Phantom Limb Pain


Article Author:
Aaron Hanyu-Deutmeyer
Marco Cascella


Article Editor:
Matthew Varacallo


Editors In Chief:
Chaddie Doerr


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
10/19/2019 5:19:59 PM

Introduction

In the United States (U.S.), 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 including residual limb pain (RLP) and phantom limb pain (PLP). PLP is clinically defined as the perception of pain or discomfort in a limb that no longer exists. Although PLP most commonly presents as pathological sequelae in amputee patients, the underlying pathophysiology remains poorly understood. Furthermore, 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 RLP. This latter condition, 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] Of note, more than half of people with PLP also have RLP. It is important to know the difference between the two because the causes and treatments for each differ, but also be aware that both of these elements can coexist at the same time.[3] 

PLP and RLP represent an important challenge in medicine, in terms of epidemiology and therapeutic difficulties. Ninety-five percent of patients, indeed, report experiencing some amputation-related pain, with 79.9% reporting phantom pain and 67.7% reporting RLP. Again, these clinical manifestations can significantly worsen the health-related quality of life (HR-QOL) and in some cases are very difficult to manage. 

Etiology

The exact etiology of PLP 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 (CNS) 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 U.S. 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

Despite, the phantom limb sensation was described by French military surgeon Ambroise Pare (1510-1590) in the sixteenth century, even today we do not have a clear explanation of this complex phenomenon and, therefore, the pathophysiology is explained by a wide range of mechanisms. These mechanisms. which are the basis of theories, they are not necessarily mutually exclusive

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 in 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

PLP 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 PLP from RLP. The goal of the physical exam is to rule out the causes of RLP. 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. in terms of pain intensity, RLP usually is not severe, and features pressing, throbbing, burning, squeezing, and stabbing sensations.

Evaluation

The diagnosis of PLP 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 PLP has not proven to be very effective. While treatment for RLP tends to focus on an organic cause for the pain, PLP focuses on symptomatic control.

Pharmacotherapy

  • NSAIDs/Tylenol are the most commonly used treatment for PLP. [10]
  • Opioids. Although observational and randomized controlled trials have demonstrated the effectiveness of certain opioids such as tapentadol for neuropathic pain [11] and PLP, they should be used in conjunction with antidepressants or neural modulating agents (i.e., gabapentin, pregabalin). [12]. Furthermore, their use in a condition of benign pain should be done with caution in order to avoid potential effects from tolerance and dependence. [13]
  • Antidepressants are commonly used for addressing PLP. Amitryptiline, in particular, tends to be the tricyclic antidepressant (TCA) of choice as it has shown the best overall results, but other studies looking at nortriptyline 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. [14] Duloxetine is another medication that has been showing some positive results. [15]  
  • Anticonvulsants (gabapentin, pregabalin) have shown mixed results. [16]  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. [17]
  • N-methyl-d-aspartate (NMDA) receptor antagonist mechanism is not clear. These drugs 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 [17].  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 [18].
  • Beta-blockers (propranolol) and calcium channel blocker (nifedipine) show unclear data.
  • Topical Analgesics like Capsaicin have been shown in some small studies to reduce hypersensitivity and PLP, but the evidence is still weak and requires more investigation. [19][20]
  • 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 both the phantom limb and RLP. Treatment of the hyperhidrosis with botulinum toxin type B injections has shown in several small studies to reduce RLP, PLP, and sweating. [21]  Botulinum toxin type A is also being investigated, but so far has not been shown to decrease pain intensity compared to lidocaine/methylprednisolone. [17]
  • 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 [22].  Lidocaine infusion was not found to have any significant improvement compared to placebo [23]
  • Other pharmacological strategies such as calcitonin have no clear evidence.

Non-Pharmacologic Options

  • Transcutaneous electrical nerve stimulation (TENS) shows moderate evidence supporting its use. Low-frequency and high-intensity are thought to be the most effective for PLP. It may also be used to help relieve RLP.
  • Mirror therapy. A small randomized trial of mirror therapy in patients with lower leg amputation showed a significant benefit of PLP.[24] Another study was minimally helpful.
  • Biofeedback shows limited evidence.
  • Acupuncture research is still ongoing.
  • Spinal cord stimulation (SCS) is obtained through an implantable device that stimulates transdural the dorsal columns of the spinal cord. It is often an effective therapy for PLP. 
  • Apart from TENS and SCS, other neuromodulation approaches such as peripheral nerve stimulation (PNS) can be helpful for both PLP and RLP.
  • 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 RLP 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 PLP, but no large studies have been conducted. [25] [26]
  • A sympathetic block may also help.
  • Stump revision

Differential Diagnosis

  • Septic arthritis
  • Osteomyelitis
  • Foreign body reaction
  • Neuroma
  • Arthritis

Enhancing Healthcare Team Outcomes

PLP is very complex and difficult to treat. It is best managed by an interprofessional team The first treatment is usually conservative and should include nonpharmacological and nonsurgical methods. The prosthetic professional should assess the stump and train the patient in the use of the prosthetic device. A mental health nurse and psychotherapist should help ease anxiety and depression. If this fails, The pharmacist should educate the patient on the different pharmacological agents available, their effectiveness and adverse effects. A pain specialist should be involved as well

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 HR-QOL should be improved. 

Patient education is key and members of the team should communicate with each other so that the patient is provided with optimal treatment. The outcomes for most patients are guarded and the quality of life is poor.


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Phantom Limb Pain - Questions

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Phantom limb pain (PLP) is best described as what type of pain?



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Phantom limb pain is an example of which type of pain?



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A 68-year-old female patient with type 2 diabetes and hypertension presents to the clinic for routine follow up and states she continues to have pain in her right foot despite it being amputated 4 years ago. Since the pain was never particularly intense, it was treated with occasional assumptions of NSAIDs. Now the pain seems to be more constant and intense. There are also annoying symptoms such as the sensation of pins and warming and cold sensations. She wears a well-fitting prosthesis, and there is no evidence of ulceration or skin breakdown. The doctor notes strong psychological distress. Which of the following is the next best step in the management of this patient?



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A 47-year-old male patient due to an accident at work suffers the amputation of his right hand. The postoperative course was complicated by an infection of the surgical wound. Furthermore, he experienced pain in the early post-amputation period although the symptomatology resolved with wound healing. How is residual limb pain (previously known as stump pain) differentiated from phantom limb pain?



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A 47-year-old patient underwent amputated of right leg owing to gangrene. He suffers from pain with pins and needles sensations in the limb that is no longer there. The amputation took place about a year before, but the pain never disappeared as it is sometimes particularly intense. Which of the following mechanisms contribute to the generation of the pain experienced by this patient?



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A patient with uncomfortable paresthesias and abnormal sensation falls into which category of phantom pain?



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What category of phantom pain is present in a patient with mild pain and distress?



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What treatment should be used for patients with phantom pain and a positive lidocaine trial?



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What is the pharmaceutical drug of choice in patients with phantom pain and a positive ketamine trial?



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In what category of phantom pain is a patient with paresthesias without daily activity interference?



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In what category of phantom pain is a patient with severe pain and daily interference?



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A 65-year-old patient with uncontrolled diabetes, coronary artery disease, hypertension, congestive heart failure, and right-sided low back pain and radiculopathy to his foot requires amputation of his right foot due to complications from his uncontrolled diabetes. The day after the amputation the patient is complaining of pain at the amputation site that is poorly controlled with his pain medications. Which of the following factors increases the patient's risk of developing phantom limb pain?



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Which condition might be treated with lumbar sympathetic blockade?



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A 36-year-old patient must undergo right radical mastectomy for cancer. The patient read that she could feel a sensation of residual breast tissue and painful sensations. This data creates profound anxiety that adds to the concerns for the intervention and for the oncological pathology. Which of the following risk factors is most consistent with the underlying diagnosis in ths patient?



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A 70-year-old male status post-left below-knee amputation (BKA) 1 year ago, presents with complaints of phantom limb pain. Despite non-steroidal anti-inflammatory medications, acetaminophen, gabapentin, and duloxetine, he has not had an improvement in his pain. He wants to try non-pharmacological treatment options for his pain. Which of the following will be most beneficial for this patient?



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A 35-year-old veteran with phantom limb pain from his right below-knee amputation presents to the office and wants to talk about treatment options. He has tried mirror therapy, physical therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, gabapentin, tricyclic antidepressant (TCAs), and duloxetine without significant improvement in his pain levels. He read about ketamine infusions, and that it could be used to help people with chronic pain. By what mechanism of action is ketamine thought to improve pain?



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Which of the following symptoms are most likely in a patient with phantom limb pain?



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A 25-year-old male patient presents to your clinic after left trans-radial amputation 16 weeks ago from a motor vehicle accident. He is complaining of tingling and burning pain of the left hand. The pain is intermittent and located only in his non-existent hand. On physical exam, the incision appears healed, and he has a full sensation to light touch on the residual limb. The patient has tried over the counter acetaminophen and ibuprofen with minimal relief. Routine labs performed 2 months ago were normal. Which of the following is the next best medication in treatment?



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A 65-year-old male amputee presents to the clinic due to burning pain in his amputated right foot. He has a below the knee amputation on the right side due to a motor vehicle accident 6 months ago and started developing this pain two months ago. The pain has steadily gotten worse over time. The pain is described as sharp, burning, and constant. On physical exam, the residual limb incision is well healed, and there is no evidence of skin breakdown. He has a past medical history significant for diabetes and hypertension. He is currently on captopril and insulin. Which of the following is the most likely cause of the pain?



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Phantom Limb Pain - References

References

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