What is Phantom Limb Syndrome?

In 1551, phantom pain was first described by Ambroise Paré. Paré was a surgeon in the French army, and he was reported to have amputated as many as 200 limbs in a day [1]. In his experience with soldiers following amputations, he wrote,

For patients, long after the amputation is made, say they still feel pain in the amputated part. Because they complain about it strongly, a thing worthy of wonder and almost incredible to people who have not experienced this.

 The first modern description of phantom limb syndrome was originated by American physician Silas Weir Mitchell in 1871 as the sensation of a limb that is not there. A patient experiencing phantom limb sensations will feel as if the missing limb is still a part of the body, which often leads to the person to forget that their limb is gone and try to use it. Phantom sensations are sensations of pain in body parts that no longer exist. After a limb has been lost or amputated, 90 to 98% of patients suffer from phantom limb syndrome, which can also be experienced as pain [2], [3].

Studies show that the phantom limb syndrome was caused by the changes occurring within the cortex of the brain after the amputation of a limb. Not only this, it seems that the brain continues to receive signals from the nerve endings that initially supplied signals to and from the amputated limb [2], [3], [4]. Phantom limbs are also thought to be caused by brain rewiring itself, adjusting to the changes in the body. In many cases, patients feel a wide variety of symptoms linked to phantom limbs such as a tickling feeling, cramps, pain in various forms, numbness, cold, warmth, tightness and itchiness [4]. Although such sensations do occur, pain is the most common and long-term sensation among them [4].

Pain in the residual portion of the amputated limb is called “stump pain”. Resulting from a peripheral stimulus, hyperalgesia is an increased pain sensitivity [2], [5]. Primary hyperalgesia can be classified as increased pain sensitivity within the site of injury, which seems as a result of changes in the peripheral nervous system while the secondary hyperalgesia develops outside the injury site and is intervened by changes in central nervous system [2], [4], [5].

Phantom Limb Pain

Phantom Limb Pain (PLP) is a chronic neuropathic pain observed in 45 to 85 percent of patients who undergo major amputations [2], [3]. Chronic pain (in this case, PLP) affects the patient’s life in many ways. Not only it is physical, but experiencing chronic pain can also be mentally draining over time [2]. Subsequently, chronic pain may even lead to depression. In most cases, the consistency and intensity of chronic neuropathic pain decline over time. If it does not, after 6 months, the prognosis for the upcoming pain decrease is low. Severe pain persists in about 5-10% of patients [2]. It is thought that the development and continuum of PLP is linked to extremity amputations causing changes in axon properties and neuronal circuitry in both peripheral and central nervous systems. Studies also show that they may be related to the lack of consistency of motor intention and sensory feedback and corresponding activation of the brain frontal and parietal areas [1], [2].

Figure 1: Illustration of a person suffering from phantom limb pain [6].

Commonness of PLP

  • In the USA, approximately 45-85% of the 1.7 million people with amputations suffer from PLP [2], [7], [8], [9], [10], [11].
  • Lifetime prevalence of PLP was found to be high: between 76% and 87% [12].
  • According to a study, 93.5% of upper limb amputees experienced PLP in the course of a month. In light of this data, it can be said that PLP is more common among upper limb amputees than lower ones [12].
  • Prevalence of PLP is also more common among females [2], [13], [14].

Reducing Phantom Limb Pain

According to a National Library of Medicine study, the leading cause of chronic pain is peripheral neuropathy, which phantom limb pain is a kind of, with an estimated 20 million people in the USA suffering from it. It is well known for a while now that the pain can be reduced by antiepileptic drugs and analgesics, though they are mostly ineffective and their side effects make them impractical [2], [3].

An ideal approach for reducing neuropathic pain is thought to be the development of new techniques that can prevent the development of neuropathic pain, or eliminate the pain permanently. Understanding when and where a new technique should be applied is also important [2].

Treatment & Methods

The most common medications used in the treatment of PLP are Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) [1], [2], [3]. Tricyclic antidepressants also take part against neuropathic pain. The action of tricyclic antidepressant is due to the inhibition of serotonin-norepinephrine uptake blockade, N-methyl-D-aspartate (NMDA) receptor antagonism, and sodium channel blockade [2]. Even though the role of tricyclic antidepressants is primarily important for various neuropathic pain conditions, it is found to be not definitive against phantom limb pain. Tricyclic antidepressants are also shown to be ineffective in pain control [2], [3].

Opioids (levorphanol, oxycodone, methadone, and morphine) provide analgesia by binding to peripheral and central opioid receptors without causing the loss of proprioception, touch, or consciousness [2], [3], [4]. Cortical reorganization, which disrupts the mechanisms of PLP, is also reduced by opioids. Nevertheless, opioids are associated with more side effects than tricyclic antidepressants [4].

Application of the local anesthetic lidocaine to the dorsal root ganglion surface was observed to rapidly and reversibly extinguish PLP [4].

The secretion of therapeutic peptides by mesenchymal stem cells (MSCs) can be enhanced by genetic engineering. When enhanced, MSCs express the analgesic peptide glial cell line-derived neurotrophic factor, which results in a moderate, but significant, reduction in hyperalgesia. Thus, genetically modified MSCs secreting analgesic peptides are a potential DRG-targeted cell therapy for treating neuropathic pain [4].

Numerous studies about the causes, treatment and prevalence of phantom limb pain have shown that there are multiple mechanisms involved in inducing neuropathic pain as there are many ways and methods for treating pain from the most basic drugs to the genetically engineered cells, and treatments focusing on the individual’s mental health. This proves that researchers assembled from various fields make it possible to observe the disease and the cause from a much different perspective.

References:

  1.  J. Boomgaardt, K. Dastan, T. Chan, A. Shilling, A. Abd-Elsayed, and L. Kohan, “An Algorithm Approach to Phantom Limb Pain,” J Pain Res, vol. 15, pp. 3349–3367, 2022, doi: 10.2147/JPR.S355278.
  2. D. P. Kuffler, “Origins of phantom limb pain,” Mol Neurobiol, vol. 55, no. 1, pp. 60–69, Jan. 2018, doi: 10.1007/S12035-017-0717-X/METRICS.
  3. B. Subedi, G. G.-P. research and treatment, and undefined 2011, “Phantom limb pain: mechanisms and treatment approaches,” hindawi.comB Subedi, GT GrossbergPain research and treatment, 2011•hindawi.com, Accessed: Jan. 22, 2024. [Online]. Available: https://www.hindawi.com/journals/prt/2011/864605/abs/
  4.  D. P. Kuffler, “Coping with Phantom Limb Pain,” Molecular Neurobiology 2017 55:1, vol. 55, no. 1, pp. 70–84, Sep. 2017, doi: 10.1007/S12035-017-0718-9.
  5. J. Loeser, R. T.- PAIN®, and undefined 2008, “The Kyoto protocol of IASP basic pain terminology,” Elsevier, Accessed: Jan. 22, 2024. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S0304395908002327
  6. “New Theory for Phantom Limb Pain Points the Way to More Effective Treatment – Neuroscience News.” Accessed: Jan. 22, 2024. [Online]. Available: https://neurosciencenews.com/phantom-limb-treatment-9810/
  7.  C. Richardson, S. Glenn, … T. N.-T. C. journal of, and undefined 2006, “Incidence of phantom phenomena including phantom limb pain 6 months after major lower limb amputation in patients with peripheral vascular disease,” journals.lww.com, Accessed: Jan. 22, 2024. [Online]. Available: https://journals.lww.com/clinicalpain/Fulltext/2006/05000/Incidence_of_Phantom_Phenomena_Including_Phantom.5.aspx?casa_token=-KjY5mNyfzoAAAAA:HU-qZL4gaY7m716Rf-BWw4VY9BIsftsvOM8PVxqajF_PT1dqzxBjLFmo4xp1EHBeBuUUVGla6SdWcGp-hCMcsDNbCik8p2-r&casa_token=koXr2XvUQP4AAAAA:UshrrHRBhSMBt1KKN6T7qFoSWY_pZ0FztdQ07Snlaq_mC-ZCR5wOe4FGa-sw46oFAACSGddoLJy7g2RjQII4m0DTo0LQbWlH
  8. G. Reiber, L. McFarland, … S. H.-J. of, and undefined 2010, “Servicemembers and veterans with major traumatic limb loss from Vietnam war and OIF/OEF conflicts: Survey methods, participants, and summary findings,” rehab.research.va.govGE Reiber, LV McFarland, S Hubbard, C Maynard, DK Blough, JM Gambel, DG SmithJournal of rehabilitation research and development, 2010•rehab.research.va.gov, Accessed: Jan. 22, 2024. [Online]. Available: https://www.rehab.research.va.gov/jour/10/474/Reiber.html
  9. M. Schley, P. Wilms, … S. T.-J. of T., and undefined 2008, “Painful and nonpainful phantom and stump sensations in acute traumatic amputees,” journals.lww.comMT Schley, P Wilms, S Toepfner, HP Schaller, M Schmelz, CJ Konrad, N BirbaumerJournal of Trauma and Acute Care Surgery, 2008•journals.lww.com, Accessed: Jan. 22, 2024. [Online]. Available: https://journals.lww.com/jtrauma/Fulltext/2008/10000/Hypoxia_Is_Not_the_Sole_Cause_of_Lactate.20.aspx?casa_token=ollXIRS8BkoAAAAA:86f2QvSVPg8cNk9sNE9F82righA8bUrl7KZ37JmpjOfJ9fG-74Ca2qHdDRKobOpvCHGvXEn2E0qn6-li8OzGWNW2_dteAPhs&casa_token=8CZLpGJ1Rc4AAAAA:Bc8ZPQA9MqoD3c2JdRxDH8mNgR49EvoqUcQh5eD7nBK2GxihMJwZFpTjDQd35FedcMlLOQtp1fkgy7L98xep_Rmz7UbGFvAU
  10. D. Probstner, ; Luiz, C. Santos Thuler, ; Neli, M. Ishikawa, and R. M. Papais Alvarenga, “Phantom limb phenomena in cancer amputees,” Wiley Online LibraryD Probstner, LCS Thuler, NM Ishikawa, RMP AlvarengaPain practice, 2010•Wiley Online Library, vol. 10, no. 3, pp. 249–256, 2010, doi: 10.1111/j.1533-2500.2009.00340.x.
  11. C. Kooijman, P. Dijkstra, J. Geertzen, A. E.- Pain, and undefined 2000, “Phantom pain and phantom sensations in upper limb amputees: an epidemiological study,” Elsevier, Accessed: Jan. 22, 2024. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S0304395900002645?casa_token=hPWN6m6QTCgAAAAA:LArZiSG6uZbDBd3YdHCiUVEg9DNe3utvJPOH9QqKhUt2g9ozTO5O0p0cC1GMtFZ00ET7QC59O-k
  12.  A. Stankevicius, S. B. Wallwork, S. J. Summers, B. Hordacre, and T. R. Stanton, “Prevalence and incidence of phantom limb pain, phantom limb sensations and telescoping in amputees: A systematic rapid review,” European Journal of Pain, vol. 25, no. 1, pp. 23–38, Jan. 2021, doi: 10.1002/EJP.1657.
  13. A. Hirsh, T. Dillworth, D. Ehde, M. J.-T. J. of Pain, and undefined 2010, “Sex differences in pain and psychological functioning in persons with limb loss,” Elsevier, Accessed: Jan. 22, 2024. [Online]. Available: https://www.sciencedirect.com/science/article/pii/S1526590009005756
  14. J. Davidson, K. Khor, L. J.-D. and rehabilitation, and undefined 2010, “A cross-sectional study of post-amputation pain in upper and lower limb amputees, experience of a tertiary referral amputee clinic,” Taylor & FrancisJH Davidson, KE Khor, LE JonesDisability and rehabilitation, 2010•Taylor & Francis, vol. 32, no. 22, pp. 1855–1862, 2010, doi: 10.3109/09638281003734441.

Visual References: 

[6]       “New Theory for Phantom Limb Pain Points the Way to More Effective Treatment – Neuroscience News.” Accessed: Jan. 22, 2024. [Online]. Available: https://neurosciencenews.com/phantom-limb-treatment-9810/

Inspector:Beril GÜREL

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