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Trial record 66 of 425 for:    Pregabalin

Effect of Oral Pregabalin on Spinal Neurotransmitters in Patients Undergoing Knee Replacement

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ClinicalTrials.gov Identifier: NCT00729690
Recruitment Status : Completed
First Posted : August 7, 2008
Results First Posted : December 19, 2012
Last Update Posted : December 19, 2012
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Asokumar Buvanendran, Rush University Medical Center

Tracking Information
First Submitted Date  ICMJE August 5, 2008
First Posted Date  ICMJE August 7, 2008
Results First Submitted Date  ICMJE October 18, 2012
Results First Posted Date  ICMJE December 19, 2012
Last Update Posted Date December 19, 2012
Study Start Date  ICMJE August 2008
Actual Primary Completion Date June 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 20, 2012)
  • NRS Pain Score AUC (NRS*hr) - 1st 24 Hours [ Time Frame: 24 hours ]
    Numerical Response scale NRS(0-10) Pain scores were collected every 4 hours after the initial dose and the Area Under the Curve (AUC) calculated. Calculated for the 1st 24 hours after initial dose (0-24hr). AUC measured in NRS pain score points per hour (NRS*hr). Larger AUC values indicate higher levels of reported pain.
  • NRS Pain Score AUC (NRS*hr) - 1st 12 Hours [ Time Frame: 12 hours Post dose ]
    Numerical Response scale NRS(0-10) Pain scores were collected every 4 hours after the initial dose and the Area Under the Curve (AUC) calculated. Calculated for the 1st 12 hours after initial dose (0-12hr). AUC measured in NRS pain score points per hour (NRS*hr). Larger AUC values indicate higher levels of reported pain.
Original Primary Outcome Measures  ICMJE
 (submitted: August 6, 2008)
VAS pain scores will be obtained beginning at 4 h after the initial dose, and total intrathecal medication consumption will be recorded at each 8 h interval over a 32-hour period. [ Time Frame: 1 week ]
Change History Complete list of historical versions of study NCT00729690 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 20, 2012)
  • Active Knee Flexion [ Time Frame: PostOp day 2 ]
    The degree of active knee flexion (ROM) tolerated by the patient will be assessed at days 1 and 2 post-surgery. Active flexion is the unassisted moment of the joint by the subject. On postoperative (PostOp) day 2
  • Passive Knee Flexion [ Time Frame: PostOp day 2 ]
    Passive flexion is the moment of the joint with the assistance of a clinician (The clinician or therapist physically hold and moves the knee through it's range of motion).
Original Secondary Outcome Measures  ICMJE
 (submitted: August 6, 2008)
Physical therapy will be initiated twice daily starting on the first postoperative day. The degree of active and passive knee flexion (ROM) tolerated by the patient will be assessed at days 1 and 2 post-surgery. [ Time Frame: 1week ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of Oral Pregabalin on Spinal Neurotransmitters in Patients Undergoing Knee Replacement
Official Title  ICMJE Effects of Oral Pregabalin on Spinal Neurotransmitters in Patients Undergoing Total Knee Replacement (TKA)
Brief Summary This study involves research. Pregabalin is a Food and Drug Administration (FDA) medication approved in the United States for the treatment of nerve pain related to diabetes and post-herpetic neuralgia "shingles", and for seizures in adults. The purpose of this research is to study the effect of oral Pregabalin on spinal neurotransmitters in subjects undergoing Total Knee Replacement Surgery (TKA). TKA is associated with considerable postoperative pain which if unrelieved may result in prolonged hospital stay, inability to participate in rehabilitation programs, poor outcomes, and greater use of health-care resources. This study examines the effect of pregabalin administered for TKA on pain-related neurotransmitter concentrations.
Detailed Description

Gabapentin and the related more potent compound pregabalin have been shown to reduce postoperative pain in animal models (1). Pregabalin given before and after surgery reduced opioid use following spinal fusion surgery (2). Studies have identified the alpha 2 delta auxiliary subunit of voltage-gated calcium channels as the molecular target of pregabalin (and gabapentin), although the specific spinal site of action (presynaptic, postsynaptic) is not known.

Total knee arthroplasty (TKA) has proved to be a successful surgical treatment of knee joints affected by osteoarthritis. Currently in the United States, more than 400,000 TKAs are performed every year with reported success rates ranging from 85% to 90% (American Academy). In an aging population, the number of annual TKA procedures is expected to reach 3.48 million by the year 2030 (3).

TKA is associated with considerable postoperative pain which if unrelieved may result in prolonged hospital stay, inability to participate in rehabilitation programs, poor outcomes, and greater use of health-care resources. Perioperative pregabalin improves postoperative outcomes after TKA (4). This study examines the effect of pregabalin administered perioperatively for TKA on pain-related neurotransmitter concentrations, intrathecal analgesic consumption and range of motion (ROM). Pregabalin effects on neurotransmitter concentrations may identify pathways by which α2δ binding by pregabalin reduces postoperative pain.

Objectives:

Primary Endpoint: Measure effect of pregabalin on spinal neurotransmitters after TKA Secondary Endpoint: Correlate changes in spinal neurotransmitters with pregabalin to improvements in patient outcomes after TKA (e.g. ROM).

Other Endpoints: Suggest spinal anatomical sites of action of oral pregabalin as relates to neurotransmitter modulation and pain.

Methods:

Patient selection After approval of the Institutional Review Board of Rush University Medical Center, Chicago, Illinois, USA, 48 patients scheduled to undergo elective primary TKA by a single orthopedic surgeon will be contacted and assessed for study eligibility with a screening medical history.

A study consent form will be sent to patients who agreed to participate in the clinical study. After obtaining consent, the patient will be allocated a study number and the study drug dispensed to each participant. Using a random number table, patients will be allocated to one of three groups, without stratification by demographic characteristics:

Group 1 (n=16, multi-dose pregabalin): patients receive pregabalin 150 mg orally 1 hour prior to surgery and then repeat 150 mg doses at 12 and 24 hours after initial dose.

Group 2 (n=16, single dose pregabalin): patients receive pregabalin 150 mg orally 1 hour prior to surgery, and then placebo doses at 12 and 24 hours after initial dose.

Group 3 (n=16, placebo): patients receive matching placebo at the same 3 time points as Groups 1 and 2.

The 12 hour dosing interval was based on our pharmacokinetic study showing that after a 300 mg oral pregabalin dose, cerebrospinal fluid (CSF) pregabalin concentration reaches its peak at 8 h or later (5). Study drug administration on the day of surgery was timed to precede surgical incision by 60 +/- 30 minutes.

The physicians and nurses managing the patient during surgery and in the recovery room, the personnel involved with postoperative pain assessment and management of the intrathecal infusion, and the study patients will be blinded to group assignments. Treatment assignment codes will not be available to the investigators until all patients completed the study. A global pain score using the visual analogue scale (VAS) with 0 corresponding to "no pain" and 10 to "the worst imaginable pain" for the patient will be obtained before surgery. In the operating room, patients will be sedated with midazolam (0.05 mg/kg titrated to effect) and an intrathecal catheter placed in the sitting position, at the L3-4 or L4-5 vertebral level to deliver spinal anesthesia with bupivacaine 0.5%, (7.5 mg) and fentanyl 25mcg. Subjects will be maintained at normothermia in the operating room. A sensory analgesic level of T10 will be obtained prior to commencement of surgery. At completion of surgery an intrathecal infusion of fentanyl 0.5 mcg/ml and bupivacaine 0.1 mg/ml will be initiated using a continuous basal infusion with superimposed patient controlled intrathecal analgesia (PCIA) bolus doses. Initial infusion rates will be 4 ml/h basal intrathecal infusion plus PCIA of 1 ml q 12 min with a 4-hour lockout of 40 ml. The patients will be instructed prior to surgery to use PCIA mode at their discretion to maintain the VAS pain score <4, following a previously applied protocol (6). A standardized surgical technique will be used in all subjects.

The intrathecal catheter will be left in place for 32 h postoperatively to provide analgesia, and lumbar CSF (0.5 ml) will be withdrawn (0.5 mL) at 2, 4, 8, 12, 24, and 32 h after the initial oral dose. CSF will be frozen at -80 Centigrade (C) for subsequent assay of neurotransmitter levels. Even though CSF pregabalin does not reach its peak concentration until at least 8 h after an oral dose, earlier time points are important because:

  1. Even at 2 h post-dose the CSF pregabalin concentration is already 29% of peak value, and may cause changes in neurotransmitter levels, compared to placebo.
  2. CSF inflammatory mediators, such as Interleukin-6 (IL-6), increase as early as 3 h after start of surgery after total hip arthroplasty (7), and so it can be expected that neurotransmitter levels will also show early changes due to the TKA surgery alone. Any characterization of pregabalin effects on neurotransmitters after surgery needs to also measure these early changes in neurotransmitter levels, since later time points (e.g. 24 h) are not independent of events occurring earlier.

Adverse Events:

Any adverse events will be noted and reported.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE PAIN
Intervention  ICMJE
  • Drug: Pregabalin

    Group 1 (n=16, multi-dose pregabalin): patients receive pregabalin 150 mg orally 1 hour prior to surgery and then repeat 150 mg doses at 12 and 24 hours after initial dose.

    Group 2 (n=16, single dose pregabalin): patients receive pregabalin 150 mg orally 1 hour prior to surgery, and then placebo doses at 12 and 24 hours after initial dose.

    Group 3 (n=16, placebo): patients receive matching placebo at the same 3 time points as Groups 1 and 2.

    Other Name: Lyrica
  • Drug: Pregabalin
    Group 2 (n=16, single dose pregabalin): patients receive pregabalin 150 mg orally 1 hour prior to surgery, and then placebo doses at 12 and 24 hours after initial dose.
    Other Name: Lyrica
  • Drug: Placebo
    Group 3 (n=16, placebo): patients receive matching placebo at the same 3 time points as Groups 1 and 2.
    Other Name: Lyrica
Study Arms  ICMJE
  • Experimental: 1 Multi-Dose Pregabalin
    Group 1 (n=16, multi-dose pregabalin): patients receive pregabalin 150 mg orally 1 hour prior to surgery and then repeat 150 mg doses at 12 and 24 hours after initial dose.
    Intervention: Drug: Pregabalin
  • Experimental: 2 single-dose pregabalin
    Group 2 (n=16, single dose pregabalin): patients receive pregabalin 150 mg orally 1 hour prior to surgery, and then placebo doses at 12 and 24 hours after initial dose.
    Intervention: Drug: Pregabalin
  • Placebo Comparator: 3 Placebo
    Group 3 (n=16, placebo): patients receive matching placebo at the same 3 time points as Groups 1 and 2.
    Intervention: Drug: Placebo
Publications * Buvanendran A, Kroin JS, Della Valle CJ, Moric M, Tuman KJ. Cerebrospinal fluid neurotransmitter changes during the perioperative period in patients undergoing total knee replacement: a randomized trial. Anesth Analg. 2012 Feb;114(2):434-41. doi: 10.1213/ANE.0b013e31823dc5fb. Epub 2011 Dec 9.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 6, 2008)
48
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 2011
Actual Primary Completion Date June 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • History of osteoarthritis
  • Subjects who can understand and communicate in English

Exclusion Criteria:

  • Younger than 55 years or older than 75 years.
  • American Society of Anesthesiologists physical status IV
  • Prior use of pregabalin or gabapentin will not be an exclusionary criterion; however patients will have been withdrawn from these medications at least 14 days before surgery
  • Patients who are currently enrolled in another investigational study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 55 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00729690
Other Study ID Numbers  ICMJE 08021105
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Asokumar Buvanendran, Rush University Medical Center
Study Sponsor  ICMJE Asokumar Buvanendran
Collaborators  ICMJE Pfizer
Investigators  ICMJE
Principal Investigator: Asokumar Buvanendran, MD Rush University Medical Center
Principal Investigator: Jeffery S Kroin, PhD Rush University Medical Center
PRS Account Rush University Medical Center
Verification Date November 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP