PainPhase 4NCT02685735

Predicting, Understanding and Speeding Recovery After TKA

A Phase 4 study testing Gabapentin in people with Pain and Total Knee Replacement, run by Wake Forest University Health Sciences at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial 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… Read more about this study

Who is it for?: Ages 18 to 70 years
Conditions the study is for: Pain, Total Knee Replacement, Total Hip Replacement
What is being tested?: Gabapentin
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 350 participants
Where: 1 siteUnited States
Study dates: 2 Jun 2016to 9 Feb 2022
Phase: Phase 4
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 70 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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

Who cannot join

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

Trial locations and contacts

1 site in 1 country.

United States1 site

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

Other trials in United States

About this study

Official title: Predicting, Understanding, and Speeding Recovery After Total Knee Arthroplasty

Read the 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.

Conditions: Pain, Total Knee Replacement, Total Hip Replacement
Being tested: Gabapentin, Placebo
Medical subject headings: Pain

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

GabapentinDrug
Also called neurontin
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.
PlaceboDrug
Also called Inert ingredient
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.

Study groups in NCT02685735
Study group	Role	What they receive
Gabapentin	Active comparator	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. Receives: Drug: Gabapentin
Placebo	Placebo comparator	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. Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: 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.
Measured: Postoperative Day 1 through Postoperative Day 60

Secondary outcomes (3)

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.
Measured: 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
Measured: 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.
Measured: Preoperative, 2 months after surgery, 6 months after surgery

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

2 Jun 20169 Feb 2022

First posted19 Feb 2016 (estimated)
Study start2 Jun 2016
Primary completion9 Feb 2022
Study completion9 Feb 2022

Why it stopped: lack of continued funding support

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Other trials for PainStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 4
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 350 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02685735
Sponsor's protocol ID: IRB00032506
Other IDs: 5P01GM113852
Status last verified: May 2023
First submitted: 1 Jun 2015
Last updated: 15 Aug 2025
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 15 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Predicting, Understanding, and Speeding Recovery After Total Knee Arthroplasty
ClinicalTrials.gov ID: NCT02685735
Acronym / sponsor ID: IRB00032506
Conditions: Pain, Total Knee Replacement, Total Hip Replacement
Phase: Phase 4
Study type: Interventional
Recruitment status: TerminatedReason stopped: lack of continued funding support
Enrolment: 350 participants (actual)
Lead sponsor: Wake Forest University Health SciencesUniversity, hospital or other
Collaborators: National Institute of General Medical Sciences (NIGMS)
Study start: 2 Jun 2016 (actual)
Primary completion: 9 Feb 2022 (actual)
Study completion: 9 Feb 2022 (actual)
First posted: 19 Feb 2016 (estimated)
Results: Posted 4 Oct 2023

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 2

Arm	Type	Receives
Gabapentin	Active comparator	Drug: GabapentinSubjects 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.
Placebo	Placebo comparator	Drug: PlaceboSubjects 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.

Who may qualify

Ages: 18 to 70 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (3 listed)

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

Key exclusion criteria (8 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
GabapentinAlso: neurontinDrug 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
PlaceboAlso: Inert ingredientDrug 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	Placebo

Primary outcome

Comparison of Adjusted Trajectory Model for Pain Between Gabapentin and Placebo--Intercept
Time frame: 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.
Comparison of Adjusted Trajectory Model for Pain Between Gabapentin and Placebo-- Slope
Time frame: 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.
Effect Pupil Diameter, Catastrophizing-optimism Construct, and Gabapentin on Model Fit of the Trajectory of Change in Worst Daily Pain After Surgery
Time frame: 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.

3 secondary outcomes

Wisconsin Card Sort Task
Time frame: Preoperative, 2 months after surgery, 6 months after surgery
Iowa Gambling Task
Time frame: Preoperative, 2 months after surgery, 6 months after surgery
Tampa Scale of Kinesiophobia
Time frame: Preoperative, 2 months after surgery, 6 months after surgery

Results and safety

Results posted to the registry on 4 Oct 2023, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Gabapentin	135	117
Placebo	139	123

Primary outcome: Comparison of Adjusted Trajectory Model for Pain Between Gabapentin and Placebo--Intercept

Time frame: The first day after hospital discharge up to 5 days post surgery. Mean (95% Confidence Interval). Unit: score on a scale

Measure	Gabapentin n = 117	Placebo n = 123
Value	7.57 (7.17 to 7.88)	7.52 (7.16 to 7.88)

Gabapentin vs Placebo: p = 0.882, Mixed Models Analysis

Primary outcome: Comparison of Adjusted Trajectory Model for Pain Between Gabapentin and Placebo-- Slope

Time frame: Postoperative Day 1 through Postoperative Day 60. Mean (95% Confidence Interval). Unit: score on a scale/ln(day)

Measure	Gabapentin n = 117	Placebo n = 123
Value	-0.110 (-0.113 to -0.107)	-0.114 (-0.117 to -0.111)

Gabapentin vs Placebo: p = 0.137, Mixed Models Analysis

Primary outcome: Effect Pupil Diameter, Catastrophizing-optimism Construct, and Gabapentin on Model Fit of the Trajectory of Change in Worst Daily Pain After Surgery

Time frame: Postoperative Day 1 through Postoperative Day 60. Number. Unit: unitless

Measure	Adjusted Daily Worst Pain Trajectory Model (Model 1) n = 240	Pain Trajectory Model Plus Pupil, Cognitive Style, and Study Drug Factors (Model 2) n = 240
Value	43604	343523

Adjusted Daily Worst Pain Trajectory Model (Model 1) vs Pain Trajectory Model Plus Pupil, Cognitive Style, and Study Drug Factors (Model 2): p <0.0001, Chi-squared

Population analysed: 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.

3 secondary outcomes are reported in the full results.

Adverse events

Time frame: through study completion, an average of 1 year per participant. Other adverse events reported at 3% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Gabapentin	1 of 135 (0.7%)	17 of 135 (12.6%)	1 of 135
Placebo	0 of 139 (0%)	2 of 139 (1.4%)	1 of 139

Limitations and caveats (from the sponsor): Early termination leading to 240 rather than 250 participants analyzed.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 15 Aug 2025.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Individual participant dataSharing planned: No

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

James C Eisenach, MD principal investigator

Wake Forest University Health Sciences

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Gabapentin in people with Pain and Total Knee Replacement, run by Wake Forest University Health Sciences at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 15 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 4 Oct 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Comparison of Adjusted Trajectory Model for Pain Between Gabapentin and Placebo--Intercept (time frame: The first day after hospital discharge up to 5 days post surgery). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02685735.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Aug 2025.