Pain, Total Hip Replacement, Total Knee Replacement
Conditions
Brief summary
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.
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.
Interventions
DRUGGabapentin
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.
DRUGPlacebo
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.
Sponsors
National Institute of General Medical Sciences (NIGMS)
Wake Forest University Health Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect Pupil Diameter, Catastrophizing-optimism Construct, and Gabapentin on Model Fit of the Trajectory of Change in Worst Daily Pain After Surgery | Postoperative Day 1 through Postoperative Day 60 | 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. |
| Comparison of Adjusted Trajectory Model for Pain Between Gabapentin and Placebo-- Slope | Postoperative Day 1 through Postoperative Day 60 | 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. |
| Comparison of Adjusted Trajectory Model for Pain Between Gabapentin and Placebo--Intercept | The first day after hospital discharge up to 5 days post surgery | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tampa Scale of Kinesiophobia | Preoperative, 2 months after surgery, 6 months after surgery | 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. |
| Wisconsin Card Sort Task | Preoperative, 2 months after surgery, 6 months after surgery | 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. |
| Iowa Gambling Task | Preoperative, 2 months after surgery, 6 months after surgery | 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Biomarkers of Stress | Preoperative | 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. |
| Biomarkers of Noradrenergic Functioning | Preoperative | 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. |
Countries
United States
Participant flow
Recruitment details
Enrollment occurred from June 2, 2016 to August 2, 2021 at the Orthopeadic Clinics of Atrium Wake Forest Baptist and Davie County facilities and May 9, 2017 to July 21, 2020 at Cleveland Clinic facilities. Change in clinical practice resulted in inability to recruit subjects on high doses of opioid preoperatively, so recruitment of 50 subject in Aim 3 which was intended to separately examine interactions in this population did not occur.
Pre-assignment details
Enrollment occurred greater or equal to 2 weeks prior to surgery. A total of 76 individuals were excluded prior to assignment to groups during the period prior to surgery because of cancellation of the planned surgery.
Participants by arm
| Arm | Count |
|---|---|
| Gabapentin Subjects will receive gabapentin, 900 mg/day for the first week, 1800 mg/day for the next 3 weeks, and 900 mg/day for the last week. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards. | 117 |
| Placebo Subjects will receive placebo pills and the number of pills will be the same as gabapentin in the active treatment arm. Treatment will begin 2 weeks prior to surgery and continue 3 weeks afterwards. | 123 |
| Total | 240 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 3 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Preop testing found to be incomplete | 2 | 2 |
| Overall Study | Surgery Cancelled | 4 | 9 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Total | Gabapentin | Placebo |
|---|---|---|---|
| Age, Continuous | 60.8 years STANDARD_DEVIATION 8.5 | 60.8 years STANDARD_DEVIATION 7.8 | 60.7 years STANDARD_DEVIATION 9.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 237 Participants | 116 Participants | 121 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Optimism/acceptance of pain to catastrophizing cognitive style | 0.00 units on a scale STANDARD_DEVIATION 1 | -0.12 units on a scale STANDARD_DEVIATION 1 | 0.00 units on a scale STANDARD_DEVIATION 1.08 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 33 Participants | 18 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 205 Participants | 98 Participants | 107 Participants |
| Region of Enrollment United States | 240 participants | 117 participants | 123 participants |
| Resting pupil diameter | 6.0 mm STANDARD_DEVIATION 1.8 | 6.1 mm STANDARD_DEVIATION 1.9 | 5.9 mm STANDARD_DEVIATION 1.8 |
| Sex: Female, Male Female | 131 Participants | 60 Participants | 71 Participants |
| Sex: Female, Male Male | 109 Participants | 57 Participants | 52 Participants |
| Worst daily pain | 4.75 units on a scale STANDARD_DEVIATION 2.54 | 4.78 units on a scale STANDARD_DEVIATION 2.77 | 4.71 units on a scale STANDARD_DEVIATION 2.31 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 135 | 1 / 139 |
| other Total, other adverse events | 17 / 135 | 2 / 139 |
| serious Total, serious adverse events | 1 / 135 | 0 / 139 |
Outcome results
Primary
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.
Time frame: The first day after hospital discharge up to 5 days post surgery
Population: The intention-to-treat population included all randomized patients who had at least one baseline pupil measurement, received at least one dose of study drug, and provided at least one pain score after the day of surgery.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Gabapentin | Comparison of Adjusted Trajectory Model for Pain Between Gabapentin and Placebo--Intercept | 7.57 score on a scale |
| Placebo | Comparison of Adjusted Trajectory Model for Pain Between Gabapentin and Placebo--Intercept | 7.52 score on a scale |
Comparison: The estimates were conducted using a linear mixed effects model contrasting differences in the gabapentin group versus placebo. In all cases, these differences are adjusted for prognostic variables including baseline pain, age, sex, pupil diameter, and catastophizing-optimism construct.p-value: 0.882Mixed Models Analysis
Primary
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.
Time frame: Postoperative Day 1 through Postoperative Day 60
Population: The intention-to-treat population included all randomized patients who had at least one baseline pupil measurement, received at least one dose of study drug, and provided at least one pain score after the day of surgery.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Gabapentin | Comparison of Adjusted Trajectory Model for Pain Between Gabapentin and Placebo-- Slope | -0.110 score on a scale/ln(day) |
| Placebo | Comparison of Adjusted Trajectory Model for Pain Between Gabapentin and Placebo-- Slope | -0.114 score on a scale/ln(day) |
Comparison: The estimates were conducted using a linear mixed effects model contrasting differences in the gabapentin group versus placebo. In all cases, these differences are adjusted for prognostic variables including baseline pain, age, sex, pupil diameter, and catastrophizing-optimism construct.p-value: 0.137Mixed Models Analysis
Primary
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.
Time frame: Postoperative Day 1 through Postoperative Day 60
Population: The intention-to-treat population included all randomized patients who had at least one baseline pupil measurement, received at least one dose of study drug, and provided at least one pain score after the day of surgery. The primary analysis, as pre-specified in the statistical analysis plan and upon which sample size was determined, tested whether growth curve model for change in pain over 2 months was better fit when group, pupil diameter, and cognitive construct scores were added.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gabapentin | Effect Pupil Diameter, Catastrophizing-optimism Construct, and Gabapentin on Model Fit of the Trajectory of Change in Worst Daily Pain After Surgery | 43604 unitless |
| Placebo | Effect Pupil Diameter, Catastrophizing-optimism Construct, and Gabapentin on Model Fit of the Trajectory of Change in Worst Daily Pain After Surgery | 343523 unitless |
Comparison: The null hypothesis (H0) is that modeled trajectory of change in pain intensity report after total hip or total knee arthroplasty does not differ between oral gabapentin and placebo in a manner dependent on its interaction with preferred cognitive style and pre-surgery pupil resting diameter . The alternative hypothesis (H1) is that there is a difference between the two groups which is dependent on these interactions.p-value: <0.0001Chi-squared
Secondary
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
Time frame: Preoperative, 2 months after surgery, 6 months after surgery
Population: The total completed for this secondary outcome is 111 in the gabapentin group and 115 in the placebo group. The reason for not completing was failure to complete the task on at least one of the three occasions that these were performed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gabapentin | Iowa Gambling Task | Preoperative | 8 score on a scale |
| Gabapentin | Iowa Gambling Task | 2 months after surgery | 6 score on a scale |
| Gabapentin | Iowa Gambling Task | 6 months after surgery | 5 score on a scale |
| Placebo | Iowa Gambling Task | Preoperative | 7 score on a scale |
| Placebo | Iowa Gambling Task | 2 months after surgery | 6 score on a scale |
| Placebo | Iowa Gambling Task | 6 months after surgery | 5 score on a scale |
Secondary
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.
Time frame: Preoperative, 2 months after surgery, 6 months after surgery
Population: The total completed for secondary analyses is 113 in the gabapentin group and 117 in the placebo group. The reason for not completing was failure to complete questionnaires on at least one of the three occasions that these were performed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gabapentin | Tampa Scale of Kinesiophobia | 6 months after surgery | 37 score on a scale |
| Gabapentin | Tampa Scale of Kinesiophobia | Preoperative | 37 score on a scale |
| Gabapentin | Tampa Scale of Kinesiophobia | 2 months after surgery | 36 score on a scale |
| Placebo | Tampa Scale of Kinesiophobia | 2 months after surgery | 37 score on a scale |
| Placebo | Tampa Scale of Kinesiophobia | 6 months after surgery | 36 score on a scale |
| Placebo | Tampa Scale of Kinesiophobia | Preoperative | 38 score on a scale |
Secondary
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.
Time frame: Preoperative, 2 months after surgery, 6 months after surgery
Population: The total completed for this secondary outcome is 113 in the gabapentin group and 116 in the placebo group. The reason for not completing was failure to complete questionnaires on at least one of the three occasions that these were performed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gabapentin | Wisconsin Card Sort Task | Preoperative | 4 score on a scale |
| Gabapentin | Wisconsin Card Sort Task | 2 months after surgery | 10 score on a scale |
| Gabapentin | Wisconsin Card Sort Task | 6 months after surgery | 18 score on a scale |
| Placebo | Wisconsin Card Sort Task | Preoperative | 2 score on a scale |
| Placebo | Wisconsin Card Sort Task | 2 months after surgery | 8 score on a scale |
| Placebo | Wisconsin Card Sort Task | 6 months after surgery | 18 score on a scale |
Other Pre-specified
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.
Time frame: Preoperative
Population: Data were not collected
Other Pre-specified
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.
Time frame: Preoperative
Population: Data were not collected