Pregabalin for Central Sensitization in TKA

Evaluating the Efficacy and Safety of Pregabalin in Total Knee Arthroplasty Patients With Central Sensitization

The study purpose is to determine if giving pregabalin before and after total knee arthroplasty (TKA) can improve pain and meaningful function after surgery in patients that have central sensitization (CS).

Participants will be identified who are indicated for TKA. Interested patients will complete a standard Knee Injury and Osteoarthritis Outcomes Score (KOOS), asked their pain score (on a scale of 0 to 10), and complete the Central Sensitization Inventory (CSI). If they meet inclusion criteria and agree to participate, they will complete the informed consent before being randomized 1:1 to usual care (control group) or pregabalin (study group). The study group participants will take pregabalin starting 7 days prior to surgery. They will also be scheduled to have a pre-operative physical therapy (PT) appointment which will include tests and measures standard to PT. Tests will include a Timed Up and Go Test (TUG), a Sit to Stand 5 Times Repeat Test (5TSTS) and Patient Specific Functional Scale (SFS) measures.

On the day of surgery participants will be asked about any adverse effects of study medication and determine need to withdraw from study. The post-operative plan will be reviewed, including dose of study medication. For the pregabalin group the doses will be doubled for 7 days, then reduced for 7 days, then off. All participants will be given standard peri-operative pain management for TKA . All participants will complete standard of practice physical therapy.

After surgery (usually within 7 days) a physical therapist will perform standard post-operative evaluation and treatment for all participants. This includes a re-evaluation of the same pre-operative functional tests of TUG, 5TSTS and PSFS outcome measures. The study pharmacist will also call the patient to determine if there are any medication-related adverse effects and how much opioid medication the patient is taking at that time (morphine milligram equivalents- MME/day on average).

At the 6 week post-operative visit all participants will again complete the KOOS survey, report a pain score, complete the CSI survey and determine MME based on patient report of quantity of opioid medication used. A physical therapist will complete the functional assessment of the TUG, 5TSTS and PSFS outcome measures.

Study Overview

• Status: Terminated
• Conditions: Osteo Arthritis Knee; Central Nervous System Sensitization
• Intervention / Treatment: Drug: Pregabalin 75mg

Detailed Description

The study purpose is to determine if giving pregabalin before and after total knee arthroplasty (TKA) can improve pain and meaningful function after surgery in patients that have central sensitization (CS). Central sensitization occurs when the brain (central nervous system) becomes hypersensitized and hypervigilant, over-reacting to any painful (and sometimes nonpainful) stimuli. Patients with greater central sensitization have been shown to have significantly more pain after surgery, including TKA. We are proposing to explore whether treatment with a nerve pain medication, pregabalin, can improve post-operative pain and function in these patients. This medication has been shown to improve central sensitization pain in the chronic pain setting but has not been studied for this purpose in the acute surgical pain setting.

Participants will be identified at the visit in which they are indicated for TKA. Patients indicated for a TKA will be approached about participating in the study. Either at that visit or later by phone or e-mail, interested patients will complete a standard Knee Injury and Osteoarthritis Outcomes Score (KOOS), which is part of the standard orthopedic evaluation. They will also be asked their pain score (on a scale of 0 to 10), and complete the Central Sensitization Inventory (CSI). If they meet study inclusion criteria, and they agree to participate, they will complete the informed consent (in person or on-line) and then be randomized 1:1 to usual care (control group) or pregabalin (study group). The study group participants will take pregabalin starting 7 days prior to surgery. The participant will receive usual medication counseling for this medication. They will also be scheduled to have a pre-operative physical therapy (PT) appointment at the time of their pre-op visit, which will include tests and measures standard to PT, but must include a Timed Up and Go Test (TUG), a Sit to Stand 5 Times Repeat Test (5TSTS) and Patient Specific Functional Scale (SFS) measures.

On the day of surgery participants will be asked about any adverse effects of study medication, and determine need to withdraw from study (for any reason). The post-operative plan will also be reviewed, including dose of study medication, for the pregabalin group. For the pregabalin group the doses will be doubled for 7 days, then reduced for 7 days, then off. All participants will be given standard peri-operative pain management for TKA (a nerve block and/or spinal unless contraindicated, anti-inflammatory drugs (NSAID) and acetaminophen (unless contraindicated) as well as oral opioid (usually oxycodone or hydromorphone) to use as needed for severe pain. All participants will complete standard of practice physical therapy on day of surgery or until discharged to home.

After surgery (usually within 7 days) a physical therapist will perform standard post-operative evaluation and treatment for all participants. This includes a re-evaluation of the same pre-operative functional tests of TUG, 5TSTS and PSFS outcome measures. At this time, the pharmacist will also call the patient to determine if there are any medication-related adverse effects and how much opioid medication the patient is taking at that time (morphine milligram equivalents- MME/day on average).

Standard follow-up after TKA is 6 weeks. At this visit all participants will again complete the KOOS survey, report a pain score, complete the CSI survey and determine, based on patient report, of quantity of opioid medication used (MME). A physical therapist will complete the functional assessment of the TUG, 5TSTS and PSFS outcome measures.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals & Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Patients undergoing native joint unilateral TKA due to Grade 3-4 primary osteoarthritis
• Patients with score of at least 40 on Central Sensitization Inventory
• Patients who will complete PT within the U of Iowa Health Care system
• Patients who have been nonsmokers for > 2 years
• Patients between the ages of 50 and 85

Exclusion Criteria:

• Patients already taking pregabalin or had an adverse effect with pregabalin in the past
• Patients indicated for joint revision surgery
• Patients taking at least 30 morphine milligram equivalents per day for the past 1 month
• Patients with an estimate GFR < 30 ml/min
• Patients who do not have an understanding of English
• Patients who are pregnant or women of child-bearing years
• Patients who are prisoners
• Patients who score < 40 on the CSI
• Patients who answer Yes to any questions on the Columbia Suicide Severity Rating Scale or express suicidal ideation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control; Participants will receive standard peri-operative pain management
Experimental: Study (Pregabalin); Participants will receive pregabalin orally 75mg twice daily x 7 days prior to surgery, 150mg twice daily x 7 days after surgery, followed by 75mg twice daily x 7 days. Then Stop.	Drug: Pregabalin 75mg; participants will receive pregabalin orally 75mg twice daily x 7 days prior to surgery, then 150mg twice daily x 7 days after surgery, followed by 75mg twice daily x 7 days, then stop.; Other Names: Study

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Calculate the Change Using the Knee Osteoarthritis Outcome Survey- Activities of Daily Living Subscale	The difference in change on the Knee Osteoarthritis Outcome Survey (KOOS) - Activities of Daily Living subscale will be calculated between the treatment groups. The survey will be administered at baseline and at the subject's 6-weeks post procedure follow-up. The survey is scored on a continuous scale as follows: 1 = none, 2 = mild, 3 = moderate, 4 = severe, 5 = extreme.	Approximately 6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Calculate the Change Using the Knee Osteoarthritis Outcome Survey-Symptoms	The difference in change on the Knee Osteoarthritis Outcome Survey (KOOS) - Symptoms subscale will be calculated between the treatment groups. The survey will be administered at baseline and at the subject's 6-weeks post procedure follow-up. The survey is scored on a continuous scale as follows: 1 = never, 2 = rarely, 3 = sometimes, 4 = often, 5=always.	Approximately 6 weeks
Calculate the Change Using the Knee Osteoarthritis Outcome Survey-Stiffness	The difference in change on the Knee Osteoarthritis Outcome Survey (KOOS) - Stiffness subscale will be calculated between the treatment groups. The survey will be administered at baseline and at the subject's 6-weeks post procedure follow-up. The survey is scored on a continuous scale as follows: 1 = none, 2 = mild, 3 = moderate, 4 = severe, 5 = extreme.	Approximately 6 weeks
Calculate the Change Using the Knee Osteoarthritis Outcome Survey-Sports and Recreational Activities	The difference in change on the Knee Osteoarthritis Outcome Survey (KOOS) - Sports and Recreational Activities subscale will be calculated between the treatment groups. The survey will be administered at baseline and at the subject's 6-weeks post procedure follow-up. The survey is scored on a continuous scale as follows: 1 = none, 2 = mild, 3 = moderate, 4 = severe, 5 = extreme.	Approximately 6 weeks
Calculate the Change in Central Sensitization Inventory Score	The difference in change on the Central Sensitization Inventory assessment will be calculated between the treatment groups. The survey will be administered at baseline and at the subject's 6-weeks follow-up. The survey is scored on a continuous scale as follows: 1 = never, 2 = rarely, 3 = sometimes, 4 = often, 5 = always.	Approximately 6 weeks
Calculate the Change of Physical Function Using the Timed Up & Go Assessment	The change of physical function using the Timed Up & Go Assessment (TUG) will be evaluated at four intervals during the study; baseline, during the immediate post-operative time period (day of surgery or post-operative day 1), 7-day follow-up, and at 6-week follow-up. Patients will stand up from a chair, walk approximately 10 feet, turn, walk back and sit back down. This activity will be timed in seconds. The change from baseline until 6-week follow-up will be reported.	Approximately 6 weeks
Calculate the Change of Physical Function Using the Stand to Sit Assessment	The change of physical function using the Stand to Sit Assessment (STS) will be evaluated at four intervals during the study; baseline, during the immediate post-operative time period (day of surgery or post-operative day 1), 7-day follow-up, and at 6-week follow-up. Patients will stand up and sit down from a chair 5 times in a row, as quickly as they can. This activity will be timed in seconds. The change from baseline until 6-week follow-up will be reported.	Approximately 6 weeks
Calculate the Change of Physical Function Using the Patient-Specific Functional Scale Assessment	The change of physical function using the Patient-Specific Functional Scale Assessment (PSFS) will be evaluated at four intervals during the study; baseline, during the immediate post-operative time period (day of surgery or post-operative day 1), 7-day follow-up, and at 6-week follow-up. At baseline, patients will asked to identify activities they are having difficulty/unable to do and would like to gain the mobility back after procedure. The activities will be scored on a continuous rating with The change from baseline until 6-week follow-up will be reported.	Approximately 6 weeks
Measure the Amount of Pain Reported After Procedure	Using a numerical rating scale (0-10), patients will be asked to report their pain level. The scale is from 0 to 10 with 0 being no pain and 10 representing the most intense pain. The pain scores will be collected on 7-day post procedure follow-up and at the 6-week follow up. The change between the timepoints will be reported.	Approximately 6 weeks
Measure Post-operative Opioid Usage	Review with subjects the type and amount of additional pain (opioid) medication required to control their pain. This will be examined approximately 7-day post procedure and at the 6-week post procedure follow-up. The amount of opioid medication taken by the subject will be converted to morphine equivalents for reporting purposes.	Approximately 6 weeks

Collaborators and Investigators

• Sponsor: University of Iowa
• Investigators: Principal Investigator: Lee Kral, Pharm. D., University of Iowa

Study record dates

Study Major Dates

• Study Start (Actual): February 21, 2023
• Primary Completion (Actual): January 25, 2024
• Study Completion (Actual): January 25, 2024

Study Registration Dates

• First Submitted: July 13, 2022
• First Submitted That Met QC Criteria: July 13, 2022
• First Posted (Actual): July 15, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 11, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Pain; Arthroplasty; Central Nervous System Sensitization; Osteo Arthritis Knee; Pregabalin
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Joint Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Osteoarthritis, Knee; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Central Nervous System Depressants; Sensory System Agents; Analgesics; Membrane Transport Modulators; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; Anticonvulsants; Calcium Channel Blockers; Pregabalin
• Other Study ID Numbers: 202105361

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
• product manufactured in and exported from the U.S.: No