Phantom Limb Pain

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 extremities 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 that 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 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.
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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 dorsal columns of the spinal cord. It is often 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
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Differential Diagnosis

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