Study to Identify the Genetic Variations Associated With Phantom Limb Pain

The purpose of this study is to determine if there is a genetic component to phantom limb pain. DNA will be analyzed for single nucleotide polymorphisms (SNPs) between the control and phantom limb pain group. Total RNA will also be isolated and profiled to asses the degree to which our gene(s) of interest are expressed in the presence or absence of phantom limb pain. Some proteins, such as inflammatory antibodies or the neurotrophin brain-derived neurotrophic factor (BDNF), will also be assessed for their association(s) with phantom limb pain.

Study Overview

• Status: Unknown
• Conditions: Phantom Limb
• Intervention / Treatment: Procedure: Blood Draw

Detailed Description

Most patients (90-95%)with major limb amputations experience a phantom limb--the vivid impression that the limb is still present. In many cases, the sensation is painful for reasons that are currently not well understood. A small subset of amputees (<10%) never experience phantom limb pain (PLP), the painful sensation felt in the amputated limb. This difference suggests that there may be a genetic component that precludes some patients from ever experiencing PLP. Understanding the genetic components of PLP may help in predicting which patients will experience PLP and which amputees will respond to the various treatment options available.

In order to understand the genetic aspects and ultimately develop more effective treatment options in the future, patients with and without PLP will be asked to give 30 mls of blood after overnight fasting. These blood samples will be de-identified and sent to the National Institutes of Health (NIH) in Bethesda, Maryland, where all of the genetic analyses will take place.

• Study Type: Observational
• Enrollment (Actual): 726

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20889
      • Walter Reed National Military Medical Center (WRNMMC)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Subjects to be recruited at WRNMMC will be military health care beneficiaries age 18 and older who have sustained one or more amputations.

Description

Chronic PLP Group:

• At least 18 years of age.
• Written informed consent and written authorization for use or release of health and research study information
• Single or multiple upper and/or lower limb amputation
• At least three months post-amputation
• Ability to follow study instructions and likely to complete required visit(s)
• Experienced PLP for at least one month and at least 3 times per week
• Phantom limb pain differentiated from residual limb pain by physical exam.
• Subjects taking blood thinners or other medications that do not increase risk during a blood draw.

Non-Chronic PLP Group:

• At least 18 years of age.
• Written informed consent and written authorization for use or release of health and research study information
• Single or multiple upper and/or lower limb(s) amputation
• At least three months post-amputation
• Ability to follow study instructions and likely to complete required visit(s)
• Experienced PLP less than 10 times total and/or for less than two weeks
• Subjects taking blood thinners or other medications that do not increase risk during a blood draw.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Phantom Limb Pain; Subjects will have lower or upper extremity amputation(s) that have resulted in the presence of phantom limb pain.	Procedure: Blood Draw; Single blood draw of 30 ml; Other Names: Venipuncture
No Phantom Limb Pain; Subjects in the group will have a lower or upper extremity amputation(s) without the presence of phantom limb sensation.	Procedure: Blood Draw; Single blood draw of 30 ml; Other Names: Venipuncture

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of Unique Single Nucleotides Polymorphisms (SNPs) associated with Phantom Limb Pain (PLP)	The primary outcome measure for this study is the identification of unique SNPs that may correlate with PLP. Patients will undergo a one-time blood draw and fill out a survey characterizing their phantom limb pain. The PLP characteristics along with DNA analysis using Affymetrix SNP chip technology will be used to match genotype with phenotype.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between Phantom Limb Pain (PLP) and Blood Levels of Antibodies Associated with Peripheral Nerve Damage	The underlying hypothesis of the secondary outcome measure is that damage to peripheral nerves provokes a humoral immune response to neuronal and glial proteins that can be detected by measuring specific antibodies in blood. The data obtained will lead to a more complete understanding of pathogenic mechanisms in PLP and potential biomarkers for sub-classification, prognosis, and intervention.	5 years
Correlation between Phantom Limb Pain (PLP) and Serum Levels of Brain-derived Neurotrophic Factor (BDNF)	BDNF has been implicated in pain nociception and is therefore pertinent to our study of phantom limb pain. After peripheral nerve injury, BDNF expression is dramatically increased in pain receptors of the brainstem.	5 years
Correlation between Phantom Limb Pain (PLP) and Unique Transcribed RNA	Many underlying causes for neuropathic pain involve changes in messenger ribonucleic acid (mRNA) levels because of altered gene expression or transcript stability. The study will isolate total RNA from blood and measure the relative amounts of transcribed RNA under the condition of phantom limb pain or no phantom limb pain.	5 years

Collaborators and Investigators

• Sponsor: Henry M. Jackson Foundation for the Advancement of Military Medicine
• Collaborators: Uniformed Services University of the Health Sciences
• Investigators: Principal Investigator: Paul F. Pasquina, MD, MC, Walter Reed National Military Medical Center (WRNMMC)

Publications and helpful links

General Publications

• Kooijman CM, Dijkstra PU, Geertzen JHB, Elzinga A, van der Schans CP. Phantom pain and phantom sensations in upper limb amputees: an epidemiological study. Pain. 2000 Jul;87(1):33-41. doi: 10.1016/S0304-3959(00)00264-5.
• Ramachandran VS, Hirstein W. The perception of phantom limbs. The D. O. Hebb lecture. Brain. 1998 Sep;121 ( Pt 9):1603-30. doi: 10.1093/brain/121.9.1603.
• Jensen TS, Krebs B, Nielsen J, Rasmussen P. Phantom limb, phantom pain and stump pain in amputees during the first 6 months following limb amputation. Pain. 1983 Nov;17(3):243-256. doi: 10.1016/0304-3959(83)90097-0.
• Montoya P, Larbig W, Grulke N, Flor H, Taub E, Birbaumer N. The relationship of phantom limb pain to other phantom limb phenomena in upper extremity amputees. Pain. 1997 Aug;72(1-2):87-93. doi: 10.1016/s0304-3959(97)00004-3.
• Sherman RA, Sherman CJ, Parker L. Chronic phantom and stump pain among American veterans: results of a survey. Pain. 1984 Jan;18(1):83-95. doi: 10.1016/0304-3959(84)90128-3.
• Katz J, Melzack R. Pain 'memories' in phantom limbs: review and clinical observations. Pain. 1990 Dec;43(3):319-336. doi: 10.1016/0304-3959(90)90029-D.

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Actual): April 1, 2014
• Study Completion (Anticipated): August 1, 2019

Study Registration Dates

• First Submitted: October 24, 2011
• First Submitted That Met QC Criteria: October 27, 2011
• First Posted (Estimate): October 31, 2011

Study Record Updates

• Last Update Posted (Actual): April 10, 2019
• Last Update Submitted That Met QC Criteria: April 9, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: Brain-Derived Neurotrophic Factor; Visual Analog Pain Scale; Single Nucleotide Polymorphism; Phantom Limb; Genetic Variation; DNA Sequence Analysis; Amputation, Traumatic; Inflammatory Antibody; Peripheral Nerve Damage
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Postoperative Complications; Pain; Neurologic Manifestations; Neurobehavioral Manifestations; Perceptual Disorders; Pain, Postoperative; Phantom Limb
• Other Study ID Numbers: 20429; HU0001-11-1-0005 (Other Grant/Funding Number: Uniformed Services University of Health Sciences (USUHS))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No