PAIN PERCEPTION IN PHANTOM LIMB
Diseases

Author: virginia bobbio
Date: 03/04/2014

Description

Authors: Virginia Bobbio & Luca Dalla Santacà

DEFINITION

A phantom limb is the sensation that an amputated or missing limb (even an organ, as the appendix) is still attached to the body and is moving appropriately with other body parts. Approximately 60 to 80% of individuals with an amputation experience phantom sensation in their amputated limb, and the majority of the sensations are painful. Phantom sensations may also occur after the removal of body parts other than limbs, e.g. after breast amputation, extraction of a tooth (phantom tooth pain) or eye removal (phantom eye syndrome). The missing limb often feels shorter and may feel as if it is in a distorted and painful position. Occasionally, the pain can be worsened by stress, anxiety, and weather changes. Phantom limb pain is usually intermittent. The frequency and intensity of attacks usually declines with time.
Although not all phantom limbs are painful, patients will sometimes feel as if they are gesturing, feel itches, twitch, or even try to pick things up. For example, Ramachandran and Blakeslee describe that some people’s representations of their limbs do not actually match what they should be: for example one patient reported that her phantom arm was about “6 inches too short”.
A slightly different sensation known as phantom pain can also occur in people born without limbs, and people who are paralyzed. Phantom pains occur when nerves that would normally innervate the missing limb cause it. It is often described as a burning or similarly strange sensation and can be extremely agonizing for some people, but the exact sensation differs widely for different individuals. Other induced sensations include warmth, cold, itching, squeezing, tightness, and tingling. So the most important feature of this syndrome is the painful condition of the amputated limb, called Phantom Limb Pain ( PLP ).

Phantom phenomena and body scheme after limb amputation, 2014

NEUROLOGICAL BASES
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In a historical perspective, PLP had been considered mostly of psychological origin, with the prevalent belief that PLP was generated “in the patient’s head”. However , the development of advanced diagnostic methods, recently including neuroimaging, has facilitated explorations of changes in peripheral and central neural networks after amputation and their putative contribution to the development of PLP. The findings acknowledged the neuropathic nature of PLP and also suggested that both peripheral, as well as central mechanisms, including neuroplastic changes in central nervous system, can contribute to PLP.

PERIPHERAL MECHANISM

During amputation, peripheral nerves are severed. This results in massive tissue and neuronal injury, causing disruption of the normal pattern of afferent nerve input to the spinal cord. This is followed by a process called deafferentation and the proximal portion of the severed nerve sprouts to form neuromas. There is an increased accumulation of molecules enhancing the expression of sodium channels in these neuromas, that results in hype-excitability and spontaneous discharges. This abnormal peripheral activity is thought to be a potential source of the stump pain, including phantom pain. Studies reporting the reduction of phantom pain with drugs blocking the sodium channels lend further support to this theory. However, this cannot explain the mechanism of PLP in patients with congenital absence of limbs.

CENTRAL NEURAL MECHANISMS

CHANGES AT SPINAL CORD LEVEL

The axonal sprouts at the proximal section of the amputated peripheral nerve form connections with the neurons in the receptive field of the spinal cord. Some neurons in the spinal cord areas which are not responsible for pain transmission also sprout into the Lamina II of the dorsal horn of the spinal cord, which is involved in the transmission of nociceptive afferent inputs. This is followed by increased neuronal activity, expansion of the neuronal receptive field, and hyperexcitability of other regions. This process is called central sensitization. During this process, there is also an increase in the activity at NMDA receptors mediated by neurotransmitters such as substance P, tachykinins, and neurokinins at the dorsal horn of the spinal cord. This is followed by a phenomenon called the “windup phenomenon” in which there is an upregulation of those receptors in the area. This process brings about a change in the firing pattern of the central nociceptive neurons. The target neurons at the spinal level for the descending inhibitory transmission from the supraspinal centers may be lost. There also may be a reduction in the local intersegmental inhibitory mechanisms at the level of the spinal cord, resulting in spinal disinhibition and nociceptive inputs reaching the supra spinal centers. This lack of afferent input and changes at the level of the spinal cord have been proposed to result in the generation of PLP.

CHANGES AT BRAIN LEVEL


Cortical reorganization is perhaps the most cited reason for causing PLP in recent years. During reorganization, the cortical areas representing the amputated extremity are taken over by the neighbouring representational zones in both the primary somatosensory and the motor cortex. The process and extent of cortical reorganization have been studied in both animal and human models following amputation and deafferentation. Cortical reorganization partly explains why the afferent nociceptive stimulation of neurons within the stump or surrounding area produces the sensation in the missing limb. The extent of cortical reorganization has been found to be directly related to the degree of pain and the size of the deafferentiated region. Multiple imaging studies have correlated greater extent of somatosensory cortex involvement with more intense phantom limb experience .
Another proposed mechanism of PLP is based on the “body schema” concept that was originally proposed by Head and Holmes in 1912. The body schema can be thought of as a template of the entire body in the brain and any change to the body, such as an amputation, results in the perception of a phantom limb. A further expansion of the body schema concept is the “neuromatrix and neurosignature” hypothesis proposed by Ronald Melzack in 1989. The neuromatrix can be conceptualized as a network of neurons within the brain that integrates numerous inputs from various areas including somatosensory, limbic, visual, and thalamocortical components. It then results in an output pattern that evokes pain or other meaningful experiences. The term “neurosignature” was proposed by Melzack to refer to the patterns of activity generated within the brain that are continuously being updated based upon one’s conscious awareness and perception of the body and self. The deprivation of various inputs from the limbs to the neuromatrix causes an abnormal neurosignature to be produced that results in the generation of PLP.The other hypothesis relative to the mechanism of PLP has been derived from the research into illusory perceptions. It has been shown that the parietal and frontal lobes are also involved besides the primary somatosensory cortex in the perception of the abnormal somatosensory phenomenon. Painful sensations, such as PLP, may be related to the incongruence of motor intention and sensory feedback and a corresponding activation of the parietal and frontal brain areas.

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Phantom-limb pain: characteristics, causes, and treatment, 2002

Sodium channels and mechanisms of neuropathic pain, 2006

SYMPTOMS

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Most people who've had a limb removed report that it sometimes feels as if their amputated limb is still there. This painless phenomenon, known as phantom limb sensation, can also occur in people who were born without limbs. Phantom limb sensations may include feelings of coldness, warmth or itchiness or tingling — but should not be confused with phantom pain.
Phantom limb pain (PLP) is a complex phenomenon that includes a wide variety of symptoms ranging from tingling and itching to burning and aching. Its onset can be immediate, but it may also appear for the first time many years after the amputation. In addition to pain in the phantom limb, some people experience other sensations such as tingling, cramping, heat, and cold in the portion of the limb that was removed. Any sensation that the limb could have experienced prior to the amputation may be experienced in the amputated phantom limb. Phantom limb pain may cause sensations of:

  • Shooting, stabbing, piercing or burning pain
  • Pleasure
  • An article of clothing or jewelry
  • The limb still being attached and functioning normally
  • Numbness, tickling or cramping

By definition, phantom pain feels as if it comes from a body part that no longer remains.
Characteristics of phantom pain include:

  • Onset within the first few days of amputation
  • Tendency to come and go rather than be constant
  • Usually affects the part of the limb farthest from the body, such as the foot of an amputated leg
  • May be described as shooting, stabbing, boring, squeezing, throbbing or burning
  • Sometimes feels as if the phantom part is forced into an uncomfortable position
  • May be triggered by weather changes, pressure on the remaining part of the limb or emotional stress
    Although PLP occurs more often in adults, some studies demonstrated that it also occurs commonly in children and adolescents.

The prevalence of phantom limb sensation and pain in pediatric amputees, 1995

THERAPIES

For some people, phantom pain gets better over time without treatment. For others, managing phantom pain can be challenging.
There are different types of treatments for PLP:

Pharmacological treatments

  • Acetaminophen and NSAIDs
    The analgesic mechanism of acetaminophen is not clear but serotonergic and multiple other central nervous system pathways are likely to be involved. NSAIDs inhibit the enzymes needed for the synthesis of prostaglandin and decrease the nociception peripherally and centrally.
  • Opioids
    Opioids bind to the peripheral and central opioid receptors and provide analgesia without the loss of touch, proprioception, or consciousness. They may also diminish cortical reorganization and disrupt one of the proposed mechanisms of PLP. Randomized controlled trials have demonstrated the effectiveness of opioids (oxycodone, methadone, morphine, and levorphanol) for the treatment of neuropathic pain including PLP.
  • Antidepressants
    Tricyclic antidepressants are among the most commonly used medications for various neuropathic pains including PLP. The analgesic action of tricyclic antidepressant is attributed mainly to the inhibition of serotonin-norepinephrine uptake blockade, NMDA receptor antagonism, and sodium channel blockade.

Non-pharmacological treatments

  • Transcutaneous Electrical Nerve Stimulation (TENS)
    Historically, there have been multiple studies showing the effectiveness of TENS of the contralateral limb versus ipsilateral to decrease PLP. Low-frequency and high-intensity TENS is thought to be more effective than other doses.
  • Mirror therapy
    A mirror box is a box with two mirrors in the center (one facing each way), invented by Vilayanur S. Ramachandran to help alleviate phantom limb pain , in which patients feel they still have a limb after having it amputated.
    In a mirror box the patient places the good limb into one side, and the stump into the other. The patient then looks into the mirror on the side with good limb and makes "mirror symmetric" movements, as a symphony conductor might, or as we do when we clap our hands. Because the subject is seeing the reflected image of the good hand moving, it appears as if the phantom limb is also moving. Through the use of this artificial visual feedback it becomes possible for the patient to "move" the phantom limb, and to unclench it from potentially painful positions.
  • Surgical intervention
    Surgical interventions are usually employed when other treatment methods have failed. A case report relates the effectiveness of lesioning the dorsal root entry zone (DREZ) on upper limb phantom pain resulting from brachial plexus avulsions.

Phantom Limb Pain: Mechanisms and Treatment Approaches, 2011

HORMONAL USAGE FOR TREATING PHANTOM LIMB SYNDROME: THE USE OF CALCITONIN FOR TREATING PLP

As concerns non-pharmacological treatments for phantom limb pain attacks, some have considered the idea of using calcitonin hormone infusions; it has been then considered a good analgesic for alleviating pain in this type of disease.
Example:
After an above-knee leg amputation, a 29-year-old pregnant woman (at eight weeks gestation) reported severe PLP. The pain persisted for more than two weeks and was not relieved by multiple regimens of opioid and nonopioid medications. On postamputation day 16, a 30-minute i.v. infusion of 200 IU of calcitonin (salmon) was administered; the woman reported transient excruciating pain during the final 5 minutes of the infusion. There was little overall change in her pain status over the next three days. On postinfusion day 4, the patient reported reductions in the frequency and severity of PLP episodes, and a trend of improved PLP symptom control was noted over the next 48 hours, allowing the pain management team to begin tapering some medication dosages and thus reduce the woman's overall narcotic exposure.

Calcitonin for phantom limb pain in a pregnant woman, 2012

In another study instead, conducted on patients with chronic phantom limb pain, the tested hypothesis was that calcitonin, ketamine, and their combination are effective in treating chronic phantom limb pain. Twenty patients received, in a randomized, double-blind, crossover manner, 4 i.v. infusions of: 200 IE calcitonin; ketamine 0.4 mg/kg (only 10 patients); 200 IE of calcitonin combined with ketamine 0.4 mg/kg; placebo, 0.9% saline. Intensity of phantom pain (visual analog scale) was recorded before, during, at the end, and the 48 h after each infusion. Pain thresholds after electrical, thermal, and pressure stimulation were recorded before and during each infusion. Ketamine, but not calcitonin, reduced phantom limb pain. The combination was not superior to ketamine alone. The conclusion has been that ketamine, but not calcitonin, affects central sensitization processes that are probably involved in the pathophysiology of phantom limb pain.

Chronic phantom limb pain: the effects of calcitonin, ketamine, and their combination on pain and sensory thresholds., 2008

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