Study to Identify the Genetic Variations Associated With Phantom Limb Pain

• Correlation between Phantom Limb Pain (PLP) and Blood Levels of Antibodies Associated with Peripheral Nerve Damage [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  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.
• Correlation between Phantom Limb Pain (PLP) and Serum Levels of Brain-derived Neurotrophic Factor (BDNF) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  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.
• Correlation between Phantom Limb Pain (PLP) and Unique Transcribed RNA [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Many underlying causes for neuropathic pain involve changes in 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.

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.

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.

Subjects to be recruited at WRNMMC will be military health care beneficiaries age 18 and older who have sustained one or more amputations. To minimize within group genetic variability, the study focuses on European American populations only.

• Phantom Limb Pain
  Subjects will have lower or upper extremity amputation(s) that have resulted in the presence of phantom limb pain.
  Intervention: Procedure: Blood Draw
• No Phantom Limb Pain
  Subjects in the group will have a lower or upper extremity amputation(s) without the presence of phantom limb sensation.
  Intervention: Procedure: Blood Draw

• 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.
• Kooijman CM, Dijkstra PU, Geertzen JH, 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.
• Ramachandran VS, Hirstein W. The perception of phantom limbs. The D. O. Hebb lecture. Brain. 1998 Sep;121 ( Pt 9):1603-30. Review.
• 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.
• Katz J, Melzack R. Pain 'memories' in phantom limbs: review and clinical observations. Pain. 1990 Dec;43(3):319-36. Review.
• 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):243-56.

Inclusion Criteria:

• Chronic Phantom Limb Pain Group:

  • European American subjects, at least 18 years of age
  • Written informed consent and written authorization for use or release of health research study information
  • Single or multiple upper and/or lower limb amputation
  • Ability to follow study instructions and likely to complete required visit
  • Experience phantom limb pain for at least one month and at least 3 times per week
  • Phantom limb pain differentiated from residual limb pain by physical exam

• Non-chronic Phantom Limb Pain Group:

  • European American subjects, at least 18 years of age
  • Written informed consent and written authorization for use or release of health research study information
  • Single or multiple upper and/or lower limb amputation
  • Ability to follow study instructions and likely to complete required visit
  • Experience phantom limb pain less than 10 times total and/or for less than two weeks
  • Phantom limb pain differentiated from residual limb pain by physical exam

Exclusion Criteria:

• Chronic Phantom Limb Pain Group:

  • Age less than 18
  • Non-European American descent
  • Less than three months lapsed since amputation
  • Known uncontrolled systemic disease- known cancer not in remission, known on-going infection, lupus, kidney disease requiring dialysis, any other systemic disease which might affect ability to participate in this study's blood draw
  • Any condition or situation that, in the investigator's opinion, may put the subject at significant risk or confound study results
  • Experience phantom limb pain for less than one month or less than 3 times/week
  • Hemophilia or other chronic disease or medication regimen that would make a blood draw dangerous or inadvisable for the subject as determined by querying the subject

• Non-chronic Phantom Limb Pain Group:

  • Age less than 18
  • Non-European American descent
  • Less than three months lapsed since amputation
  • Known uncontrolled systemic disease- known cancer not in remission, known on-going infection, lupus, kidney disease requiring dialysis, any other systemic disease which might affect ability to participate in this study's blood draw
  • Any condition or situation that, in the investigator's opinion, may put the subject at significant risk or confound study results
  • Experience phantom limb pain for less than one month or less than 3 times/week
  • Hemophilia or other chronic disease or medication regimen that would make a blood draw dangerous or inadvisable for the subject as determined by querying the subject