Postamputation pain is broadly categorized based on its location. Residual limb pain refers to pain that is localizable to the residuum, whereas phantom limb pain is perceived as emanating from portions of the limb that are no longer physically present. By definition, phantom pain is neurogenic in nature.¹ Conversely, residual limb pain is often attributable to nonneurogenic sources.² The residual limb is constantly placed under physical stress through weight bearing, ambulation, and prolonged prosthesis use. These physical factors lead to soft-tissue breakdown, bursa formation, myodesis disruption, skeletal stress, heterotopic ossification, and arthritis, which commonly cause pain in patients with either upper and/or lower limb loss.² End neuromas serve as the primary source of neurogenic pain within the residual limb, although people with limb loss are also susceptible to the same nerve compression syndromes that plague those with intact limbs.³ In fact, proximal nerve compression may contribute to the symptomatology of the obligate distal nerve injury.⁴

The prevalence of postamputation pain varies based on the subpopulation studied and the methodology used, with retrospective and cross-sectional studies serving as the basis for much of the available literature. The pervasive reliance on medical record review for outcomes is particularly problematic given the diagnostic challenge of identifying a primary pain etiology in the setting of multiple potential or overt neurogenic and somatic sources. Pooled prevalence rates of lower extremity residual limb pain have been reported to be 59%, with the same study identifying a pooled prevalence of neuroma pain to be 15%.² Phantom limb pain has been found to be present in 64% of patients with limb loss after pooled analysis of available studies.⁵ Preoperative pain, proximal level of amputation, concomitant residual limb pain, and lower limb amputation were identified as risk factors for phantom limb pain.⁵

Although it is helpful to appreciate the scope of the problem, efforts to manage and prevent postamputation pain are even more reliant on an understanding of the biologic processes that underlie neurogenic pain following amputation. Unfortunately, a limited understanding of central and peripheral pain mechanisms has proven to be the greatest obstacle to developing a rational approach to postamputation pain management. In the absence of a comprehensive understanding, clinicians must combine basic science and clinical observations with sound theory to bridge these knowledge gaps. Although unquestionably an oversimplification, a framework that differentiates peripheral and central pain mechanisms can be useful for assessing pain interventions. Likewise, an understanding of physiologic nerve regeneration can provide a template on which to design and judge reconstructive strategies for management of the divided nerves within a residual limb.

While recognizing the cortical role in pain perception, neuroma pain can largely be considered peripheral in origin.⁶ In the absence of a regenerative target and favorable environment, axonal nerve damage induces a state of abnormal regeneration and inflammation that results in bulbous thickening of the transected nerve end.⁶ An unrepaired nerve transection uniformly results in neuroma formation, although the relatively low prevalence of neuroma pain following amputation suggests that only a small number of neuromas become symptomatic.² If better understood, the environmental and intrinsic factors that drive this differentiation would be clear targets for intervention. When painful, the neuroma bulb is often the symptomatic focus, but the entirety of the peripheral nerve is affected, as evidenced by changes at the level of the dorsal root ganglion.⁷ This recognition suggests there may be a role for proximal decompression in conjunction with end neuroma management.⁸ Hyperexcitability from ion channel dysfunction results in focal sensitivity to pressure or palpation that is typical for neuroma pain. When combined with uncontrolled axonal sprouting, reduced axonal depolarization potentials, and scar tissue formation, this dysfunction drives the ectopic firing that typifies neuroma pain.⁷ Neuroma formation occurs within 1 month of nerve injury and neuroma pain is typically present within 3 months of amputation, although clinical presentation can vary widely based on patient activity and neuroma location.⁹

Phantom limb pain is largely considered to be a central phenomenon, although it can exist concurrently with neuroma pain and may be exacerbated by manipulation of the residual limb.¹ Most patients with limb loss experience phantom limb sensations and/or the ability to control phantom movements. Unfortunately, most of the patients also report intense episodic pain that is often characterized as throbbing, cramping, stabbing, or burning and is thought to originate within the amputated segment.¹⁰ Although reported rates of phantom limb pain are higher in the developed world, it is a global problem that affects nearly all patients with limb loss to some degree.⁵ Although the mechanisms underlying phantom limb pain are yet to be fully elucidated, cortical reorganization is thought to be a major contributor. The cortical remapping theory suggests that the brain responds to limb loss by reorganizing its somatosensory map. No treatment has been found to be universally effective, but the reported efficacy of therapies that specifically target cortical remapping, such as mirror therapy and virtual reality, supports a central origin for phantom limb pain.¹ However, it is also known that sensitized nerve endings in the residual limb and dorsal root ganglion cells are associated with aberrant sensory afferent feedback that can produce somatosensory cortical changes.^11,12 Both the absence of physiologic input and the excess of pathophysiologic feedback appear to be drivers for pathologic cortical reorganization.

The process of central sensitization often serves to blur the distinction between central and peripheral pain processes. Central sensitization refers to neuronal hyperexcitability and reduced inhibition in the central nervous system that results from peripheral pathology.¹³ Driven by increases in membrane excitability and reduced inhibition, central sensitization represents an abnormal state of responsiveness of the nociceptive system, where pain is no longer coupled to the presence, intensity, or duration of peripheral stimuli.¹³ This uncoupling of the pain response from the peripheral lesion produces pain that is often refractory to peripheral pain interventions. Unfortunately, there is still much to be learned about the timeframe for sensitization and the patient and anatomic factors associated with a susceptibility to this process. In the absence of a more complete understanding, the significant therapeutic challenge posed by central sensitization can be used to justify a proactive approach to neurogenic pain management.

Surgical techniques to manage or prevent neurogenic pain after amputation have been classified as active and passive strategies.¹⁴ Active strategies aim to facilitate physiologic regeneration of the transected nerve, whereas passive techniques are intended to prevent regeneration, alter the neuroma environment, or reduce physical stimulation of the nerve ending. When applying the previous framework for understanding postamputation pain, it becomes apparent that passive nerve management strategies aim solely to address the peripheral pain focus, without the ability to influence the central processes that contribute to postamputation pain. The common practice of traction neurectomy seeks simply to relocate the inevitable neuroma to an area where it is less vulnerable to direct stimulation.¹⁵ Cap or burial techniques are passive methods that use various tissues or foreign materials to isolate the regenerating nerve end from environmental factors that encourage regeneration.¹⁴ Similarly, implantation of the transected nerve end into innervated muscle was explicitly hypothesized to prevent neuroma formation by limiting exposure to nerve growth factor.¹⁶ As evidenced by the high rates of neuroma recurrence and pain, these passive strategies do not address the reduced depolarization potentials, nerve hypersensitivity, and ectopic discharges that produce dysfunctional sensory afferent feedback that typifies neuroma pain, even without mechanical stimulation. In addition, these passive strategies provide no mechanism to address the central processes that underlie phantom limb pain.

By providing the substrates necessary for coordinated nerve regeneration, advanced nerve management techniques use active strategies for minimizing or preventing postamputation pain.¹⁴ Preclinical data and a growing volume of clinical studies suggest that these approaches may be more effective than conventional passive techniques for the treatment and prevention
of postamputation pain.^17,18 When used for the treatment of established postamputation pain, an ideal strategy would effectively prevent neuroma recurrence following neurectomy, while also serving to reverse any associated central pain processes. In the prophylactic setting, these strategies should aim to inhibit formation of a symptomatic neuroma in the periphery, while also preventing central sensitization of pain. The most commonly described active strategies for management or prevention of postamputation pain are nerve allograft reconstruction, regenerative peripheral nerve interface (RPNI) creation, and targeted muscle reinnervation (TMR). Allograft reconstruction provides a conduit with which to direct regenerating axons, whereas RPNI is intended to provide a denervated muscle target and associated neurotrophic signal. TMR offers the transected nerve a denervated target, a neurotrophic signal, and a pathway or conduit across which to regenerate.