Introduction
The phenomenon of phantom limbs has probably been known since antiquity, but the first medical descriptions were not published until the 16th century. Historically, Silas Weir Mitchell (1829-1914) is credited with coining the term phantom limb , and more than anyone else, Mitchell brought phantom limbs to the attention of the medical community (for a historical review, see Finger and Hustwit ). Tragically, over the past several decades, wars and land mine explosions in many parts of the world have been responsible for numerous cases of traumatic amputation. In Western countries, the main reasons for amputation are diabetes and peripheral vascular disease in elderly people. The mechanisms underlying pain in amputees are still not fully understood, and although a large number of treatments have been suggested, the results of treatment are often poor. Phantom phenomena may also occur following the amputation of other body parts, such as the breast and rectum, but the present chapter focuses on the clinical characteristics, mechanisms, possible preventive measures, and treatment of phantom pain after limb amputation.
It is useful to distinguish between several elements of the phantom complex:
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Phantom pain: painful sensations referred to the missing limb
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Phantom sensation: any sensation in the missing limb except pain
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Stump pain: pain referred to the amputation stump
There is an overlap between these elements, and in the same individual, phantom pain, phantom sensations, and stump pain often coexist.
Clinical Characteristics of Phantom Limb Pain
Prevalence
The prevalence of phantom pain shows great variability in the literature. Early studies reported figures in the range of 2% to 4%, but most recent studies agree that 60% to 80% of patients experience phantom pain following amputation (see Table 26.1 for details). The prevalence is probably not influenced by age in adults, gender, side, or level and cause (civilian versus traumatic) of the amputation. However, a recent prospective study of 85 amputees showed that female gender and upper limb amputation were associated with a higher risk for phantom pain. Phantom pain is less frequent in very young children and congenital amputees.
| Author | Year | No. of Amputees | Amputees with Phantom Pain (%) | Amputees with Phantom Sensations (%) | Amputees with Stump Pain (%) |
|---|---|---|---|---|---|
| Ewalt et al. | 1947 | 2284 | 2 | 95 | — |
| Henderson and Smyth | 1948 | 300 | 4 | — | — |
| Parkes | 1973 | 46 | 61 | — | 13 |
| Jensen et al. | 1983 | 58 | 72 | 84 | 57 |
| Sherman and Sherman | 1984 | 2694 | 78 | — | — |
| Sherman and Sherman | 1985 | 764 | 85 | — | 58 |
| Houghton et al. | 1994 | 176 | 78 | 82 | — |
| Wartan et al. | 1997 | 526 | 55 | 66 | 56 |
| Nikolajsen et al. | 1997 | 56 | 75 | — | — |
| Smith et al. | 1999 | 92 | 63 | 80 | 76 |
| Ehde et al. | 2000 | 255 | 72 | 79 | 74 |
| Kooijman et al. | 2000 | 72 | 51 | 76 | 49 |
| Lacoux et al. | 2002 | 40 | 33 | 93 | 100 |
| Ephraim et al. | 2005 | 914 | 80 | — | 68 |
| Hanley et al. | 2006 | 57 | 62 | — | 57 |
| Richardson et al. | 2006 | 52 | 79 | 100 | 52 |
| Schley et al. | 2008 | 96 | 45 | 54 | 62 |
| Bosmans and Geertzen | 2010 | 85 | 32 | — | — |
| Desmond and MacLachlan | 2010 | 141 | 43 | — | 43 |
| Byrne | 2011 | 60 | 58 | 78 | 53 |
Time Course
Prospective studies in patients undergoing amputation, mainly because of peripheral vascular disease, have shown that the onset of phantom pain is usually within the first week after amputation. The appearance of phantom pain may, however, be delayed for months or even years. The prevalence of phantom pain often remains the same over the years, but the severity and intensity of phantom pain attacks generally decrease with time.
Intensity and Frequency
Although phantom pain is present in 60% to 80% of amputees, the number of patients with severe pain is substantially smaller and in the range of 5% to 15%. In a prospective study of lower limb amputees, the mean intensity of pain 6 months after amputation was 22 (range, 3 to 82) on a visual analog scale (VAS, 0 to 100). Similar results were found in another prospective study. The pain is usually intermittent and only a few patients are in constant pain. Episodes of pain attacks are most often reported to occur daily or at daily or weekly intervals.
Localization and Character
Phantom pain is primarily localized to the distal parts of the missing limb. In upper limb amputees, pain is normally felt in the fingers and palm of the hand, and in lower limb amputees, it is generally experienced in the toes, foot, or ankle. Phantom pain is often described as shooting, pricking, and burning. Other terms used are stabbing, pricking, pins and needles, tingling, throbbing, cramping, and crushing. Some patients have vivid descriptions, such as “a hammer is slammed at my calf” and “ants are crawling around inside my foot.”
Clinical Characteristics of Phantom Limb Pain
Prevalence
The prevalence of phantom pain shows great variability in the literature. Early studies reported figures in the range of 2% to 4%, but most recent studies agree that 60% to 80% of patients experience phantom pain following amputation (see Table 26.1 for details). The prevalence is probably not influenced by age in adults, gender, side, or level and cause (civilian versus traumatic) of the amputation. However, a recent prospective study of 85 amputees showed that female gender and upper limb amputation were associated with a higher risk for phantom pain. Phantom pain is less frequent in very young children and congenital amputees.
| Author | Year | No. of Amputees | Amputees with Phantom Pain (%) | Amputees with Phantom Sensations (%) | Amputees with Stump Pain (%) |
|---|---|---|---|---|---|
| Ewalt et al. | 1947 | 2284 | 2 | 95 | — |
| Henderson and Smyth | 1948 | 300 | 4 | — | — |
| Parkes | 1973 | 46 | 61 | — | 13 |
| Jensen et al. | 1983 | 58 | 72 | 84 | 57 |
| Sherman and Sherman | 1984 | 2694 | 78 | — | — |
| Sherman and Sherman | 1985 | 764 | 85 | — | 58 |
| Houghton et al. | 1994 | 176 | 78 | 82 | — |
| Wartan et al. | 1997 | 526 | 55 | 66 | 56 |
| Nikolajsen et al. | 1997 | 56 | 75 | — | — |
| Smith et al. | 1999 | 92 | 63 | 80 | 76 |
| Ehde et al. | 2000 | 255 | 72 | 79 | 74 |
| Kooijman et al. | 2000 | 72 | 51 | 76 | 49 |
| Lacoux et al. | 2002 | 40 | 33 | 93 | 100 |
| Ephraim et al. | 2005 | 914 | 80 | — | 68 |
| Hanley et al. | 2006 | 57 | 62 | — | 57 |
| Richardson et al. | 2006 | 52 | 79 | 100 | 52 |
| Schley et al. | 2008 | 96 | 45 | 54 | 62 |
| Bosmans and Geertzen | 2010 | 85 | 32 | — | — |
| Desmond and MacLachlan | 2010 | 141 | 43 | — | 43 |
| Byrne | 2011 | 60 | 58 | 78 | 53 |
Time Course
Prospective studies in patients undergoing amputation, mainly because of peripheral vascular disease, have shown that the onset of phantom pain is usually within the first week after amputation. The appearance of phantom pain may, however, be delayed for months or even years. The prevalence of phantom pain often remains the same over the years, but the severity and intensity of phantom pain attacks generally decrease with time.
Intensity and Frequency
Although phantom pain is present in 60% to 80% of amputees, the number of patients with severe pain is substantially smaller and in the range of 5% to 15%. In a prospective study of lower limb amputees, the mean intensity of pain 6 months after amputation was 22 (range, 3 to 82) on a visual analog scale (VAS, 0 to 100). Similar results were found in another prospective study. The pain is usually intermittent and only a few patients are in constant pain. Episodes of pain attacks are most often reported to occur daily or at daily or weekly intervals.
Localization and Character
Phantom pain is primarily localized to the distal parts of the missing limb. In upper limb amputees, pain is normally felt in the fingers and palm of the hand, and in lower limb amputees, it is generally experienced in the toes, foot, or ankle. Phantom pain is often described as shooting, pricking, and burning. Other terms used are stabbing, pricking, pins and needles, tingling, throbbing, cramping, and crushing. Some patients have vivid descriptions, such as “a hammer is slammed at my calf” and “ants are crawling around inside my foot.”
Factors Affecting Phantom Limb Pain
Preamputation Pain
Some retrospective studies have pointed to preamputation pain as a risk factor for phantom pain. Houghton and colleagues found a significant relationship between preamputation pain and phantom pain in the first 2 years after amputation in vascular amputees, but in traumatic amputees, only phantom pain immediately after the amputation was related to preamputation pain. The relationship between preamputation pain and phantom pain has also been confirmed by prospective studies. In a prospective study by Nikolajsen and associates, a relationship between preamputation pain and phantom pain was found 1 week and 3 months after the amputation. However, phantom pain never developed in some patients with severe preamputation pain, whereas severe phantom pain developed in others with only modest preoperative pain.
Another question is to what extent the pain experienced before amputation may “survive” as phantom pain. In a retrospective study by Katz and Melzack, 68 amputees were questioned about preamputation pain and phantom pain from 20 days to 46 years after amputation. Fifty-seven percent of those who had experienced preamputation pain claimed that their phantom pain was a replicate of the pain that they had before the amputation. The number of patients with similar descriptions of preamputation pain and phantom pain was, however, much lower in two prospective studies. In the study by Nikolajsen and associates, the character and localization of pain were recorded before and at specific time intervals after the amputation. Although 42% of patients claimed that their phantom pain was a replicate of the pain that they experienced before the amputation, the degree of similarity between preamputation and postamputation descriptions of pain was not higher in patients who claimed similarity than in those who claimed no similarity between phantom pain and preamputation pain. Thus, retrospective memories about pain should be judged carefully. It is likely that the pain experienced preoperatively may resemble the phantom pain in some patients, but this is not the case in the vast majority of patients.
Psychological Factors
Amputation of a limb is a traumatic experience, and many amputees exhibit a range of psychological symptoms such as depression, anxiety, grief, and self-pity. In a survey of 914 amputees, depressive symptoms were shown to be a significant predictor of the intensity of phantom pain. As in other chronic pain conditions, coping strategies influence the experience of pain. Passive coping strategies, especially catastrophizing, are associated with phantom limb pain. Other psychosocial factors, such as social support, also play an important role in the adjustment to phantom pain.
Other Factors
Phantom pain may be modulated by several other internal and external factors such as attention, distress, coughing, urination, and manipulation of the stump. It is unclear whether the use of a functionally active prosthesis, as opposed to a cosmetic prosthesis, reduces phantom pain.
Both experimental and clinical studies have shown that there is a significant genetic contribution to the development of chronic pain, including neuropathic pain after nerve injury.
It has been claimed that phantom pain may be provoked by spinal anesthesia in lower limb amputees. However, Tessler and Kleiman prospectively investigated 23 spinal anesthetics in 17 patients with previous lower limb amputations and found that phantom pain developed in only 1 patient but resolved in 10 minutes.
Phantom Sensations
Phantom sensations are more frequent than phantom pain and are experienced by nearly all amputees (see Table 26.1 for details). Phantom sensations do not usually pose a major clinical problem; however, more than 30% of amputees may find these sensations moderately to severely bothersome. The two phenomena are strongly correlated. In a study by Kooijman and associates, phantom pain was present in 36 of 37 upper limb amputees with phantom sensations but in only 1 of 17 without phantom sensations. Similar to phantom pain, nonpainful sensations usually appear within the first days after amputation. Immediately after amputation, the phantom limb often resembles the preamputation limb in shape, length, and volume. Over time, however, the phantom fades, with sensation of the distal parts of the limb disappearing. For example, upper limb amputees may feel their hand and fingers, and lower limb amputees may feel their foot and toes. Telescoping (shrinkage of the phantom) is reported to occur in about a third of patients. The phantom gradually approaches the amputation stump and eventually becomes attached to it ( Fig. 26.1 ).
Stump Pain
Stump pain is common in the early postamputation period. In a prospective study that included 54 lower limb amputees, all patients experienced some stump pain in the first week after amputation, with a median intensity of 15.5 (range, 0 to 61) on a 0 to 100 VAS. Stump pain can, however, persist beyond the stage of postsurgical healing. The prevalence of chronic stump pain varies in the literature, but severe pain is probably seen in only 5% to 10% of cases (see Table 26.1 for details).
Stump pain may be described as pressing, throbbing, burning, squeezing, or stabbing. Some patients have spontaneous movements of the stump ranging from slight, hardly visible jerks to severe contractions. Careful sensory examination of the amputation stump may reveal areas with sensory abnormalities such as hypoesthesia, hyperalgesia, or allodynia.
Stump pain and phantom limb pain are strongly correlated. In a survey of 648 amputees, Sherman and Sherman found that stump pain was present in 61% of amputees with phantom pain but in only 39% of those without phantom pain. Similar results have also been found in more recent studies.
Mechanisms of Phantom Pain
The mechanisms underlying phantom limb pain are not completely understood. However, it is now clear that nerve injury is followed by a number of morphologic, physiologic, and chemical changes in both the peripheral and central nervous system and that all these changes are likely to play a role in the induction and maintenance of phantom limb pain. The first events are likely to occur in the periphery, which subsequently generates a cascade of events that sweep more centrally until cortical brain structures are finally recruited. The involvement of cortical structures may be responsible for the complex and vivid characteristics of certain phantom phenomena. The following three sections present a brief overview of peripheral, spinal, and supraspinal mechanisms.
Peripheral Mechanisms
Both experimental and clinical studies confirm that mechanisms in the periphery (i.e., in the stump or in dorsal root ganglion [DRG] cells) play a role in the phantom limb concept. Following a nerve cut, the formation of neuromas is seen universally. Such neuromas show abnormal spontaneous and evoked activity after mechanical or chemical stimulation. The ectopic and increased spontaneous and evoked activity from the periphery is assumed to be the result of an increased and also de novo expression of sodium channels.
Percussion of the stump or of the identified stump neuromas induces stump and phantom pain. In a classic microneurographic study of two amputees, Nyström and Hagbarth showed that tapping of neuromas was associated with increased activity in afferent C fibers and increased phantom pain sensation. Consistent with these findings, a more recent study showed that there is an inverse correlation between phantom pain intensity and pressure pain threshold of the stump early after amputation. Injection of local anesthetic into the stump may reduce or abolish the phantom pain and tap-evoked pain temporarily.
It has been claimed that surgical removal of a neuroma abolishes phantom pain. For example, Sehirlioglu and colleagues retrospectively studied 75 lower limb amputees who underwent neuroma removal and reported that all patients were free of any pain symptoms after a mean follow-up period of 2.8 years. However, in a prospective study of six patients, pain was relieved in only two following surgical neuroma removal.
Several studies have indicated the important role of DRG neurons in the mechanism of phantom pain. DRG cells exhibit dramatic changes in the expression of different sodium channels following axonal transection. Cell bodies in the DRG show abnormal spontaneous activity and increased sensitivity to mechanical and neurochemical stimulation. In the study by Nyström and Hagbarth, local anesthesia of neuromas abolished tap-induced afferent discharges and tap-induced accentuation of phantom pain, but spontaneous pain and recorded spontaneous activity were unchanged; these findings are consistent with the generation of activity in DRG cells.
The sympathetic nervous system may also play an important role in generating and particularly in maintaining phantom pain. Sympatholytic blocks can abolish or reduce phantom pain, and in patients with pain relieved after sympatholytic blockade, the pain can be rekindled by injection of noradrenaline into the skin. Long after limb amputation, injection of epinephrine around a stump neuroma is reported to be intensely painful. Lin and associates showed in 20 patients that perineuronal administration of norepinephrine results in a dose-dependent increase in pain, which was partially reversed by pretreatment with phentolamine. Catecholamine sensitivity may also be manifested in the skin, with a cooler extremity on the amputated side, and it has been suggested that the intensity of phantom pain is inversely related to the skin temperature of the stump.
Spinal Mechanisms
Clinical observations indicate that spinal factors are involved in the generation of phantom limb pain. For example, phantom limb pain may appear or disappear following spinal cord neoplasia. Aydin and colleagues described a woman who suffered from phantom limb pain following lower limb amputation at the age of 5 years. At the age of 65 years, the pain gradually disappeared, parallel to the evolution of cauda equina compression because of an intraspinal tumor. The phantom limb pain gradually reappeared after surgical removal of the tumor.
A very large number of experimental studies support the importance of spinal factors. After nerve injury there is an increase in the general excitability of spinal cord neurons, where C fibers and Aδ afferents gain access to secondary pain-signaling neurons. Sensitization of dorsal horn neurons is mediated by release of glutamate and neurokinins. This sensitization may manifest itself in several ways, including reduced flexion reflex thresholds in response to noxious mechanical and thermal stimulation in the limb contralateral as well as ipsilateral to the injury, increased persistent neuronal discharges with prolonged pain after stimulation (wind-up phenomena), and expansion of peripheral receptive fields.
Some amputees show abnormal sensitivity to pressure and to repetitive stimulation of the stump with a von Frey filament. The pharmacology of spinal sensitization involves increased activity in N -methyl- d -aspartate (NMDA) receptor–operated systems, and many aspects of the central sensitization can be reduced by NMDA receptor antagonists. In human amputees, stump or phantom pain evoked by repetitive stimulation of the stump can be reduced by the NMDA antagonist ketamine.
Supraspinal Mechanisms
Amputation produces a cascade of events in the periphery and in the spinal cord. It is reasonable to assume that these changes will eventually sweep more centrally and alter neuronal activity in cortical and subcortical structures. Also, the phantom limb concept with its complex perceptual qualities and its modification by various internal stimuli (e.g., attention, distraction, or stress) shows the phantom image to be a product of the brain.
Animal studies have demonstrated functional plasticity of the primary somatosensory cortex after amputation. After dorsal rhizotomy, a lowered threshold to evoked activity in the thalamus and cortex can be demonstrated, and adult monkeys display cortical reorganization in which the mouth and chin invade cortices corresponding to the representation of the arm and digits that have lost their normal afferent input.
Studies in humans using different cerebral imaging techniques have also documented cortical reorganization after amputation. In a series of studies, Flor’s group has shown a correlation between phantom pain and the amount of reorganization in the somatosensory cortex. Birbaumer and associates studied the effect of regional anesthesia on cortical reorganization in upper limb amputees and found that brachial plexus blockade abolished pain and reorganization in three of six amputees. Huse and coworkers showed in a small group of amputees that cortical reorganization and pain were reduced during treatment with morphine. In contrast to cases of traumatic amputation, in a group of four patients with congenital absence of a limb without a phantom, Reilly and Sirigu demonstrated that the motor cortex does not contain a representation of the missing limb in this patient group.
Changes have also been observed at subcortical levels. Using neuronal recording and stimulation techniques, it was shown that thalamic neurons, which do not normally respond to stimulation, begin to respond and show enlarged somatotopic maps in amputees. In addition to functional plasticity, structural alterations also follow amputation. Draganski and colleagues demonstrated a decrease in the gray matter of the thalamus in 28 amputees. The decrease was correlated with the time span after the amputation and explained as a structural correlate of the loss of afferent input.
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