In 1866, American neurologist S. Weir Mitchell published a short story in the Atlantic Monthly about a man who had undergone an amputation for both of his legs during the Civil War. Mitchell reported that despite receiving this operation, the man remained unaware that his legs were absent in the hospital and complained of cramping pains in his left leg. Mitchell named this phenomenon by coining the term “Phantom Limb Pain”, descriptions of this phenomena date as far back as the 16th century. Phantom Limb Pain (PLP) is described as the false sensation of a limb that has been amputated. In the United States, it is estimated that there are around 1.9 million amputees above the age of 20 and various studies have shown the onset incidence of PLP among amputees to be between 42.2 to 78.8%. Immediately after loss of a limb between 90 to 98% of amputees experience PLP. Despite the obvious need for pharmacological treatments for PLP, this has proven difficult due to an incomplete understanding of its underlying cause.
While PLP was previously believed to be a psychiatric illness, the accumulation of evidence from more recent patient studies suggest that the pathological source of PLP is located in multiple levels of the neural axis, most crucially in the cortex. There are two predominant hypotheses as to the cause of PLP: peripheral mechanisms and central neural mechanisms. Peripheral mechanisms can be thought of as a precursor to central mechanisms.
Inceptive hypothesis of PLP’s pathology is that nerve endings at the stump of the amputated limb grow into nodules called neuromas through a process called deafferentation. The accumulation of molecules which enhance the expression of sodium channels in these newly formed neuromas cause hyperexcitability of the neurons which leads to uncontrolled discharges. These impulses travel to the somatosensory areas of the cerebral cortex via the spinal cord and thalamus. These abnormal impulses are transmitted to the brain which interprets these signals as pain. This theory is supported by several studies. They show that drugs that inhibit the sodium channels lead to the transmission of impulses from neuromas and can reduce PLP.
Central Neural Mechanisms
-Spinal Cord: Axonal sprouts at the site of amputation form connections with neurons in the receptive field of the spinal cord. This process of sensitisation includes an increase in neuronal activity, expansion of the neuronal receptive field, and hyperexcitability of other regions. There is also a simultaneous increase in the activity of NMDA receptors, which are controlled by two types of neurotransmitters called tachykinins and neurokinins in sensory neurons contained in the spinal cord. Subsequently, what is known as the ‘windup phenomenon’ occurs and the number of receptors in this area (Dorsal Horn of the spinal cord) are increased. This causes a change in the firing pattern of sensory neurons (called central nociceptive neurons) that in turn can cause the loss of target neurons at the spinal cord level, which lowers the inhibitions of transmission from cortical centres. An increase in nociceptive inputs to the supraspinal centres can also be caused by a decrease in local intersegmental inhibitory mechanisms. These changes at spinal cord level which remove working inputs are thought to be the cause of PLP.
-Brain: Cortical Reorganisation - a function of neuroplasticity - has received increased support in the past few years as the cause of PLP. This occurs after deafferentation when changes to the somatosensory and motor areas of the cortex associated with the amputated limb occurs. Areas representing the missing limb are taken over by surrounding representational areas. This is thought to be a result of dormant synapses becoming activated when these neighbouring areas increase their reception field, which infringes onto the representational areas of the amputated limb. For example in the case of an amputated hand, the sensory area for the hand is located next to the sensory area for the face. In studies have shown that stimulation of sensory neurons in the face can cause simultaneous sensations to be felt in the phantom limb. This explains why stimulation of neurons in areas surround a phantom limb can cause sensation in the missing limb. Further imaging studies have linked the size of the distinct somatosensory region to the intensity of PLP experienced.
An additional mechanism which is believed to be responsible for PLP is body schema. Body Schema is the representation of the positions of various body parts in space. This is usually registered autonomously and updated based on the movement of body parts. This congenital template to how body parts should be arranged means that alterations to the body, such as amputation of a limb, is perceived as a phantom limb.
There are both pharmacological and nonpharmacological treatments available for PLP.
There are several pharmacological treatment such of the use of analgesics and anesthetics to prevent agitation of the new amputations site causing central neural sensitization. Nonsteroidal Anti-inflammatory drugs can be used to inhibit the action of enzymes essential for the synthesis of prostaglandin and decrease nociception in peripheral and central mechanisms. Antidepressants are also a treatment for PLP. They work by inhibiting the serotonin-norepinephrine uptake blockade; NMDA receptors and sodium channel blockade.
Nonpharmacological treatments includes both invasive and noninvasive treatments. Perhaps the least invasive treatment for PLP is mirror therapy. The treatment involves the amputee patient watching the reflection of their intact limb in a mirror. This matches their proprioception with visual sensory feedback of the amputated limb tricking the brain into perceiving movement of the amputated limb to be painless.
Transcutaneous electrical nerve stimulation (TENS) is another non-invasive treatment option involving the stimulation of nerves at the skin surface near the area of pain using a weak electrical current. This interrupts impulses from the neuromas which are perceived as pain preventing them from reaching the brain. TENS machines a relatively portable and this treatment has little to no side effects. Spinal cord stimulation is a slightly more invasive treatment which works in the same way as TENS. In this treatment small electrodes are inserted along the spinal cord to allow for the weak electrical current to be delivered directly to the spinal cord. If the prior treatments are unsuccessful then deep brain stimulation can be used as a treatment where electrodes are inserted directly into the brain through MRI guided surgery. Then electrical current can now be delivered within the brain.
Analgesics - A drug which relieves pain
Deafferentation- Interruption in sensory fibres usually resulting in the loss of sensory input from a portion of the body
Sodium Channels- Channels which cause the initiation of nervous impulses by conducting sodium ions through a cell's membrane
Nociception - Response by sensory nervous system to harmful stimuli
Opioids - Substances that bind to opioid receptors which results in reduced sensitisation to pain
Proprioception - The sense of the relative positions of the different body parts of one’s body
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