Phantom Limb Pain Mechanisms
/By Symone Lowery-Hughes
September, 2015
“...Those obdurate and sometimes tormenting ghosts of arms and legs lost years or decades before but not forgotten by the brain.”-V.S. Ramachandran
Phantom sensations are sensory perceptions of a missing limb. Phantom limb pain is a neuropathic pain in the amputated limb and mostly reported in limb amputees. Phantom limb pain can be broadly categorized by supraspinal, spinal and peripheral mechanisms [1]. Supraspinal mechanisms include somatosensory cortical reorganization of body image. Spinal reorganization in the dorsal horn occurs after interruption of a peripheral nerve. Peripherally, damaged axonal nerves initiate inflammation and regenerative sprouting causing increased ectopic afferent input. Central and Peripheral mechanisms are thought to be contributing to phantom limb pain for which aggressive pain management is required. The interplay of multiple mechanisms renders phantom limb pain challenging to treat.
During surgical removal of a limb, nerves are interrupted resulting in nerve injury. These nerves unsuccessfully attempt to reconnect consequently forming neuromas. Peripheral nerve damage also initiates inflammation. The main chemical contributors involved in nerve damage inflammation are histamine, bradykinin and phospholipases [2]. Histamine is involved in inflammatory swelling and stimulates nociceptors initiating pain impulses. Bradykinin increases nerve action potentials actively producing pain and stimulates the release of prostaglandins from nearby tissues. Phospholipases sensitizes nociceptors through a series of chemical activation. With prolonged exposure, nociceptors continually respond to lower concentrations of chemical mediators. A mild stimulus now produces rapid increase in action potentials. Sensitized nociceptors also cause ectopic discharges and induce firing in neighboring nerve endings. The Central Nervous System interprets this constant input as an increase in the severity of pain. Furthermore, alterations in the sodium channel membrane potential in the newly formed neuromas cause abnormal discharging [3]. Ectopic discharges from afferent neurons are the result of up-regulation of sodium channels [2]. The result is extreme sensitivity to pain.
Spinal cord mechanisms for phantom limb pain are thought to be due to changes in the dorsal horn of the spinal cord after deafferentation from a peripheral nerve injury. Peripheral nerve injury causes inflammation that stimulates release of chemical mediators. Bradykinin stimulates pain-carrying nerve fibers that cause the release of glutamate and Substance P. Glutamate and Substance P cause excitation of nerves, passing nociceptive information to the brain [4]. The increase in glutamate leads to gamma amino butyric acid (GABA) disinhibition in the dorsal horn. Loss of GABA, an inhibitory neurotransmitter, results in hyper-excitability and spontaneous neural activity [2]. The absence of inhibitory effects for sensory input arising from the missing peripheral limb causes increased activity of dorsal horn neurons. This increased dorsal horn neuron activity lead to a sort of “sensory epileptic discharge” [1].
Supraspinal mechanisms involve reorganization of the somatosensory cortex region around the area representing the deafferentated limb [1]. After surgical interruption of peripheral axons, neurotrophins trigger sprouting of central terminals of sensory axons outside their normal region. Spontaneous sprouting and loss of inhibitory fibers causes cortical reorganization. Cortical reorganization is associated with the sensory and motor homunculus. Maladaptive neural changes alter the body sense of self resulting in phantom sensations. There appears to be a shift of cortical representation of adjacent body parts in respect to the area of peripheral nerve injury [4, 5]. Increased excitability of neurons lead to a lowered threshold needed to stimulate activity in the cortex. Therefore, mild stimulations of the stump lead to exaggerated pain sensation from the absent limb. Excessive activity in the CNS continues because of a lack of signals from the limb [2].
Treatments for phantom limb pain should involve a multimodal approach that includes pharmacotherapy, injection, alternative therapies, and surgery [1]. Pharmacotherapy treatment approaches include the use of N-methyl-D-aspartate (NMDA) receptor antagonists, opioids, anticonvulsants, antidepressants, local anesthetics, and calcitonin. Alternative and complementary theories include cognitive behavioral therapy, mirror therapy, biofeedback, etc. This group of treatment facilitates adaptation to pain, body image, and negative emotions. Surgical therapies can consist of neuromodulatory techniques and reconstruction. Neuromodulatory techniques target maladaptive neuroplastic changes at the peripheral, spinal, and supraspinal levels. Reconstruction targets peripheral nerves.
Phantom limb pain is thought to be due to a combination of peripheral and central mechanisms. This condition proves to be challenging to treat due to its complexity. As clinical studies continue to expand perhaps these ghostly replicas will begin to fade.
References
1. Hsu E. & Cohen S. (2013). Postamputation Pain: Epidemiology, Mechanisms, and Treatment. Journal of Pain Research, 6: 121-136.
2. Middleton C. (2003) The Causes and Treatments of Phantom Limb Pain. Nurse Times. 99: 35, 30-33
3. Nikolajsen L & Jensen T. S. (2001) Phantom Limb Pain. British Journal of Anaesthesia. 87; 107-116.
4. Giummarra, M. J., Gibson, S. J., Georgiou-Karistianis, N, & Bradshaw, J. L. (2007) Central Mechanisms in Phantom Limb Perception: The Past, Present and Future. Brain Research Reviews 54: 219-232.
5. Subedi, B. & Grossberg, G. T. (2011) Phantom Limb Pain: Mechanisms and Treatment Approaches. Pain Research and Treatment. 1: 1-8.
6. Ramachandran, V.S. & Blakeslee S (1999). Phantom in the Brain: Probing the Mysteries of the Human Mind. Oliver Saks (Fwd). New York: HarperCollins Publishers.
