Managing pain after amputation often is challenging. Aggressive pain control starts in the perisurgical phase and remains a vital part of treatment throughout all phases of recovery after limb loss. The two most recognized categories of pain after amputation are residual limb pain and phantom limb pain. Although these pain syndromes often coexist, they likely have very different pathophysiologies and therefore warrant different treatment strategies.

Further complicating pain management strategies are the various phenotypes of pain that exist. Ideally, pain treatment algorithms should be tailored for each individual patient. Often, the pain from the amputation can limit or slow rehabilitation more than the disability from the amputation itself. Although the exact pathophysiology of pain has not been fully discerned, three theories or models (the gate control theory of pain, the neuromatrix theory of pain, and the biopsychosocial model of chronic pain) provide some insight on how the nervous system and environmental factors modulate the experience of pain.^1,2

This chapter discusses several aspects of postamputation pain, including definitions, basic epidemiology, pathophysiology, and the various treatment options, including both pharmacologic and nonpharmacologic strategies. The available literature on current treatments is reviewed, and strategies are proposed for optimizing effective long-term pain management.

In the United States, more than 1.7 million individuals were estimated to be living with limb loss in 2010. This number is projected to increase to 3.6 million by the year 2050. Peripheral vascular disease and diabetes (55%) are the most common causes of amputation, followed by trauma (45%), cancer (<1%), and congenital anomalies (<1%). In the United States, approximately 150,000 surgical amputations are performed annually, mostly for dysvascular indications.⁶

Although previous reports indicate a relatively low prevalence of postamputation pain (in the range of 5% to 10%), more recent surveys indicate that the problem may be much greater. At least one report indicates that of the people with amputations who were surveyed, the prevalence of phantom limb pain ranges from 43% to 80%, and residual limb pain ranges from 43% to 68%.7 Surveys also indicate that for more than 50% of patients who experience phantom limb pain, their frequency of painful attacks decreases within the first 6 months after amputation. In addition to being discomforting and distressing, phantom limb pain also has a negative effect on quality of life. More than 25% of those with postamputation pain who were surveyed reported that their pain was extremely bothersome, and 85% of these individuals indicated consequential social isolation and an inability to seek and maintain employment.^8,9

Preexisting pain and poor coping skills may be risk factors for the development of phantom limb pain, particularly for patients with lower limb loss associated with peripheral vascular disease.¹⁰ In some studies, more than 50% of individuals with limb loss express symptoms of depression, which likely has a high correlation with pain intensity.¹¹ The presence of pain for more than 1 month before amputation has been reported to be associated with an increased incidence of postamputation pain.¹² Hence, it is important to recognize and aggressively treat the patient with preemptive analgesia as well as address signs and symptoms of comorbid depression and anxiety.

Two broad categories of pain often used to describe postamputation pain are nociceptive and neuropathic. The nociceptive pathway often is thought to mediate residual limb pain, whereas a neuropathic phenomenon is thought to more likely mediate phantom limb pain. Understanding the differences between each pain pathway can be helpful in targeting treatment.

Nociceptive pain is thought to initiate peripherally, typically at the site of tissue or organ damage. Most theories implicate an initial inflammatory cascade, where various sensitizing chemicals—such as bradykinin, serotonin, nitric oxide, and cytokines—are released locally and activate peripheral pain receptors (nociceptors). Once these nociceptors are activated either mechanically or chemically, they generate an electric potential at the distal nerve terminal. If this electric potential exceeds the axon’s threshold potential (which often is sensitized or lowered after injury), a resulting action potential then propagates afferently to the dorsal root ganglion and the central nervous system (CNS). After reaching the brain, activation of the somatosensory and limbic systems creates a summative response, causing the patient to experience pain. These basic sequences of pain transmission are referred to as transduction, conduction, transmission, and perception.¹³

In addition to the local inflammatory effect of tissue damage after amputation, the distal ends of transected nerves begin sprouting in a disorganized pattern, forming neuromas, which also may be painful. Neuromas can generate afferent nociceptive action potentials either ectopically or when mechanically irritated. Common sources of mechanical irritation include soft-tissue scarring, inflammation, heterotopic bone formation, or direct pressure from prosthetic sockets. Chronic peripheral nerve firing from neuromas, tissue damage, or inflammation may cause upregulation and sensitization of CNS neurons, contributing to enhanced nociceptive signal transmissions in the spinal cord and the brain. In the face of sustained chronic pain, a persistent, abnormal, unpleasant sensory stimulus leads to peripheral and central sensitization.¹⁴ The term allodynia describes the phenomenon when nonpainful peripheral limb stimulation leads to perceived pain and is frequently associated with neuropathic pain. Other features of neuropathic pain may be paresthesias (ectopic sensations in the limb, typically described as pins and needles) or dysesthesias (ectopic painful sensations in the limb, such as burning and lancinating, knife-like, stabbing pain). Neuropathic pain often is challenging to treat.

Historically, phantom limb pain was considered a psychologic disorder; however, current theories classify the phenomenon as a neuropathic process, with likely involvement at the peripheral, spinal, and supraspinal levels. Some of the proposed theories of phantom limb pain provide potential targets for management (Figure 1).

After an injury, the peripheral nervous system, the dorsal root ganglion, and the sympathetic nervous system undergo changes at the cellular level. An increase in the number of transmitters and receptors results in increased sensitivity to pain. These changes affect both ascending and descending pathways within the spinal cord, where the decreased firing of inhibitory interneurons leads to hyperexcitability of painful signals. In addition, downregulation of opioid receptors causes even further excitability of nociceptive signals. Facilitation of N-methyl-D-aspartate (NMDA) receptors at the dorsal horn leads to a wind-up phenomenon and reinforces ectopic activity by A delta and C fibers, which usually carry nociceptive signals, as well as A beta fibers, although these fibers typically are not involved in nociception.¹⁴

Changes at the cellular level eventually lead to cortical reorganization. Based on the understanding of cortical homunculus and its disproportionate representation of body regions, Ramachandran et al¹⁵ demonstrated that referred sensation of phantom limb pain could be induced when stimuli were applied to the lower part of the face of a person with an upper limb amputation. This phenomenon is likely explained by maladaptive CNS plasticity, where the part of the sensory cortex that was previously mapped to the now amputated limb begins receiving input from other adjacent cortical areas, thereby expanding the receptive field of a missing body part. Reorganization takes place in multiple aspects of the CNS, including the brain stem, the thalamus, the prefrontal cortex, the primary sensory cortex, the motor cortex, the insula, the anterior cingulate cortex, and the parietal cortex. Even in the absence of a limb after amputation, the proprioceptive system still remembers the limb position and creates a proprioceptive memory bank. The resulting disconnect between previous proprioceptive memory and current visual sense makes the patient feel the continued existence of a missing limb.¹⁶ Therefore, the various areas of the brain that are involved in the development of phantom limb pain suggest a complex interplay of visual, sensory, motor, and affective feedback. Further evidence of these pathophysiologic changes is supported through functional MRI studies, which demonstrate reorganization, expansion, and, in certain parts of the brain, even shrinkage in the setting of chronic pain.¹⁷ Fortunately, evidence exists to suggest that these CNS changes are not necessarily permanent. In certain chronic pain conditions such as fibromyalgia, adequate pain control can reverse the CNS changes seen on functional MRI.¹⁸

When assessing individuals with postamputation pain, obtaining a complete history and a thorough physical examination continue to be fundamental in establishing an accurate diagnosis and treatment strategy. Special attention should be focused on assessing a patient’s functional status and prosthetic use. A careful examination of the residual limb may reveal common problems, such as skin irritation or breakdown, cyst formation, bursitis, neuromas, heterotopic bone, or myodesis failure. Assessing both prosthetic socket fit and alignment may reveal potential sources of abnormal gait and posture that are causing secondary
musculoskeletal pain.¹⁹ Underlying joint pathology should be assessed within the residual limb. Furthermore, clinicians should be reminded that pain from proximal joints or even root injuries may be referred into the distal residual limb. Imaging studies of the residual limb or the spine may help further refine diagnoses. Similarly, laboratory testing should be considered to screen for underlying infection or inflammatory processes.

Screening questionnaires and pain scales, such as the Oswestry Low Back Pain Disability Questionnaire, the McGill Pain Questionnaire, and the Brief Pain Inventory, can help better categorize the quality of pain and functional level. Relying on standard numeric scale assessments of pain, such as the visual analog scale, may have limited clinical value; thus, it also is important to incorporate function-related questions. Some of these questionnaires can be time consuming and may not be practical for use in a busy clinical environment. A recently validated scale, the Defense and Veterans Pain Rating Scale, has a single numeric pain intensity scale plus four supplemental questions to assess sleep, mood, stress, and activity. The main goal of the scale is to provide a simple and quick data-gathering tool to assess how pain affects a patient’s function and quality of life²⁰ (Figure 2).

The most commonly used medications to treat residual and phantom limb pain include opioids, NSAIDs, antidepressants, and anticonvulsants. Although understanding of the mechanism of analgesia and the pathophysiology of nociception has substantially improved, there has not been a corresponding increase in novel drugs introduced in the market.³⁷ In fact, during the past half century, the number of novel medication classes that have been translated into clinical use beyond the traditional classes has been sparse. Two examples of novel medications include NMDA receptor antagonists and transient receptor potential cation channel subfamily V member 1 receptor blocker, otherwise known as capsaicin.