Effect of Oral Pregabalin on Spinal Neurotransmitters in Patients Undergoing Knee Replacement
Information source: Rush University Medical Center
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: PAIN
Intervention: Pregabalin (Drug); Pregabalin (Drug); Placebo (Drug)
Phase: Phase 3
Sponsored by: Asokumar Buvanendran
Official(s) and/or principal investigator(s):
Asokumar Buvanendran, MD, Principal Investigator, Affiliation: Rush University Medical Center
Jeffery S Kroin, PhD, Principal Investigator, Affiliation: Rush University Medical Center
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.
Official title: Effects of Oral Pregabalin on Spinal Neurotransmitters in Patients Undergoing Total Knee Replacement (TKA)
Study design: Allocation: Randomized, Endpoint Classification: Bio-equivalence Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
NRS Pain Score AUC (NRS*hr) - 1st 24 Hours
NRS Pain Score AUC (NRS*hr) - 1st 12 Hours
Active Knee Flexion
Passive Knee Flexion
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
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
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.
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
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.
Any adverse events will be noted and reported.
Minimum age: 55 Years.
Maximum age: 75 Years.
- History of osteoarthritis
- Subjects who can understand and communicate in English
- 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
- Patients who are currently enrolled in another investigational study.
Locations and Contacts
Rush University Medical Center, Chicago, Illinois 60612, United States
Starting date: August 2008
Last updated: November 20, 2012