | 24 hours, 48 hours, 72 hours, 96 hours, and 120 hours post surgery, Week 2, Week 4, Week 6/ET | 
| ROM Assessment of the Passive Flexion of the Surgical Knee | The degree of passive (movement of the knee with the aid of physical therapist or designee) knee flexion and extension tolerated by each subject was recorded. Passive ROM in the sitting position was assessed with a goniometer. | 24 hours, 48 hours, 72 hours, 96 hours, and 120 hours post surgery, Week 2, Week 4, Week 6/ET | 
| Time From End of Surgery to Meet Hospital Discharge Criteria | The analysis was performed by Kaplan-Meier method with log-rank test. | time from end of surgery up to 192 hours post surgery | 
| Time From End of Surgery to Actual Discharge | The analysis was performed by Kaplan-Meier method with log-rank test. | time from end of surgery up to 192 hours post surgery | 
| Satisfaction With Current Pain Medication Measured by the Pain Treatment Satisfaction Scale (PTSS) | Measure of subject satisfaction with treatment for acute or chronic pain. Response range: 1 (strongly agree) to 5 (strongly disagree). Mean scores were calculated and transformed onto a scale of 0-100, range: 0 = worst possible satisfaction to 100 = best possible satisfaction with pain treatment. | Discharge, Week 2, Week 4, Week 6/ET | 
| Satisfaction With Medication Characteristics Measured by the PTSS | Measure of subject satisfaction with treatment for acute or chronic pain. Response range: 1 (strongly agree) to 5 (strongly disagree). Mean scores were calculated and transformed onto a scale of 0-100, range: 0 = worst possible satisfaction to 100 = best possible satisfaction with pain treatment. | Discharge, Week 2, Week 4, Week 6/ET | 
| Satisfaction With Medication Efficacy Measured by the PTSS | Measure of subject satisfaction with treatment for acute or chronic pain. Response range: 1 (strongly agree) to 5 (strongly disagree). Mean scores were calculated and transformed onto a scale of 0-100, range: 0 = worst possible satisfaction to 100 = best possible satisfaction with pain treatment. | Discharge, Week 2, Week 4, Week 6/ET | 
| Overall Satisfaction Measured by the PTSS | Measure of subject satisfaction with treatment for acute or chronic pain. Response range: 1 (strongly agree) to 5 (strongly disagree). Mean scores were calculated and transformed onto a scale of 0-100, range: 0 = worst possible satisfaction to 100 = best possible satisfaction with pain treatment. | Discharge, Week 2, Week 4, and Week 6/ET | 
| Overall Pain Relief Measured by the PTSS | Measure of subject satisfaction with treatment for acute or chronic pain. Response range: 1 (strongly agree) to 5 (strongly disagree). Mean scores were calculated and transformed onto a scale of 0-100, range: 0 = worst possible satisfaction to 100 = best possible satisfaction with pain treatment. | Discharge, Week 2, Week 4, and Week 6/ET | 
| Number of Subjects With Global Evaluation of Study Medication Scores | The Global Evaluation of Study Medication is a subject-administered single item instrument that records the subject's overall impression (global evaluation) of the study medication by asking the following question: how would you rate the study medication you received for pain? The subject chooses based on a scale of 1 (poor), 2 (fair), 3 (good), or 4 (excellent). | Discharge, Week 2, Week 4, and Week 6/ET | 
| Number of Subjects With Persistent Pain Based on 11-Point Verbal Rating Scale (VRS) | The presence of persistent pain was evaluated on the 11-point VRS. The subject answered the question: how much pain did you experience in the last 24 hours in your operated knee? A zero score of VRS was the only number considered as a no. Any positive score (1-10) of VRS was consider as yes. | Month 3, Month 6 (phone call) | 
| Neuropathic Pain Symptom Inventory (NPSI) | NPSI: subject rated questionnaire to evaluate 5 dimensions of neuropathic pain (dimensions: burning [superficial] spontaneous pain, pressing [deep] spontaneous pain, paroxysmal pain, evoked pain, and paresthesia/dyesthesia). Includes 10 descriptors ranging from 0 (no symptoms) to 10 (worst symptoms imaginable) and 2 temporal items assessing duration of spontaneous ongoing and paroxysmal pain. Questionnaire generates a score in each relevant dimension. Total score is calculated as the sum of scores of the 10 descriptors, range: 0-100. Higher score indicates greater intensity of pain. | Month 3, Month 6 (phone call) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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opioid