Predicting, Understanding and Speeding Recovery After TKA

Predicting, Understanding, and Speeding Recovery After Total Knee Arthroplasty

The objective of this research study is to better understand patterns of recovery after Total Knee Arthroplasty (TKA) amd Total Hip Replacement (THA). The study will evaluate how pain, activity and cognitive (i.e., thinking style) responses determine patterns of recovery, and the study will evaluate the efficacy of gabapentin versus placebo for improving recovery after surgery.

Study Overview

• Status: Terminated
• Conditions: Pain; Total Hip Replacement; Total Knee Replacement
• Intervention / Treatment: Drug: Gabapentin; Drug: Placebo

Detailed Description

The investigators propose a two-site, longitudinal, double-blind, randomized clinical intervention study to examine three specific aims:

Aim 1: Characterize the dynamic pain experience, activity, and cognitive response after TKA and determine patterns of recovery in these domains

Aim 2: Test whether gabapentin alters time course of recovery after TKA or THA in a manner dependent on its interaction with pre-drug pupil diameter and preferred style in the catastrophizing-optimism dimension

Aim 3: Test whether gabapentin increases pupil diameter in patients undergoing TKA or THA who are on high dose opioids preoperatively and to examine whether opioid use moderates the associations in Aim 1

Primary Hypothesis: Novel variance beyond established associations in recovery from pain following TKA or THA surgery is accounted for by the interaction between pupil diameter and Cognitive-Affective (C-A) state, and this interaction predicts efficacy of gabapentin to speed recovery.

Key secondary hypotheses: Disability, impulsivity, and attentional deficits recover after TKA or THA surgery follow a log of time pattern, and are predicted by C-A state and its interaction with pupil diameter. Gabapentin increases resting pupil diameter in patients scheduled for TKA who are receiving high doses of opioids.

• Study Type: Interventional
• Enrollment (Actual): 350
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults scheduled for elective total knee or hip replacement
• American Society of Anesthesiologists physical status 1-3
• Participants must be able to read and write English

Exclusion Criteria:

• Inability to complete questionnaires
• Pregnancy
• Litigation or workers compensation related to joint surgery
• For 250 subjects in primary analysis - taking < 100 mg morphine equivalents/day. For 50 subjects to test gabapentin's effect on pupil diameter - taking >100 mg morphine equivalents/day
• history of Raynaud's disease of the feet
• suffering from a psychotic disorder or a recent psychiatric hospitalization
• history of eye surgery or topical eye medications that would render pupillometry unreliable or would directly affect pupil diameter.
• any disorder that would affect pupil responsivity or prevent accuracy of pupillometry such as movement disorders

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Gabapentin; Subjects will be randomized, stratifying for norepinephrine serotonin reuptake inhibitor (NSRI) use, to equal number to receive gabapentin or placebo pills. Drug treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards. Subjects randomized to gabapentin will receive 900 mg/day for the first week, 1800 mg/day for the next 3 weeks, and 900 mg/day for the last week.	Drug: Gabapentin; Drug treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards. Subjects randomized to gabapentin will receive 900 mg/day for the first week, 1800 mg/day for the next 3 weeks, and 900 mg/day for the last week.; Other Names: neurontin
Placebo Comparator: Placebo; Subjects will be randomized, stratifying for norepinephrine serotonin reuptake inhibitor (NSRI) use, to equal number to receive gabapentin or placebo pills. Drug treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards.	Drug: Placebo; Drug treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards. Subjects randomized to gabapentin will receive 900 mg/day for the first week, 1800 mg/day for the next 3 weeks, and 900 mg/day for the last week.; Other Names: Inert ingredient

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of Adjusted Trajectory Model for Pain Between Gabapentin and Placebo--Intercept	Daily pain intensity report for each subject was fitted using growth curve model with parameters of intercept (modeled initial pain) and slope of change in natural log of time, adjusted for prognostic predictors for gabapentin and placebo group separately. The daily pain intensity was the WORST pain (not the average pain) in the past 24 hr on a scale where 0 is no pain and 10 is worst imaginable pain. Values represent an intercept of modeled worst daily pain on the first day after hospital discharge across all participants, extracted from the mixed effect model. The intercept is a number representative of all participants in the Arm and is an estimate with confidence limits based on the model.	The first day after hospital discharge up to 5 days post surgery
Comparison of Adjusted Trajectory Model for Pain Between Gabapentin and Placebo-- Slope	Daily pain intensity report for each subject was fitted using growth curve model with parameters of intercept (modeled initial pain) and slope of change in natural log of time, adjusted for prognostic predictors for gabapentin and placebo group separately. The daily pain intensity was the WORST pain (not the average pain) in the past 24 hr on a scale where 0 is no pain and 10 is worst imaginable pain. Slope is defined as change in pain . Values represent the slope of modeled worst daily pain (0-10 scale as described above) divided by the natural log of time (days) across all participants, extracted from the mixed effect model. The slope is a number representative of all participants in the Arm and is an estimate with confidence limits based on the model.	Postoperative Day 1 through Postoperative Day 60
Effect Pupil Diameter, Catastrophizing-optimism Construct, and Gabapentin on Model Fit of the Trajectory of Change in Worst Daily Pain After Surgery	Daily pain intensity report for each subject was fitted using growth curve model, adjusted for pre-specified prognostic predictors . The daily pain intensity was the WORST pain (not the average pain) in the past 24 hr on a scale where 0 is no pain and 10 is worst imaginable pain. Deviance values were calculated from the model fit with just pre-specified prognostic predictors (Model 1) and the model fit with these predictors plus pupil diameter, catastrophizing-optimism construct, gabapentin treatment and their interaction. Deviance is a goodness-of-fit statistic for a statistical model; it is often used for statistical hypothesis testing. It is a generalization of the idea of using the sum of squares of residuals (SSR) in ordinary least squares to cases where model-fitting is achieved by maximum likelihood. Deviance ranges from 0 to infinity. The smaller the number the better the model fits the sample data. Model fits were compared using Chi-squared test.	Postoperative Day 1 through Postoperative Day 60

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Wisconsin Card Sort Task	This is a physical card sorting game which measures attention to shifts in implicit rules as the game progresses. Perseverative errors are the number of sequential errors when rules of the game shift and reflect dysfunction of attention. This score ranges from 0 to 64 with larger numbers reflecting more dysfunction of attention.	Preoperative, 2 months after surgery, 6 months after surgery
Iowa Gambling Task	This is a computer based card game which assesses risk taking and impulsivity in which a score of -100 to 100 is calculated. Lower numbers indicate greater impulsiivity	Preoperative, 2 months after surgery, 6 months after surgery
Tampa Scale of Kinesiophobia	This 17-question scale assesses the degree of fear of pain from joint movement and is commonly used in orthopedic injury or surgery studies. The scale ranges from 17 to 68 with 17 indicating no fear of movement and 68 indicating severe fear.	Preoperative, 2 months after surgery, 6 months after surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarkers of Stress	Blood and cerebrospinal fluid will be obtained and frozen for subsequent assessment of hormones, neurochemicals, and other secreted compounds indicative of stress. Analysis will be in the future and dependent upon new literature for ideal biomarkers.	Preoperative
Biomarkers of Noradrenergic Functioning	Blood and cerebrospinal fluid will be obtained and frozen for subsequent assessment of compounds reflecting noradrenergic functioning. Analysis will be in the future and dependent upon new literature for ideal biomarkers.	Preoperative

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Collaborators: National Institute of General Medical Sciences (NIGMS)
• Investigators: Principal Investigator: James C Eisenach, MD, Wake Forest University Health Sciences

Study record dates

Study Major Dates

• Study Start (Actual): June 2, 2016
• Primary Completion (Actual): February 9, 2022
• Study Completion (Actual): February 9, 2022

Study Registration Dates

• First Submitted: June 1, 2015
• First Submitted That Met QC Criteria: February 15, 2016
• First Posted (Estimated): February 19, 2016

Study Record Updates

• Last Update Posted (Actual): October 4, 2023
• Last Update Submitted That Met QC Criteria: October 3, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Tranquilizing Agents; Psychotropic Drugs; Anti-Anxiety Agents; Anticonvulsants; Antimanic Agents; Gabapentin
• Other Study ID Numbers: IRB00032506; 5P01GM113852 (U.S. NIH Grant/Contract)

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: Yes
• Studies a U.S. FDA-regulated device product: No