Efficacy And Safety Of Pregabalin For Pain Following Total Knee Replacement

Phase 3

Completed

Conditions: Osteoarthritis
Postoperative Pain

Interventions: Drug: Placebo
Drug: pregabalin

Registration Number: NCT00442546

Lead Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 307

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
3	Placebo	-
2	pregabalin	-
1	pregabalin	-

Primary Outcome Measures

Name	Time	Method
Subject Reported Worst Pain Score in Daily Diaries Using the Worst Pain Item of the Modified Brief Pain Inventory - Short Form (m-BPI-sf)	48 hours after surgery	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.

Secondary Outcome Measures

Name	Time	Method
Cumulative Total Amount of Opioids Used During the Entire Hospital Stay	24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 168 hours, 192 hours, 216 hours	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.
Pain Interference Index Score as Measured by the m-BPI-sf	Discharge, Week 2, Week 4, Week 6/ET, Month 3, Month 6	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.
Pain Interference With Relations With People as Measured by the m-BPI-sf	Discharge, Week 2, Week 4, Week 6/ET, Month 3, Month 6	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.
Pain Interference With Enjoyment of Life as Measured by the m-BPI-sf	Discharge, Week 2, Week 4, Week 6/ET, Month 3, Month 6	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.
Pain Interference With General Activity as Measured by the m-BPI-sf	Discharge, Week 2, Week 4, Week 6/ET, Month 3, Month 6	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.
Opioids Used Post Discharge	Week 2, Week 4, Week 6/Early Termination (ET)	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.
Analgesics Used During the Hospital Stay (Acetylsalicylic Acid, Ketorolac, and Paracetamol)	24 hours, 48 hours, 72 hours	Total dose for in-hospital visits was the total dose for the day.
Analgesics Used Post Discharge (Acetylsalicylic Acid [Week 2] and Paracetamol [Weeks 2, 4, and 6]	Week 2, Week 4, Week 6/ET	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.
Analgesics Used Post Discharge (Ibuprofen) for the Pregabalin 150 mg and Placebo Treatment Groups	Week 2, Week 4, Week 6/ET	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.
Analgesics Used Post Discharge (Ibuprofen) for the Pregabalin 300 mg Treatment Group	Week 2, Week 4, Week 6/ET	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.
Analgesics Used Post Discharge (Acetylsalicylic Acid) for the Pregabalin 150 mg and Placebo Treatment Groups at Week 4	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.
Analgesics Used Post Discharge (Acetylsalicylic Acid) for the Pregabalin 300 mg Treatment Group at Week 4	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.
Analgesics Used Post Discharge (Acetylsalicylic Acid) for the Pregabalin 150 mg and Placebo Treatment Groups at Week 6/ET	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.
Analgesics Used Post Discharge (Acetylsalicylic Acid) for the Pregabalin 300 mg and Placebo Treatment Groups at Week 6/ET	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.
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	24 hours, 48 hours, 72 hours, 96 hours, 120 hours, Discharge, Week 2, Week 4, Week 6/ET	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).
The Effect of Pregabalin Compared to Placebo on the Occurrence of Opioid-Related Symptoms as Assessed Using the OR-SDS - Severity Composite Score	24 hours, 48 hours, 72 hours, 96 hours, 120 hours, Discharge, Week 2, Week 4, Week 6/ET	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).
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	24 hours, 48 hours, 72 hours, 96 hours, 120 hours, Discharge, Week 2, Week 4, Week 6/ET	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).
The Effect of Pregabalin Compared to Placebo on the Occurrence of Opioid-Related Symptoms as Assessed Using the OR-SDS - Overall Composite Score	24 hours, 48 hours, 72 hours, 96 hours, 120 hours, Discharge, Week 2, Week 4, Week 6/ET	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).
Total Clinically Meaningful Event (CME) Score	24 hours, 48 hours, 72 hours, 96 hours, 120 hours, Discharge, Week 2, Week 4, and Week 6/ET	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.
Pain Interference With Mood as Measured by the m-BPI-sf	Discharge, Week 2, Week 4, Week 6/ET, Month 3, Month 6	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.
Pain Interference With Walking Ability as Measured by the m-BPI-sf	Discharge, Week 2, Week 4, Week 6/ET, Month 3, Month 6	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.
Pain Interference With Normal Work as Measured by the m-BPI-sf	Discharge, Week 2, Week 4, Week 6/ET, Month 3, Month 6	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.
Pain Interference With Sleep as Measured by the m-BPI-sf	Discharge, Week 2, Week 4, Week 6/ET, Month 3, Month 6	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.
Daily and Weekly Worst Pain During the Hospital Stay and Post Discharge Assessed by the Pain Numerical Rating Scale (NRS)	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	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.
Daily and Weekly Average Pain During the Hospital Stay and Post Discharge Assessed by the Pain NRS	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	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.
Current Pain During the Hospital Stay Assessed by the Pain NRS	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	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).
Pain-Related Sleep Interference Post Surgery	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	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.
Change From Baseline in Visual Analogue Scale for Anxiety (VAS-Anxiety) Score Prior to Surgery	Day 1, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, and 6 hours prior to surgery	VAS-Anxiety was administered to measure pre-operative anxiety. Score: 0 = no anxiety to 100 = worst imaginable anxiety.
Timed Up-and-Go (TUG)	24 hours, 48 hours, 72 hours, 96 hours, 120 hours, Week 2, Week 4, Week 6/ET	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.
Range of Motion (ROM) Assessment of the Active Flexion of the Surgical Knee	24 hours, 48 hours, 72 hours, 96 hours, and 120 hours post surgery, Week 2, Week 4, Week 6/ET	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.
ROM Assessment of the Passive Flexion of the Surgical Knee	24 hours, 48 hours, 72 hours, 96 hours, and 120 hours post surgery, Week 2, Week 4, Week 6/ET	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.
Time From End of Surgery to Meet Hospital Discharge Criteria	time from end of surgery up to 192 hours post surgery	The analysis was performed by Kaplan-Meier method with log-rank test.
Time From End of Surgery to Actual Discharge	time from end of surgery up to 192 hours post surgery	The analysis was performed by Kaplan-Meier method with log-rank test.
Satisfaction With Current Pain Medication Measured by the Pain Treatment Satisfaction Scale (PTSS)	Discharge, Week 2, Week 4, Week 6/ET	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.
Satisfaction With Medication Characteristics Measured by the PTSS	Discharge, Week 2, Week 4, Week 6/ET	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.
Satisfaction With Medication Efficacy Measured by the PTSS	Discharge, Week 2, Week 4, Week 6/ET	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.
Overall Satisfaction Measured by the PTSS	Discharge, Week 2, Week 4, and Week 6/ET	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.
Overall Pain Relief Measured by the PTSS	Discharge, Week 2, Week 4, and Week 6/ET	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.
Number of Subjects With Global Evaluation of Study Medication Scores	Discharge, Week 2, Week 4, and Week 6/ET	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).
Number of Subjects With Persistent Pain Based on 11-Point Verbal Rating Scale (VRS)	Month 3, Month 6 (phone call)	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."
Neuropathic Pain Symptom Inventory (NPSI)	Month 3, Month 6 (phone call)	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.