Effect of Oral Pregabalin on Spinal Neurotransmitters in Patients Undergoing Knee Replacement
Condition: PAIN
Study type: Interventional
Phase: Phase 3

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.
    

Intervention name(s): Pregabalin; Pregabalin; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 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.; 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 intervention name(s): Lyrica; Lyrica; Lyrica
Intervention MeSH terms: Pregabalin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Pregabalin; CSF; Neurotransmitter