Valproic Acid for the Prevention of Post-Amputation Pain

NCT01928849 | Completed Phase 2 Results DMC

• 2 other identifiers: Pro00047194PT110575
• Study Type: interventional
• Target: 128
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Pain, Phantom; Pain, Neuropathic

Keywords

Amputation; Post-amputation Pain; Neuropathic pain; Valproic Acid; Anesthesia, Conduction; Neuralgia, stump

Outcome Measures

Primary Outcomes (1)

• Number of Patients With Chronic Post-amputation Pain

  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.

  3 months or time of final adjudication assessment, up to 6 months

Secondary Outcomes (6)

• Incidence of Pain Sub-types

  Assessments at enrollment and 3 months or time of final adjudication assessment (up to 6 months)

• Effect on Analgesic Requirement

  Assessments during hospitalization (0-24 hours and 24-48 hours post-surgery)

• Brief Pain Inventory (BPI) Short Form Score

  Assessments at enrollment and 3 months or time of final adjudication assessment (up to 6 months)

• Change in Self-Reported Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale (S-LANSS)

  Assessments at enrollment and 3 months or time of final adjudication assessment (up to 6 months)

• Defense and Veterans Pain Rating Scale (DVPRS) Score

  Assessments at enrollment and 3 months or time of final adjudication assessment (up to 6 months)

Other Outcomes (1)

• Observation of Epigenetic Alterations That Occur in the Transition From Acute to Chronic Pain.

  Changes between enrollment, end of study drug and 3 months or time of final adjudication

Study Arms (2)

Cherry syrup

PLACEBO COMPARATOR

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

Valproic Acid

EXPERIMENTAL

"Intervention arm" patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid.

Drug: Valproic Acid

Interventions

Valproic Acid DRUG

"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.

Also known as: Depacon, Depakene, Depakote, Stavzor

Valproic Acid

Cherry Syrup OTHER

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.

Cherry syrup

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Duke University: lead
• United States Department of Defense: collaborator

Study Sites (2)

Walter Reed National Military Medical Center

Bethesda, Maryland, 20814, United States

Location

Duham VA Medical Center

Durham, North Carolina, 27705, United States

Location

Related Publications (5)

• Gill D, Derry S, Wiffen PJ, Moore RA. Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2011 Oct 5;2011(10):CD009183. doi: 10.1002/14651858.CD009183.pub2.

  PMID: 21975791 BACKGROUND

• Sinn DI, Kim SJ, Chu K, Jung KH, Lee ST, Song EC, Kim JM, Park DK, Kun Lee S, Kim M, Roh JK. Valproic acid-mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation. Neurobiol Dis. 2007 May;26(2):464-72. doi: 10.1016/j.nbd.2007.02.006. Epub 2007 Feb 23.

  PMID: 17398106 BACKGROUND

• Detich N, Bovenzi V, Szyf M. Valproate induces replication-independent active DNA demethylation. J Biol Chem. 2003 Jul 25;278(30):27586-92. doi: 10.1074/jbc.M303740200. Epub 2003 May 14.

  PMID: 12748177 BACKGROUND

• Zhang Z, Cai YQ, Zou F, Bie B, Pan ZZ. Epigenetic suppression of GAD65 expression mediates persistent pain. Nat Med. 2011 Oct 9;17(11):1448-55. doi: 10.1038/nm.2442.

  PMID: 21983856 BACKGROUND

• Reiber GE, McFarland LV, Hubbard S, Maynard C, Blough DK, Gambel JM, Smith DG. Servicemembers and veterans with major traumatic limb loss from Vietnam war and OIF/OEF conflicts: survey methods, participants, and summary findings. J Rehabil Res Dev. 2010;47(4):275-97. doi: 10.1682/jrrd.2010.01.0009.

  PMID: 20803399 BACKGROUND

MeSH Terms

Conditions

Phantom Limb; Neuralgia

Interventions

Valproic Acid

Condition Hierarchy (Ancestors)

Perceptual Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Pain, Postoperative; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Pain; Peripheral Nervous System Diseases; Neuromuscular Diseases

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids

Results Point of Contact

• Title: Thomas Buchheit, MD Division Chief, Pain Medicine
• Organization: Duke University Department of Anesthesiology

Thomas.Buchheit@duke.edu

9196811924

Study Officials

• Thomas E Buchheit, MD

  Duke University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 15, 2013
• First Posted: August 27, 2013
• Study Start: December 1, 2013
• Primary Completion: September 26, 2017
• Study Completion: September 26, 2017
• Last Updated: December 19, 2018
• Results First Posted: October 25, 2018

Record last verified: 2018-11

Locations

US (2)