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Valproic Acid for the Prevention of Post-Amputation Pain

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01928849
First Posted: August 27, 2013
Last Update Posted: October 27, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
United States Department of Defense
Information provided by (Responsible Party):
Duke University
  Purpose

The objectives of this study are, to test the effectiveness of Valproic Acid (VPA) in the prevention of chronic neuropathic and post-amputation pain, as well as to further define the underlying inflammatory and epigenetic mechanisms that lead to the development of such chronic pain.

HYPOTHESES AND QUESTIONS

Hypothesis 1: The use of oral valproic acid in combination with regional anesthesia in surgical limb-injury patients will decrease the incidence of chronic nerve injury and post-amputation pain.

Goal 1: In a blinded, randomized placebo-controlled, multi-center clinical trial, investigators will determine if oral VPA added to regional anesthesia and standard perioperative management will reduce the incidence of nerve injury and post-amputation pain when compared with regional anesthesia alone.

Hypothesis 2: The transition from acute to chronic pain is mediated via epigenetic mechanisms (differential DNA methylation) in genes involved in nociception.

Goal 2: Investigators will analyze the DNA methylation patterns of patients with different types of neuropathic and post-amputation pain and determine if they are altered by VPA.


Condition Intervention Phase
Pain, Phantom Pain, Neuropathic Drug: Valproic Acid Other: Cherry Syrup Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Regional Anesthesia and Valproate Sodium for the Prevention of Chronic Post-Amputation Pain

Resource links provided by NLM:


Further study details as provided by Duke University:

Primary Outcome Measures:
  • Efficacy of Valproic Acid in reducing the Incidence of chronic neuropathic and post-amputation pain. [ Time Frame: 3 months or time of final adjudication assessment ]
    The primary endpoint is the incidence of chronic pain after surgery. The study team will use the average pain score over the past week as noted on the Self-Reported Leeds Assessment of Neuropathic Symptoms and Signs pain scale (S-LANSS) for the assessment of pain, and define chronic pain as a score greater than or equal to 3.


Secondary Outcome Measures:
  • Neuropathic limb or post-amputation pain, and the incidence of pain sub-types [ Time Frame: Assessments at enrollment and 3 months or time of final adjudication ]
    The incidence of neuropathic limb or post-amputation pain sub-types as defined by adjudication classification at each assessment time point.

  • Effect on analgesic requirement [ Time Frame: Assessments at enrollment, during hospitalization (0-24 hours and 24-48 hours post-surgery), and 3 months or time of final adjudication ]
    The effect of study drug on perioperative analgesic consumption and corresponding analysis of pain/sedation scales. Outcome defined as total opioid consumption (mg) during each 24-hour periods following surgery.

  • Brief Pain Inventory (BPI) short form [ Time Frame: baseline and 3 months or time of final adjudication ]
    The BPI short form is a multidimensional patient-completed measure that assesses the sensory component of pain intensity. We will analyze the average pain score question (ranges 0-10) and the sum of the 7 interference questions (total range 0-70) at each time point and the change in the score from baseline.

  • Change in Self-Reported Leeds Assessment of Neuropathic Symptoms and Signs pain scale (S-LANSS) [ Time Frame: baseline and 3 months or time of final adjudication ]
    The S-LANSS is a self-reported version of the Leeds Assessment of Neuropathic Symptoms and Signs pain scale. It aims to differentiate neuropathic pain from somatic or nociceptive pain. We will analyze the numeric average pain score during the past week (range from 0-10) at each time point and the change in the score from baseline.

  • Defense and Veterans Pain Rating Scale (DVPRS) [ Time Frame: baseline and 3 months or time of final adjudication ]
    The DVPRS is a pain assessment tool developed by the military in an effort to improve reliability and interpretability of pain assessment in the military population. It has been found to be an effective and valid tool in this population. We will analyze the change in numeric pain response (range 0-10) and the sum of the four supplemental questions (range 0-40) at each time point and the change in the score from baseline.

  • Richmond Agitation-Sedation Scale (RASS) [ Time Frame: baseline and during hospitalization (0-24 hours and 24-48 hours post-surgery) ]
    The RASS is a commonly used, valid and reliable assessment tool for use in hospitalized patients. Validity testing reveals good inter-rater reliability among medical, surgical, and intensive care units. We will analyze the numeric score at each assessment (range -5 (unarousable) to 4 (combative)).


Other Outcome Measures:
  • Observation of epigenetic alterations that occur in the transition from acute to chronic pain. [ Time Frame: Changes between enrollment, end of study drug and 3 months or time of final adjudication ]
    Epigenetic analysis (DNA methylation) will be correlated with pain sub-type and use of Valproic Acid.


Estimated Enrollment: 224
Study Start Date: December 2013
Study Completion Date: September 26, 2017
Primary Completion Date: September 26, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Cherry syrup
Cherry Syrup: Patients randomized to the "Control arm" of the trial will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and the placebo.
Other: Cherry Syrup
Intervention arm patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid 250mg preoperatively, and then three times per day for 6 days post-operatively.
Experimental: Valproic Acid
"Intervention arm" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid.
Drug: Valproic Acid
"Intervention" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and oral valproic acid 250mg preoperatively, then three times per day for either 6 days post-operatively or until discharge from the hospital.
Other Name: Depacon, Depakene, Depakote, Stavzor

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male and female active duty military personnel or veterans, age 18 years and older.
  • Patient is scheduled to undergo amputation, stump revision, or surgery for a limb injury with neurologic damage.
  • Patient able to provide written informed consent prior to any study procedures.

Exclusion Criteria:

  • Severe Traumatic Brain Injury (Diagnosis of traumatic brain injury resulting in documented, permanent or prolonged cognitive deficits that would preclude participation in the study)
  • Significant cognitive deficits or dementia of any cause as noted in Computerized Patient Record System(CPRS).
  • Patient has a designated Legally Authorized Representative
  • Substantial hearing loss without alternative means of communication.
  • Patient has documented spinal cord injury with permanent or persistent deficits
  • Patient is under age 18 or a legal Minor
  • Current pregnancy or lactation
  • Cirrhosis with evidence of decompensation: coagulopathy International Normalized Ratio (INR) >1.3, thrombocytopenia with platelets <100,000, ascites or hepatic encephalopathy
  • Therapy with valproic acid or other valproates, coumadin, chlorpromazine and olanzapine at the time of surgery and study drug administration
  • Current diagnosis of seizure disorder requiring anti-epileptic medication
  • Current therapy with tricyclic antidepressants (eg: amitriptyline, nortriptyline, imipramine, desipramine) at doses greater than 50mg/day
  • Currently taking zidovudine
  • Current diagnosis of malaria requiring anti-malaria medication (such as mefloquine and chloroquine)
  • Currently taking monoamine oxide inhibitors (MAOI)
  • Allergy to valproates or valproic acid
  • Contraindication to, or refusal of, regional anesthesia catheter
  • BMI > 50
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01928849


Locations
United States, Maryland
Walter Reed National Military Medical Center
Bethesda, Maryland, United States, 20814
United States, North Carolina
Duham VA Medical Center
Durham, North Carolina, United States, 27705
Sponsors and Collaborators
Duke University
United States Department of Defense
Investigators
Principal Investigator: Thomas E Buchheit, MD Duke University
  More Information

Publications:
Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT01928849     History of Changes
Other Study ID Numbers: Pro00047194
PT110575 ( Other Grant/Funding Number: US Department of Defense )
First Submitted: February 15, 2013
First Posted: August 27, 2013
Last Update Posted: October 27, 2017
Last Verified: July 2017

Keywords provided by Duke University:
Amputation
Post-amputation Pain
Neuropathic pain
Valproic Acid
Anesthesia, Conduction
Neuralgia, stump

Additional relevant MeSH terms:
Neuralgia
Phantom Limb
Pain
Neurologic Manifestations
Nervous System Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Signs and Symptoms
Perceptual Disorders
Neurobehavioral Manifestations
Pain, Postoperative
Postoperative Complications
Pathologic Processes
Anesthetics
Valproic Acid
Central Nervous System Depressants
Physiological Effects of Drugs
Anticonvulsants
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Antimanic Agents
Tranquilizing Agents
Psychotropic Drugs