Abstract
Amputation of a limb can lead to both painful and nonpainful sequelae, which occur in a majority of patients. 1.6 million Americans currently experience limb loss, with the prevalence expected to reach 3.6 million by 2050. Vascular disease (82%) and trauma (16%) are the most frequent causes. Phantom phenomena, including phantom limb pain, is thought to occur through interactions between altered peripheral, spinal, and supraspinal mechanisms. In contrast, residual limb pain, which often occurs with phantom phenomena, is associated with local pathologic processes, such as infection, heterotopic ossification, ischemia, or a neuroma of the transected nerve. The approach to a patient with postamputation pain involves a thorough evaluation of the affected limb and discussion with the patient’s therapists, prosthetists, and other providers. The most effective treatments are typically interdisciplinary in nature. Pharmacologic treatments have been more rigorously studied than other treatment options, but results are mixed, including the use of preventive analgesia to prevent phantom limb pain. Complementary therapies, such as mirror therapy, mental imagery, and noninvasive motor cortex stimulation may be beneficial. Psychological therapies are helpful in managing chronic pain in general but have not been well studied for postamputation pain. Interventional techniques such as neuroma injections, radiofrequency, and spinal cord stimulation are reportedly beneficial, but the evidence is limited to case series. Surgical therapies may include intracranial neurostimulation, peripheral neuromodulation, or resection of neuromas or heterotopic ossification. Management of postamputation pain remains challenging, but its importance will increase as patients live longer with limb loss.
Keywords
amputation, neuropathic pain, phantom limb pain, postamputation pain, residual limb pain
Amputation of a limb can lead to painful and nonpainful sequelae, such as phantom sensations, telescoping, phantom pain, and residual limb (or “stump”) pain. Although the phenomena of abnormal sensations and pain in amputated limbs were reported earlier by several physicians, Weir Mitchell is generally credited with coining the term “phantom limb” to describe the symptoms he observed in American Civil War soldiers. These phenomena occur in the majority of patients after limb amputation, although the nature, frequency, intensity, and duration of symptoms may vary considerably. As with the treatment of most chronic pain conditions, management of the pain-related complications of amputees often necessitates an individualized and interdisciplinary approach due to the multifactorial nature of the causes and variable comorbidities observed in these patients.
Definitions and Epidemiology
As of 2005, the prevalence of limb loss in the United States was at least 1.6 million, or 1 in 190; it is expected to rise to 3.6 million, or 1 in 120, by 2050. Forty-two percent of limb loss is considered “major” (i.e., not limited to fingers or toes). Vascular disease (82%) and trauma (16%) are the most frequent causes of amputation, with vascular disease predominating for major limb amputations involving the lower extremities, and industrial accidents, especially involving digits, comprising the leading cause of upper extremity amputations. Other etiologies—including primary and metastatic tumors and congenital abnormalities—constitute much less frequent causes (<2%). The prevalence of multiple limb loss is estimated to be 7.3% of trauma-related amputees, and vascular insufficiency amputees have a 27%–44% risk of contralateral limb amputation after 4 years. The most common sources of postamputation pain (PAP) more than 6 months after amputation are phantom pain and residual limb pain (RLP). In addition, those with lower extremity amputation are also at high risk for back pain and other musculoskeletal conditions (e.g., arthralgia and bursitis).
Phantom Sensations
Phantom sensations are nonpainful perceptions that occur in the region of the missing body part after a traumatic or surgical amputation. Phantom sensations are common after limb amputation surgery, with an incidence of 90% during the first 6 months. One third of patients experience phantom sensations within 24 hours after their surgery. Excision of a body part, however, is not essential for phantom sensations. Phantom sensations of the arm have been reported after avulsion of the brachial plexus without amputation of the limb. Excision of other body parts—such as the tongue, bladder, rectum, breast, or genitalia—may also present with phantom sensations.
Phantom sensations may present with various manifestations including kinetic sensations and kinesthetic and exteroceptive perceptions. Kinetic sensations are exemplified by perception of movements in the amputated body region, such as flexion/extension of the toes. Kinesthetic perceptions are characterized by distorted representations in size or position of the missing body part (e.g., feeling that the hand or foot is twisted). Exteroceptive perceptions can include paresthesias, tingling, touch, pressure, itching, heat, cold, and wetness. Complete paraplegic and quadriplegic patients can also have phantom sensations. Phantom sensations are commonly experienced in the distal portion of the limbs—hands and feet—possibly due to the rich innervation of these regions and the disproportionately large cortical representation of these regions in the homunculus.
Telescoping
Phantom limbs are also associated with a phenomenon called “telescoping”: the perception of progressive shortening of the phantom body part resulting in the sensation that the distal part of the limb is becoming more proximal. At the start of the phenomenon, the phantom sensation can feel so real that the patient may actually reach for objects or attempt to ambulate with a phantom leg. However, over time, phantom sensations of the distal extremities may change and become less distinct so that the patient may feel a hand close to the end of the residual limb but not feel the proximal arm or forearm. This phenomenon is common, occurring in up to two thirds of limb amputees.
Phantom Pain
Phantom pain, often referred to as phantom limb pain (PLP), is the perception of dysesthesias, or unpleasant sensations, in the distribution of the missing or deafferentated body part. PLP has been reported to occur in up to 79% of postamputation patients 6 months after surgery, with about 60% of patients still reporting significant PLP 2 years after surgery. The pain can vary in character, duration, frequency, and intensity. It can present as sharp, dull, burning, squeezing, cramping, shooting, or as a shocklike electrical sensation. Patients may occasionally complain of intermittent tremors or painful muscle spasms in the stump associated with paroxysms of PLP.
In a prospective study by Jensen and colleagues of 58 patients undergoing limb amputation, the authors found that PLP often changed in presentation within the first 6 months after amputation. The characteristic of the phantom pain changed from a mainly exteroceptive-like pain (knifelike or sticking) localized in the entire limb or at least involving proximal parts of the lost limb to a mainly proprioceptive type of pain (squeezing or burning) localized in the distal parts of the amputated limb. Forty-seven percent of patients experienced phantom pain within 24 hours after the amputation and 83% within the first 4 days. The study also demonstrated that the frequency, duration, and severity of PLP decreased during the first 6 months, after which the characteristics did not change significantly. Sometimes PLP can resolve spontaneously without treatment. Similar to other neuropathic conditions, PLP persisting longer than 6 months is extremely difficult to treat.
The incidence of PLP seems to be independent of the patient’s age, sex, previous health status, and cause of amputation. One factor that appears to increase its incidence after amputation is the presence of pain in the limb before the amputation. In a prospective study of 56 patients who had amputation of a lower limb, Nikolajsen and colleagues noted that the presence of preamputation pain significantly increased the incidence of both residual limb pain (RLP) and PLP after 1 week and the incidence of PLP after 3 months. Approximately 42% of the patients reported that their PLP at 3 months resembled the pain they had experienced at the time of amputation. Associations of PLP with phantom sensations and between PLP and RLP have also been demonstrated for upper limb amputees.
Residual Limb Pain
RLP, classically referred to as “stump pain,” is pain localized to the residual body part following amputation. Longitudinal studies previously reported an incidence of RLP of about 20% 2 years after amputation. However, more recent studies with longer duration of follow-up report an incidence of 56%–74%. RLP is often secondary to local pathologic processes such as infection; lesions of the skin, soft tissue, or bone; heterotopic ossification (>50% in traumatic amputations); and local ischemia. These processes can generally be classified into the following categories: postsurgical nociceptive, neurogenic, prosthogenic, arthrogenic, ischemic, referred (usually from the spine or joints), sympathetically maintained, and abnormal residual limb tissue (e.g., adhesive scar tissue). RLP can be superficial (localized to the scar region of the incision), felt deep in the distal residual limb, or encompassing the whole residual limb. RLP can frequently be differentiated from PLP based on the fact that it is classically provoked or exacerbated by traction or pressure, which often occurs during the use of a prosthesis. This factor can greatly limit function in lower extremity amputees. The management of RLP entails a detailed history and physical examination that includes ensuring a properly fitting prosthesis. Arthrogenic RLP is usually secondary to abnormal gait and asymmetrically distributed weight bearing, resulting in excessive stress on adjacent joints and/or lumbosacral spine structures. This can lead to bursitis, accelerated arthritis, sacroiliac joint disease, discogenic and facetogenic pain, and lumbosacral radiculopathy.
Special Populations
Phantom Phenomena After Mastectomy
Well over 100,000 mastectomies are performed each year in the United States. Recent studies indicate that phantom sensations are felt by 14%–48% of patients who underwent mastectomy. Most of these phantom sensations are felt intermittently, occurring once every 2 or 4 weeks. The incidence of phantom pain after mastectomy appears to be lower than that after limb amputation, ranging from 0% to 23%. This lower incidence may be related to the smaller cortical representation of breasts and the fact that breasts do not mediate kinesthetic sensory impulses. The onset of phantom sensation often appears within 3–6 months of surgery and begins to dissipate after 1 year. The phantom pain usually localizes to the entire breast or around the nipple. The relationship between preamputation pain and phantom pain or phantom sensations appears to be less after mastectomy than after limb amputation. There is, however, a striking similarity in the location and character of the pain before and after mastectomy, a phenomenon seen after other amputations. The relationship between phantom pain and preamputation pain is more significant within the first month after mastectomy. In view of the high incidence of pain after breast surgery in general, the only way to distinguish between true “phantom” pain and other sources of postmastectomy pain (e.g., intercostal brachial neuralgia, neuroma) may be via a detailed history and physical examination.
Wounded Warriors
The US military conflicts since 9/11 have placed more emphasis on the management of traumatic amputation and its complications. As of June 2015, the Department of Defense reports that 1645 individuals have suffered major limb loss since September 2001, including approximately 17% with upper extremity amputations and 30% with multiple limb loss. A majority of these injuries are related to blast exposures; therefore many have concomitant comorbidities including traumatic brain injury, posttraumatic stress disorder, peripheral nerve injuries, fractures, and soft tissue injuries. Studies have shown a higher prevalence of chronic pain among individuals with posttraumatic stress and traumatic brain injury than in similar cohorts without these conditions.
The unique mechanisms of injury and related comorbidities associated with amputations in military service members present management challenges that may not be similar to those in other patient populations with PAP. In a study of traumatic amputations in sustained by 30 military personnel during combat or training, the prevalence of PLP was similar (77%), but RLP was higher (87%) than previously reported. In addition, the average (3.3) and worst (5.4) pain intensity as measured on a numerical rating scale was less than in other amputee populations.
Pathophysiology and Mechanisms of Postamputation Pain
Evidence suggests that phantom phenomena are the result of interactions between altered peripheral, spinal, and supraspinal mechanisms.
Supraspinal mechanisms of phantom phenomena involve the reorganization of the somatosensory cortex following amputation. Ramachandran and coworkers have reported that in upper limb amputees, sensations in the phantom limb could be elicited by brushing the face. Functional magnetic resonance imaging (MRI) studies, also in upper extremity amputees, demonstrate a shift of mouth representation in the somatosensory cortex to the zone previously represented by the arm and hand (i.e., cortical reorganization). A strong correlation was also demonstrated between the size of the deafferentated area and intensity of PLP.
Spinal mechanisms for phantom phenomena likely center on functional changes in the dorsal horn of the spinal cord following a deafferentation injury. The loss of afferent input leads to decreased impulses from brainstem reticular areas, which normally exert inhibitory effects on sensory transmission. The absence of inhibitory effects of sensory input from the missing peripheral body part causes increased autonomous activity of dorsal horn neurons, in effect becoming “sensory epileptic discharges.” In addition, similar to the process of cortical reorganization, a “spinal reorganization” process may also occur in which adjacent nerve fibers establish connections in regions of the spinal cord that no longer receive afferent input. Several lines of evidence support a spinal mechanism for phantom phenomena. These include the observations that: (1) anticonvulsants and lesions in the substantia gelatinosa of the spinal cord are effective in treating phantom pain ; (2) phantom pain develops in lower extremity amputees following new lumbar disc herniation and in upper limb amputees after herpes zoster infection, both of which were successfully treated with epidural steroid injection ; (3) phantom pain can be induced with spinal analgesia ; (4) in an unusual case, long-standing phantom pain resolved with the development of a cauda equine syndrome from a spinal tumor and recurred following decompression.
Evidence supporting peripheral mechanisms of phantom phenomena includes the demonstration of spontaneous neuronal activity at the proximal ends of cut nerves, the presence of residual limb pathology in some patients with phantom pain, and the relief of phantom pain after the injection of local anesthetic into the painful residual limb. Peripheral nerve transection during an amputation initiates axonal regeneration, eventually resulting in a neuroma or a collection of nerve fibers near the end of the residual limb. Afferent fibers in a neuroma may develop ectopic activity, mechanical sensitivity, and chemosensitivity to catecholamines. Upregulation of voltage-sensitive sodium channels, downregulation of potassium channels, and expression of novel receptors in the neuroma can alter the excitability of the affected neurons and increase afferent input. A positive Tinel’s sign (tapping on the injured nerve or neuroma, leading to pain in the phantom or residual limb) represents a classic feature of a symptomatic neuroma on physical examination. Injured neurons can also generate new, nonfunctional connections (ephapses), resulting in increased afferent input to the spinal cord. These changes may lead to spontaneous pain; they help explain the amplification in pain caused by emotional distress and/or exposure to cold that leads to increased sympathetic discharge and circulating catecholamines.
PAP is likely caused by a combination of the mechanisms already described as well as others that have yet to be elucidated, since treatments to date have yielded only modest relief of PAP. However, our understanding of the interactions between peripheral, spinal, and supraspinal physiology are the basis for a mechanistic approach to treatment. A summary of the factors thought to be relevant in the development of phantom pain is depicted in Fig. 29.1 .
Evaluation
The first step in the management of PAP is to attempt to identify a specific etiology that can be the target for developing a treatment strategy. The residual limb should be inspected and palpated for skin breakdown, pressure sores, infection, bony abnormalities (e.g., spurs, heterotopic ossification), ischemia (e.g., choke syndrome, changes in color or temperature), or masses. Localized soft tissue tenderness, particularly in the presence of a positive Tinel’s sign, which reproduces pain symptoms, may indicate a neuroma. Imaging (e.g., x-rays, computed tomography [CT], MRI, and more commonly ultrasound) and laboratory testing (e.g., CBC, ESR, CRP) can support or rule out concerns from the history and physical examination, but these are not routinely indicated.
Consultation with an experienced prosthetist for rectifying an ill-fitting prosthesis is often helpful, since patients may experience exaggeration of their pain or even precipitation of phantom pain and/or sensations from use of the prosthetic limb. In addition, changes in gait and altered body mechanics may result in musculoskeletal pain. Physical and occupational therapy to correct gait and postural compensations that result in arthritic or referred pain may also be useful.
Treatment
Amputation of a limb affects not only the physical functioning of the individual but may also have significant psychological, social, and societal consequences. Therefore the treatment of PAP is more likely to be successful with an individualized and interdisciplinary approach. Since few controlled trials specifically focus on PAP, treatment strategies often need to be extrapolated from related conditions. After an appropriate evaluation narrows the differential diagnosis, treatments may include pharmacotherapy, physiotherapy and modalities, complementary and alternative therapies, psychological therapies, interventional therapies, and surgery.
Pharmacotherapy
Most medication options for PAP require extrapolation from the treatment of other conditions. For somatic pain, acetaminophen, nonsteroidal antiinflammatory drugs, and/or opioids may be indicated. Neuropathic pain is more likely to respond to adjuvant analgesics such as tricyclic antidepressants (e.g., nortriptyline), anticonvulsants (e.g., gabapentin), or selective norepinephrine reuptake inhibitors (e.g., duloxetine). The results of available randomized controlled trials specifically for the pharmacologic treatment of PAP are summarized in Table 29.1 , and some are discussed here.
| Study | N | Treatment/Placebo | Chronicity a | Adverse Events | Follow-Up | Effect b |
|---|---|---|---|---|---|---|
| Antidepressants | ||||||
| Robinson et al. | 39 |
| >3 months | Dry mouth, dizziness | 6 weeks | − |
| Wilder-Smith et al. | 94 |
| 10–16 years | Nausea, tiredness, dizziness, constipation, headache (all more common with tramadol) | 1 month | + |
| Anticonvulsants | ||||||
| Bone et al. | 19 |
| >6 months | Somnolence, dizziness, headache, nausea | 6 weeks | + |
| Smith et al. | 24 |
| >6 months | Not described | 6 weeks | − |
| Nikolajsen et al. | 46 |
| POD #1 (prevention) | Nausea, stomachache, fatigue, confusion, nightmares, itching, ataxia | 6 months | − |
| NMDA Antagonists | ||||||
| Nikolajsen et al. | 11 |
| Avg. 4 years | Insobriety, mood elevation, discomfort | 45 min | + |
| Eichenberger et al. | 20 |
| Avg. 12 years | Loss of consciousness, light visual hallucination, hearing impairment (all with ketamine); facial flushing (calcitonin) | 48 h | + |
| Ben Abraham et al. | 10 |
| Avg. 4.8 months | None reported | 10 days | + |
| Maier et al. | 36 |
| >12 months | Vertigo, fatigue, headache, nausea, restlessness, excitation, cramps | 3 weeks | − |
| Schwenkreis et al. | 16 |
| >12 months | Not described | 3 weeks | − |
| Wiech et al. | 8 |
| Chronic | Fatigue, agitation, dizziness, nausea, headache | 30 days | − |
| Calcitonin | ||||||
| Jaeger and Maier | 21 |
| 0–7 days postamputation | Headache, vertigo, nausea, vomiting, augmented phantom sensations, drowsiness, hot flashes | 1 year | + |
| Eichenberger et al. | 20 |
| Avg. 12 years | Loss of consciousness, light visual hallucination, hearing impairment (all with ketamine); facial flushing (calcitonin) | 48 h | + |
| Opioids | ||||||
| Huse et al. | 12 |
| Chronic | Constipation | 4 weeks | + |
| Wu et al. | 32 |
| >6 months | Sedation | 30 min | + |
| Wilder-Smith et al. | 94 |
| 10–16 years | Nausea, tiredness, dizziness, constipation, headache (all more common with tramadol) | 1 month | + |
| Wu et al. | 56 |
| >6 months | Constipation, nausea, drowsiness, dizziness (all more common with morphine) | 6 weeks | + (morphine only) |
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