Phantom Limb Pain

Article Author:
Aaron Hanyu-Deutmeyer
Article Author (Archived):
Marco Cascella
Article Editor:
Matthew Varacallo
Updated:
8/23/2019 3:29:58 PM
PubMed Link:
Phantom Limb Pain

Introduction

Phantom limb pain (PLP) is clinically defined as the perception of pain or discomfort in a limb that no longer exists.  Although PLP most commonly presents as a pathological sequelae in amputee patients, the underlying pathophysiology remains poorly understood. PLP can present along a wide clinical spectrum and varying severity of symptoms.  The condition should be differentiated from other related but separate clinical conditions, including residual limb pain (RLP).  RLP (formerly known as "stump pain") is pain that originates from the actual site of the amputated limb.  It is most common in the early post-amputation period and tends to resolve with wound healing. Unlike PLP, RLP is often a manifestation of an underlying source, such as nerve entrapment, neuroma formation, surgical trauma, ischemia, skin breakdown, or infection.[1][2]

In the United States, 30,000 to 40,000 amputations are performed each year. Amputations can occur for many reasons including severe trauma, tumors, vascular disease, and infection. Pain after amputation of a limb is a common symptom and is separated into two types of pain: residual limb pain (RLP) and phantom limb pain (PLP). Ninety-five percent of patients report experiencing some amputation-related pain, with 79.9% reporting phantom pain and 67.7% reporting residual limb pain. It is important to know the difference between the two because the causes and treatment for each differ, but also be aware that both of these elements can coexist at the same time.[3]

Etiology

The exact etiology of phantom limb pain is unclear. Multiple theories have been debated, and the only agreement is that multiple mechanisms are likely responsible. The predominant theory for years involved the irritation of the severed nerve endings causing phantom pain. This was enforced by evidence that almost all amputation patients will develop neuromas in the residual limb. Over the last few decades, advances in imaging and laboratory techniques have shown evidence of central nervous system involvement. Imaging studies such as MRI and PET scans show activity in the areas of the brain associated with the amputated limb when the patient feels phantom pain. The pain is now thought to involve many peripheral and central nervous system factors.[4][5]

Epidemiology

In 2005, there were 1.6 million people (1 in 190) living with limb loss in the United States. This same study projected a striking increase to 3.6 million cases by 2050.  The literature reports PLP affecting 60% to 85% of amputee patients.[6]  The following underlying causes are given clinical consideration:

  • Vascular etiologies (most common)
  • Trauma
  • Cancer/Malignancy
  • Congenital conditions

Pathophysiology

Peripheral Nerve Changes

During the amputation, there is a significant amount of trauma that occurs in the nerves and surrounding tissues. This damage disrupts the normal afferent and efferent signals involved with the missing limb. The proximal portions of the severed nerves start to sprout neuromas, and the nerves become hyper-excitable due to an increase in sodium-channels and resulting spontaneous discharges.

Spinal Cord Changes

In the spinal cord, a process called central sensitization occurs. Central sensitization is a process where neural activity increases, the neuronal receptive field expands, and the nerves become hypersensitive. This is due to an increase in the N-methyl-D-aspartate, or NMDA, activity in the dorsal horn of the spinal cord making them more susceptible to activation by substance P, tachykinins, and neurokinins followed by an upregulation of the receptors in that area. This restructuring of the neural components of the spinal cord can cause the descending inhibitory fibers to lose their target sites. The combination of increased activity to nociceptive signals as well as a decrease in the inhibitory activity from the supraspinal centers is thought to be one of the major contributors to phantom limb pain. [7]

Brain Changes

Over the past few years, there has been significant research into cortical reorganization and is a commonly cited factor in phantom limb pain.  During this process, the areas of the cortex that represent the amputated area are taken over by the neighboring regions in both the primary somatosensory and the motor cortex. Cortical reorganization partially explains why nociceptive stimulation of the nerves in the residual limb and surrounding area can cause pain and sensation in the missing limb. There is also a correlation between the extent of cortical reorganization and the amount of pain that the patient feels. [8]

Psychogenic Factors

Chronic pain has been shown to be multi-factorial with a strong psychological component. Phantom limb pain can often develop into chronic pain syndrome and for treatment to have a higher chance of success the patient's pain behaviors and pain processing should be addressed. Depression, anxiety, and increased stress are all triggers for phantom limb pain. [9]

History and Physical

Phantom limb pain is often described as tingling, throbbing, sharp, pins/needles in the limb that is no longer there. It occurs more commonly in upper extremity amputations than lower extremity and tends to be intermittent in frequency. Pain severity varies, and onset can be immediate or years afterward. It is important to try and distinguish phantom limb pain from residual limb pain.

The goal of the physical exam is to rule out causes of residual limb pain. First, the skin should be carefully inspected for evidence of wounds or infection. Sensation needs to be tested, along with looking for allodynia and hyperalgesia. The joint above the amputated limb should be examined for any signs of dysfunction.

Evaluation

The diagnosis of phantom limb pain is primarily a diagnosis of exclusion and heavily dependent on the patient's history.  Because of this lab tests are often not needed.  A complete blood count (CBC) can help rule out infection. An ultrasound can be ordered to look for neuromas as a possible pain generator. A psychology evaluation may be indicated if the patient is having a significant amount of extrinsic triggers that may be contributing to his or her pain.

Treatment / Management

Treatment, unfortunately, for phantom limb pain has not proven to be very effective. While treatment for residual limb pain tends to focus on an organic cause for the pain, phantom limb pain focuses on symptomatic control.

Pharmacotherapy

NSAIDs/Tylenol are the most commonly used treatment for phantom limb pain. The mechanism of action is unknown.[10]

Opioids: Randomized controlled trials have demonstrated the effectiveness of opioids for neuropathic pain and phantom limb pain.  Should be used in conjunction with antidepressants or neural modulating agents (i.e., gabapentin, pregabalin). [11]

Antidepressants are commonly used for phantom limb pain. Amitryptiline, in particular, tends to be the TCA of choice as it has shown the best overall results, but other studies looking at Nortryptyline and desipramine have shown them to be equally effective. However, most of these studies were not very rigorous and in a 6 week randomized trial between amitriptyline and placebo involving 39 patients, there was no significant difference between the two. [12] Duloxetine is another medication that has been showing some positive results. [13]  

Anticonvulsants (Gabapentin, Pregabalin) have shown mixed results. [14]  The results overall for Gabapentin have been conflicting, but a Cochrane review examining multiple studies did feel that the combined results favored Gabapentin over placebo. [15]

Calcitonin has no clear evidence.

NMDA Receptor antagonist mechanism is not clear. NMDA receptor antagonists have been shown to have benefit in pain syndromes, primarily with ketamine and dextromethorphan.  Memantine has had mixed results.  In the Cochrane review of 6 studies were included looking at Memantine versus placebo, there was no statistical improvement in pain between the groups [15].  Ketamine infusions have shown much better results than memantine, although the results between the two are not clear given their similar mechanisms.  There is level 2 evidence to support the use of Ketamine infusions for the treatment of PLP [16].

Beta-blockers (propranolol) and calcium channel blocker (nifedipine) show unclear data.

A sympathetic block may also help.

Botulinum toxin type B injections have been used to treat hyperhidrosis (excessive sweating) in the post-amputation patient.  Hyperhidrosis can not only hinder the use of a prosthetic but can adversely affect the course of phantom limb and residual limb pain. Treatment of the hyperhidrosis with botulinum toxin type B injections has shown in several small studies to reduce residual limb pain, phantom limb pain, and sweating. [17]  Botulinum toxin type A is also being investigated, but so far has not been shown to decrease pain intensity compared to lidocaine/methylprednisolone. [15] 

Topical Analgesics like Capsaicin have been shown in some small studies to reduce hypersensitivity and phantom limb pain, but the evidence is still weak and requires more investigation. [18][19]

Local anesthetics: A Cochrane review looked at two studies examining the effectiveness of local anesthetics, Lidocaine infusion at 4mg/kg and Bupivacaine 0.25% as a contralateral myofascial injection, in treating PLP in randomized trials. The one-time contralateral myofascial injection of 1cc Bupivacaine 0.25% showed significantly improved pain relief in the 8 patients studied [20].  Lidocaine infusion was not found to have any significant improvement compared to placebo [21]

Non-Pharmacologic Options

TENS shows moderate evidence supporting its use. Low-frequency and high-intensity are thought to be the most effective for phantom limb pain.

Mirror therapy: A small randomized trial of mirror therapy in patients with lower leg amputation showed a significant benefit of phantom limb pain.[22] Another study was minimally helpful.

Biofeedback shows limited evidence.

Acupuncture research is still ongoing.

Dorsal Column Stimulator(DCS) (an implantable device which stimulates transdural the dorsal columns of the spinal cord) is often effective therapy for phantom limb pain. The exact mechanism of pain relief from DCS is unknown.

Virtual and Augmented Reality has provided some novel opportunities to utilize technology as an advanced form of "mirror therapy".  Researchers have been able to program myoelectric movement patterns from the residual limb into the virtual or augmented reality headsets and then correlate those movements to the movements of the "complete" limb in the virtual world.  This has been shown in several case studies to be effective treatments for phantom limb pain, but no large studies have been conducted. [23] [24]

Enhancing Healthcare Team Outcomes

The management of PLP is not satisfactory. There is no one treatment that works reliably or consistently in all patients. Most patients are prescribed multiple agents to control pain, but tragically, this polypharmacy also has serious adverse effects that tend to lower compliance. Patients with PLP often doctor shop and try many types of conventional and non-conventional therapies to relieve the pain.

A pain referral should be ordered and the patient's quality of life should be improved.


References

[1] Cuperus AA,Disco RT,Sligte IG,van der Kuil MNA,Evers AWM,van der Ham IJM, Memory-related perceptual illusions directly affect physical activity in humans. PloS one. 2019;     [PubMed PMID: 31095650]
[2] Wittkopf PG,Lloyd DM,Coe O,Yacoobali S,Billington J, The effect of interactive virtual reality on pain perception: a systematic review of clinical studies. Disability and rehabilitation. 2019 May 8;     [PubMed PMID: 31067135]
[3] Rothgangel A,Braun S,Smeets R,Beurskens A, Feasibility of a traditional and teletreatment approach to mirror therapy in patients with phantom limb pain: a process evaluation performed alongside a randomized controlled trial. Clinical rehabilitation. 2019 May 8;     [PubMed PMID: 31066315]
[4] He Y,Qiu D,Zhou D,Li L,Wang B,Wang L, Treatment of Partial Traumatic Hemipelvectomy: A Study of 21 Cases. The Journal of bone and joint surgery. American volume. 2019 May 1;     [PubMed PMID: 31045672]
[5] Luza LP,Ferreira EG,Minsky RC,Pires GKW,da Silva R, Psychosocial and physical adjustments and prosthesis satisfaction in amputees: a systematic review of observational studies. Disability and rehabilitation. Assistive technology. 2019 Apr 23;     [PubMed PMID: 31012753]
[6] Ephraim PL,Wegener ST,MacKenzie EJ,Dillingham TR,Pezzin LE, Phantom pain, residual limb pain, and back pain in amputees: results of a national survey. Archives of physical medicine and rehabilitation. 2005 Oct     [PubMed PMID: 16213230]
[7] Knotkova H,Cruciani RA,Tronnier VM,Rasche D, Current and future options for the management of phantom-limb pain. Journal of pain research. 2012     [PubMed PMID: 22457600]
[8] Jutzeler CR,Curt A,Kramer JL, Relationship between chronic pain and brain reorganization after deafferentation: A systematic review of functional MRI findings. NeuroImage. Clinical. 2015     [PubMed PMID: 26740913]
[9] Fuchs X,Flor H,Bekrater-Bodmann R, Psychological Factors Associated with Phantom Limb Pain: A Review of Recent Findings. Pain research & management. 2018     [PubMed PMID: 30057653]
[10] Smith HS, Potential analgesic mechanisms of acetaminophen. Pain physician. 2009 Jan-Feb     [PubMed PMID: 19165309]
[11] O'Connor AB,Dworkin RH, Treatment of neuropathic pain: an overview of recent guidelines. The American journal of medicine. 2009 Oct     [PubMed PMID: 19801049]
[12] Robinson LR,Czerniecki JM,Ehde DM,Edwards WT,Judish DA,Goldberg ML,Campbell KM,Smith DG,Jensen MP, Trial of amitriptyline for relief of pain in amputees: results of a randomized controlled study. Archives of physical medicine and rehabilitation. 2004 Jan;     [PubMed PMID: 14970960]
[13] Jefferies K, Treatment of neuropathic pain. Seminars in neurology. 2010 Sep     [PubMed PMID: 20941675]
[14] Hsu E,Cohen SP, Postamputation pain: epidemiology, mechanisms, and treatment. Journal of pain research. 2013     [PubMed PMID: 23426608]
[15] Alviar MJ,Hale T,Dungca M, Pharmacologic interventions for treating phantom limb pain. The Cochrane database of systematic reviews. 2016 Oct 14     [PubMed PMID: 27737513]
[16] McCormick Z,Chang-Chien G,Marshall B,Huang M,Harden RN, Phantom limb pain: a systematic neuroanatomical-based review of pharmacologic treatment. Pain medicine (Malden, Mass.). 2014 Feb;     [PubMed PMID: 24224475]
[17] Kern KU,Kohl M,Seifert U,Schlereth T, [Effect of botulinum toxin type B on residual limb sweating and pain. Is there a chance for indirect phantom pain reduction by improved prosthesis use?]. Schmerz (Berlin, Germany). 2012 Apr     [PubMed PMID: 22527647]
[18] Privitera R,Birch R,Sinisi M,Mihaylov IR,Leech R,Anand P, Capsaicin 8% patch treatment for amputation stump and phantom limb pain: a clinical and functional MRI study. Journal of pain research. 2017     [PubMed PMID: 28761369]
[19] Kern KU,Baust H,Hofmann W,Holzmüller R,Maihöfner C,Heskamp ML, [Capsaicin 8‚ÄČ% cutaneous patches for phantom limb pain. Results from everyday practice (non-interventional study)]. Schmerz (Berlin, Germany). 2014 Aug     [PubMed PMID: 24939242]
[20] Casale R,Ceccherelli F,Labeeb AA,Biella GE, Phantom limb pain relief by contralateral myofascial injection with local anaesthetic in a placebo-controlled study: preliminary results. Journal of rehabilitation medicine. 2009 May;     [PubMed PMID: 19479153]
[21] Wu H,Sultana R,Taylor KB,Szabo A, A prospective randomized double-blinded pilot study to examine the effect of botulinum toxin type A injection versus Lidocaine/Depomedrol injection on residual and phantom limb pain: initial report. The Clinical journal of pain. 2012 Feb;     [PubMed PMID: 21750460]
[22] Finn SB,Perry BN,Clasing JE,Walters LS,Jarzombek SL,Curran S,Rouhanian M,Keszler MS,Hussey-Andersen LK,Weeks SR,Pasquina PF,Tsao JW, A Randomized, Controlled Trial of Mirror Therapy for Upper Extremity Phantom Limb Pain in Male Amputees. Frontiers in neurology. 2017     [PubMed PMID: 28736545]
[23] Ortiz-Catalan M,Sander N,Kristoffersen MB,Håkansson B,Brånemark R, Treatment of phantom limb pain (PLP) based on augmented reality and gaming controlled by myoelectric pattern recognition: a case study of a chronic PLP patient. Frontiers in neuroscience. 2014;     [PubMed PMID: 24616655]
[24] Page DM,George JA,Kluger DT,Duncan C,Wendelken S,Davis T,Hutchinson DT,Clark GA, Motor Control and Sensory Feedback Enhance Prosthesis Embodiment and Reduce Phantom Pain After Long-Term Hand Amputation. Frontiers in human neuroscience. 2018;     [PubMed PMID: 30319374]
[25] Miceli L,Bednarova R,Rizzardo A,Cuomo A,Riccardi I,Vetrugno L,Bove T,Cascella M, Opioids prescriptions in pain therapy and risk of addiction: a one-year survey in Italy. Analysis of national opioids database. Annali dell'Istituto superiore di sanita. 2018 Oct-Dec;     [PubMed PMID: 30575575]
[26] Cascella M,Forte CA,Bimonte S,Esposito G,Romano C,Costanzo R,Morabito A,Cuomo A, Multiple effectiveness aspects of tapentadol for moderate-severe cancer-pain treatment: an observational prospective study. Journal of pain research. 2019;     [PubMed PMID: 30613160]