Hong Wu
Chandan Saini
Roi Medina
Sharon L. Hsieh
Aria Meshkati
Kerry Sung
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- 1Department of Physical Medicine and Rehabilitation, Rush University Medical Center, Chicago, IL, United States
- 2Department of Physical Medicine and Rehabilitation, Emory University School of Medicine, Atlanta, GA, United States
- 3Rush University Medical College, Chicago, IL, United States
Phantom limb pain (PLP) is defined as the perception of pain in a limb that has been amputated. In the United States, approximately 30,000–40,000 amputations are performed annually with an estimated 2.3 million people living with amputations. The prevalence of PLP among amputees is approximately 64%. Over the years, various theories regarding the etiology of PLP have been proposed, with some gaining more prominence than others. Yet, there is a lack of consensus on PLP mechanisms as the current literature exploring the pathophysiology of PLP is multifactorial, involving complex interactions between the central and peripheral nervous systems, psychosocial factors, and genetic influences. This review seeks to enhance the understanding of PLP by exploring its multifaceted pathophysiology, including genetic predispositions. We highlight historical aspects of pain theories and PLP, examining how these theories have expanded to include psychosocial dimensions associated with chronic pain in amputees. Additionally, we present significant findings from both human and animal studies focused on neuroaxial systems and recent advances in molecular research to further elucidate the complex and multifactorial nature of PLP. Ultimately, we hope that the integration of current theoretical frameworks and findings will lay a more robust foundation for future research on PLP.
1 Introduction
Phantom limb pain (PLP) is defined as the pain in a limb that has been amputated, but it can also occur following the loss of other body parts, such as an eye, breast, or tooth (1, 2). This phenomenon was first documented by the French barber-surgeon Ambroise Paré in 1551, who observed the condition in soldiers who had undergone battlefield amputations (3, 4). In 1797, British Admiral Horatio Nelson, after losing an arm in a battle, described the vivid sensation of his missing arm and the transient pain in his stump (5, 6). It was not until the 19th century, during the American Civil War, that neurologist Silas Weir Mitchell contributed significantly to the understanding of the PLP (7, 8).
In the United States, the annual incidence of limb amputations is approximately 464,644 (9), and the global prevalence of PLP among amputees is estimated at 64% (10). Projections indicate that by 2050, over 3.6 million individuals may be living with limb loss (11). PLP is not only physically debilitating but also profoundly impacts mental health, often leading to decreased quality of life, depression, and anxiety (12–14).
Despite extensive research, the origin of PLP remains elusive. Several mechanisms have been proposed to explain its development, with early theories focusing on religious, psychiatric, and psychological interpretations (15, 16). Subsequently, neurobiological and psycho-cognitive models emerged, suggesting a complex interplay of both psychological and physiological factors. Early studies primarily attributed the cause of PLP to the peripheral nervous system (PNS), particularly based on the discovery of ectopic discharges originating from the neuroma at the stump (17, 18). Later research identified the involvement of the central nervous system (CNS) in PLP, highlighting the role of maladaptive cortical plasticity in PLP's development (19–21). More recent advances point to multifactorial pathophysiology, with PLP likely arising from the convergence of multiple interconnected mechanisms (2, 22, 23).
Although previous reviews have addressed the contributions of the PNS, CNS, and psychological mechanisms to the development of PLP (24–28), and have offered historical perspectives (28, 29), our review aims to provide an overview of both pathophysiological and historical insights. We focus on important human and animal studies across neuroaxial systems and the latest advancements in molecular, psychosocial, and genetic factors—areas that have been less thoroughly explored in previous literature. Furthermore, we examine other predisposing risk factors that influence the development and persistence of PLP.
1.1 Peripheral nervous system
Early models of PLP proposed that abnormal firing of sensory nerves in the stump led to misinterpretation by the brain as sensations from the missing limb. PLP was thought to arise from disrupted sensory input after amputation, with peripheral nerve mechanisms playing a central role (30–32). The discovery that neuromas—abnormal nerve tissue growths—generate ectopic discharges further supported the idea that the stump may be a major source of pain. Ectopic activity, characterized by spontaneous neuronal firing, was observed in neuromas at the amputation site and appeared to contribute to PLP (33–41).
1.2 Nerve damage and neuroma formation
After amputation, nerve fibers at the distal end undergo retrograde degeneration, while nerve fibers at the proximal end undergo sprouting to elongate to reconnect to the distal end (42, 43). During the sprouting process, axon regeneration may occur in an unstructured manner leading to neuroma formation at the amputation site (44, 45). Histopathological studies using light and electron microscopy have extensively examined neuroma formation (46–49). During the early weeks post-injury, most axons terminate in smooth, elliptical swellings known as “neuroma end bulbs,” with minimal regenerative sprouting. Interestingly, the period of greatest electrical hyperexcitability in the neuroma coincides with this minimal sprouting, suggesting that the end bulbs, rather than extensive axonal regrowth, are the primary source of abnormal impulse discharges associated with neuropathic pain (46, 48, 49).
Oliveira et al. observed a cascade of regenerative events following peripheral nerve injury, including neuronal sprouting and neuroma formation, with associated abnormal afferent activity (47). These neuromas exhibited increased ectopic activity and heightened sensitivity to mechanical stimuli, changes attributed to altered ion channel dynamics, such as upregulation of voltage-gated sodium channels (Nav) (50–53). In a similar study, Wall et al. induced neuroma formation in rats by sectioning the femoral nerve, finding that stimulation at the tip of the neuroma elicited a significant response, unlike stimulation at the proximal nerve or dorsal root ganglion (DRG). This response was attributed to fine nerve fibers within the neuroma that exhibited spontaneous activity without external stimuli, a phenomenon not seen in intact roots. These fibers were also sensitive to mechanical pressure and could be inhibited by lidocaine, further highlighting the neuroma's role in generating spontaneous, abnormal nerve impulses (54). These peripheral mechanisms, including ectopic activity, ion channel dysregulation, and disrupted sensory input, collectively contribute to the onset and persistence of PLP.
1.3 Sympathetic involvement
In addition to neuroma formation contributing to the development of PLP, the sympathetic nervous system (SNS) also plays a role in the development of PLP through several mechanisms including ephaptic transmission, activation of nociceptors and low-threshold mechanoreceptors, and sympathetic coupling in the periphery and DRG (55).
In animal studies, beta-adrenergic blockade leads to reduced sensation of PLP while adrenaline injections into neuromas lead to heightened sensation of pain and paresthesia, providing support for the sympathetic involvement in PLP (56–58). Sympathetic dysregulation in the stump of amputee patients has also been supported by evidence indicating that reduced surface blood-flow may be a physiologic correlate of the burning sensation in PLP (59). In addition, animal studies suggest increased postsynaptic norepinephrine release during emotionally stressful situations correlates with hyperalgesia and heightened spinal nociception. Changes in catecholamine levels and alpha-adrenoreceptor involvement have been implicated in the pain associated with neuroma formation, further underscoring the complexity of peripheral contributions to post-amputation pain syndromes (59, 60). Given the early onset of pain immediately after amputation and the inability of anesthetic blocks to eliminate PLP entirely, peripheral factors and the SNS alone cannot be considered the sole factors contributing to PLP but should be regarded as key factors.
1.4 Peripheral sensitization
Peripheral sensitization is a process where the peripheral nerves become more sensitive to stimuli following injury or inflammation and is believed to be influenced by the formation of neuromas. As mentioned above, neuromas can produce spontaneous ectopic discharges and lead to hyperexcitability and enhanced sensitivity to normally non-painful stimuli, a phenomenon known as allodynia (61, 62). Additionally, peripheral sensitization can result from the release of inflammatory mediators and neurotransmitters that further sensitize the nerves, creating a cycle of pain amplification (63–65). Although the exact mechanism for development and maintenance of chronic ectopic firing is not fully understood, Nav has been shown to contribute towards increased ectopic firing (66–69).
Additionally, recent investigations into the molecular pathways following peripheral nerve injury have revealed the release of adenosine triphosphate (ATP), by primary sensory and dorsal horn neurons, that bind to P2X receptors expressed by microglia adjacent to the dorsal horn (DH) (70). The binding of ATP leads to the release of brain-derived neurotrophic factor (BDNF) into the DH, increasing neuronal hyperexcitability and nullifying the inhibitory responses, as discussed above. Another recent study using mice models has further delineated this understanding (71). In this study, wild-type mice were compared to mutant mice who had a deletion of a gene that codes for a microglia-specific ATP releasing channel. The examiners found that the mutant mice, who lacked the ATP-releasing channels, had reduced allodynia in comparison to the wild-type mice (71).
Several animal and human studies have demonstrated the role of Nav in nociceptive sensation and expressivity/peripheral sensitization following peripheral nerve injury (72, 73). These findings suggest that the upregulation of the Nav channels leads to increased nerve excitability that manifests as hyperalgesia. One potential mechanism for the accumulation of these receptors within neuromas is through membrane remodeling following axotomy (66, 67). Immunostaining of human neuroma tissue has demonstrated that individuals with neuropathic pain have increased expression of Nav channels and ankyrin G, which is a protein involved in regulating Nav (74).
In addition to molecular mechanisms involving the PNS in the development of PLP, there is evidence suggesting that re-innervation by motor neurons of residual proximal muscles contributes to abnormal nerve firing. Animal studies have demonstrated that motor neurons, which formerly innervated distal target muscles, survive and re-innervate new targets in residual muscles (75, 76). Sensory afferent neurons from both the residual stump and skin have been observed re-innervating territories in the cuneate nucleus (77, 78). Because the cuneate nucleus relays sensory information to the somatosensory cortex, its stimulation by stump muscles can lead to phantom limb sensations (PLS) and possibly PLP (77).
2 Central nervous system
As the complexity of PLP became more apparent, researchers began to integrate the CNS's involvement. It became clear that PLP was not solely explained by peripheral mechanisms or simple gate modulation. The concept of cortical reorganization emerged as a key factor in the development of PLP. Studies, including those by Flor et al., demonstrated that after amputation, the brain's somatosensory cortex, which once represented the missing limb, undergoes reorganization (79). The cortical areas that previously mapped the amputated limb may become “invaded” by adjacent body areas, such as the face or residual limb. This reorganization may lead to the perception of sensations or pain in the absent limb (i.e., phantom limb sensations). This maladaptive plasticity in the brain could underlie the chronic pain and sensory disturbances often experienced in PLP.
2.1 Cortical reorganization
The understanding of PLP has evolved significantly through two main theoretical frameworks: Melzack and Wall's gate control theory (80) and Melzack's later neuromatrix theory (81). Both emphasize the CNS' role in modulating pain. The gate control theory posited that pain is not simply the result of sensory input but involves modulation within the spinal cord and brain. The theory introduced the concept of “gates” in the spinal cord that can either inhibit or facilitate pain transmission to the brain. In PLP, these gates can become sensitized after amputation, allowing abnormal pain signals to reach the brain (80). Building on this, Melzack's “neuromatrix” theory proposed that pain arises from a “neurosignature,” produced by a genetically determined synaptic architecture (neuromatrix) in the CNS. This theory expanded pain perception to include sensory, emotional, and cognitive components, explaining how the loss of sensory input from the amputated limb leads to abnormal brain activity, which misinterprets this activity as pain or sensation in the missing limb (81).
The concept of maladaptive cortical reorganization has been widely debated as a key mechanism in the CNS origin of PLP (19, 21, 81–83). This process occurs in the primary somatosensory cortex (S1) and primary motor cortex (M1), where reduced sensory input, such as from limb amputation, leads to a decreased cortical representation of the amputated body part and the subsequent expansion of adjacent body parts' cortical representations (84–86). The phenomenon arises when distal axons of the DRG become disconnected from their targets following amputation, generating ectopic activity in the residual limb. This abnormal signaling within the spinothalamic tract triggers cortical reorganization, as neighboring cortical regions invade the deafferented areas. These changes can manifest as both non-painful and painful sensations, such as PLS and PLP, in the absence of peripheral input (81). Early animal studies, such as Rasmusson's work on raccoons, demonstrated that the loss of a digit led to cortical changes, with the sensory map corresponding to the missing digit being taken over by the neighboring cortical area, leading to heightened sensitivity (86). Kaas et al. (84) showed that sensory cortical maps in primates reorganized after injury (85). Similar results were obtained in adult monkeys, owls, and squirrels, where sensory maps underwent significant alterations in response to sensory loss (87–90).
Human studies further elucidated the role of cortical reorganization in PLP. In a landmark 1995 study, Flor et al. utilized magnetoencephalography (MEG) and magnetic resonance imaging (MRI) to demonstrate that cortical reorganization in upper-limb amputees was associated with shifts in the locus of cortical responsiveness, particularly in those experiencing PLP (79). Flor's later work on congenital limb absence revealed that individuals born without limbs exhibited minimal cortical reorganization and no PLP (21), suggesting that reorganization is critical for PLP development. Furthermore, advanced neuroimaging, particularly functional MRI (fMRI), has challenged the idea that cortical reorganization alone accounts for PLP (20, 91–93). Makin et al. found that despite preserved cortical maps in amputees with PLP, disrupted inter-regional connectivity may contribute to PLP (94). Similarly, Andoh et al. observed increased activation in motor and sensory cortices, but this activation was not correlated with PLP intensity, suggesting a multi-factorial nature of the condition (93).
However, this static model of the cortical reorganization theory did not fully account for the variable and sometimes reversible nature of PLP, such as fluctuation of PLP and changes of PLP responding to interventional treatments. These observations suggest that cortical changes are not static but can be modulated or dynamically reorganized. In the late 1990–2000s, the theory of dynamic cortical reorganization emerged, and refers to a continuous reshaping of the cortical maps in response to external stimuli, motor and sensory feedback, proposing that reorganization involves both structural and functional changes, particularly in how the brain processes sensory and pain signals. Flor et al. 1995 showed that the cortical changes in response to somatosensory evoked potentials (SEPs) were related to the intensity of PLP (79). The pioneering work on mirror therapy from Ramachandran et al. in 1996 (95) revealed that visual feedback can reduce PLP by alternating the cortical map in real-time. Schwenkreis et al. used transcranial magnetic stimulation (TMS) to show that the motor cortex reorganizes to incorporate adjacent body parts after amputation, supporting the notion of dynamic brain plasticity (96). Additionally, studies demonstrated that emotional and cognitive activities can also influence the brain' response to pain suggesting a role of cognitive-behavioral therapy (CBT) in treating PLP (55).
2.2 The thalamic contributions
Thalamus, a critical relay center for sensory and motor information, plays a key role in the CNS origin of PLP (97, 98). In a typical nervous system, primary afferent pain signals from peripheral nociceptors synapse at the DH of the spinal cord and ascend via the spinothalamic or spinoreticular tracts (79, 99–101). These signals pass through the brainstem, where facilitatory or inhibitory signals modulate pain transmission before reaching the thalamus for further processing (102–105). After amputation, the thalamus undergoes reorganization similar to cortical changes, with neurons initially responsible for the amputated limb's sensory processing now responding to inputs from neighboring body areas (78, 93, 106, 107). This leads to the misperception of pain in the missing limb. The thalamus can become sensitized through an increase in Na + channels in thalamic neurons, akin to peripheral sensitization (108, 109). Studies show that the thalamic representation of the residual limb is enlarged in amputees compared to individuals with intact limbs, and micro-stimulation of the thalamus in the absence of peripheral stimuli can evoke phantom sensations and PLP (78, 86, 110, 111). This central sensitization, coupled with altered thalamic representations, contributes to the chronic nature and intensity of PLP (89, 105, 109, 112).
Additionally, the thalamus plays a key role in modulating pain perception. Changes in thalamic activity and connectivity affect how pain is processed, contributing to phenomena such as allodynia (pain from non-painful stimuli) and hyperalgesia (amplified pain responses) (113–115). The thalamus interacts with cortical and subcortical regions, including the somatosensory cortex, anterior cingulate cortex, and insula, which are involved in the sensory and emotional components of pain (116, 117). Deep brain stimulation (DBS) and transcranial stimulation (TCS) targeting the thalamus have shown efficacy in reducing PLP and other neuropathic pain conditions (118–124). These treatments support the thalamus's involvement in PLP, and ongoing research into their mechanisms may reveal new neuromodulation strategies to alleviate PLP symptoms.
2.3 Centralization of pain and windup phenomenon
Centralization refers to the increased sensitivity and responsiveness of neurons within the CNS, dorsal horns, and primary afferent fibers (125, 126). As mentioned previously, the DRG becomes hyperexcitable with increases in Nav, leading to ectopic firings that cause pain in the absence of stimuli (51–54, 127, 128). The process of central sensitization also involves sensitized C-fibers, which release glutamate and interact with neuropeptides and N-methyl-D-aspartate (NMDA) receptors to amplify spinal cord responses (126, 129–132).
The “wind-up” phenomenon, characterized by frequency-dependent increases in spinal cord neuron excitability due to C-fiber stimulation, serves as a precursor to central sensitization. Repetitive stimulation during wind-up can lead to an expanded receptive field, a significant feature of central sensitization (133, 134). Wind-up differs from central sensitization in its temporal nature, ceasing after the stimulus ends, while central sensitization can persist (126, 133, 134). This process, critical in demonstrating spinal cord plasticity, amplifies pain signaling and sets the stage for chronic pain conditions such as PLP (126, 133, 134).
In amputees, increased nociceptive activity is attributed to the loss of descending inhibitory control, particularly through reduced gamma-aminobutyric acid (GABA) and glycine-mediated inhibition due to nerve injury (105, 135–137). This disinhibition occurs both in the spinal cord and cortex, as GABAergic interneurons are damaged by axotomy, contributing to spinal hyperexcitability (136–139). Additionally, brain-derived neurotrophic factor (BDNF) plays a role in post-injury neuroplasticity, promoting excitatory effects on nociception through NMDA receptor modulation (140–145). Animal studies have shown that spinal BDNF infusion enhances nociceptive responses, which can be mitigated by NMDA antagonists (143, 146). The interplay between disinhibition, BDNF, and NMDA receptors contributes to the complex mechanisms underlying PLP, underscoring the need for further investigation into these molecular pathways.
2.4 Proprioceptive memory
Proprioceptive memory, or the brain's ability to retain awareness of body position. Even after amputation, amputees often report sensations of proprioception in the missing limb (147, 148). One theory suggests that proprioceptive information is consolidated as long-term memory during repeated motor tasks, allowing these memories to persist despite the absence of the limb (148, 149). This theory is supported by studies where individuals could sense the position of their amputated limbs even after regional anesthesia (150, 151).
The connection between proprioceptive memory and PLP is further highlighted by the phenomenon of frozen phantom limbs, which often mimic the limb's position prior to amputation, suggesting that these proprioceptive imprints remain intact (152–154). This preservation could explain therapeutic interventions like mirror therapy (MT), which aim to align visual and proprioceptive inputs, potentially clearing mismatched proprioceptive memories and alleviating PLP (95, 155). Mirror therapy has been shown to reduce PLP by providing visual feedback that matches proprioceptive input, addressing the sensory conflict that contributes to pain (156).
Moreover, PLP may arise from a mismatch between visual and proprioceptive inputs. The brain integrates visual cues with tactile and proprioceptive sensations to create body ownership, and any discrepancy between these signals may lead to the experience of PLP (157–160). These findings emphasize the complex relationship between proprioceptive memory and PLP and suggest that therapies targeting this interaction could offer novel ways to manage chronic pain following amputation.
3 Psychological factors
PLP is not only influenced by mechanisms involving the CNS and PNS but also by significant psychosocial components. Emotional and cognitive factors can influence the dynamics of cortical reorganization involved in PLP (79, 156, 161), contributing to maladaptive cortical reorganization and increased pain perception.
3.1 Stress and PLP
Chronic stress is one of the key psychological factors implicated in the exacerbation of PLP. Stress can influence neuroplastic changes in the brain, particularly in areas related to sensory and motor processing. Lotze et al. (162) demonstrated that stress was associated with cortical reorganization, thereby contributing to the sensation of PLP. Additionally, higher stress levels were linked to more intense pain in PLP patients (163, 164), suggesting that stress may exacerbate cortical maladaptation, leading to persistent pain. Furthermore, several studies (165, 166) have shown that psychological stress could modulate pain perception, including phantom pain. Stress-induced activation of brain areas involved in emotional regulation and pain processing, such as the anterior cingulate cortex, may increase sensitivity to pain stimuli, contributing to the experience of PLP.
3.2 Depression and PLP
Depression is another significant psychological factor associated with the onset and intensity of PLP. Depressive symptoms often co-occur with PLP, and patients with depression tend to report more severe PLS (13). Larbig et al. (167) found that higher levels of depression were associated with more severe PLP, and the presence of depression appeared to increase sensitivity to pain. This finding suggests that depression could alter pain processing mechanisms, potentially through disruptions in brain structures that regulate pain, such as the periaqueductal gray and serotonergic pathways. Additionally, Ahmed et al. (168) demonstrated that depressed amputees were significantly more likely to experience chronic PLP. They linked depression to lower serotonin levels, which are known to play a crucial role in pain modulation, thus reinforcing the idea that mood disorders contribute to the persistence and intensity of PLP.
3.3 Anxiety and PLP
Anxiety, particularly post-traumatic anxiety, is another important factor that can exacerbate PLP. Ramachandran and Hirstein (148) proposed that anxiety and fear might amplify the perception of PLP through increased central nervous system sensitivity. Anxiety related to the loss of a limb or concerns about complications may heighten the brain's pain processing capacity, making PLP more intense. Further supporting this notion, Desmond et al. (169) found that anxiety was correlated with more frequent and intense PLP and suggested that anxiety could enhance pain perception by activating brain regions involved in both emotional processing and pain, such as the amygdala and somatosensory cortex, which may increase the salience of pain and contribute to its persistence.
3.4 Emotional and cognitive factors in PLP
Cognitive and emotional factors, such as catastrophizing and negative emotions, could contribute to central sensitization (170, 171)—a phenomenon where the central nervous system becomes hyper-responsive to pain signals. This increased sensitivity may make PLP more intense and persistent. Several studies (171–174) found that negative emotional states and cognitive distortions could amplify the perception of pain through increased central sensitization. Individuals with post-traumatic stress disorder (PTSD) often report higher levels of PLP through neurobiological changes, such as the sensitization of pain pathways and emotional dysregulation (13). Numerous studies (175–177) supported this notion by showing that psychological interventions targeting depression and anxiety significantly reduced the intensity of chronic pain. This suggests that the psychological well-being of patients is crucial in managing PLP, as mental health treatment may help alleviate both the emotional burden and the neuroplastic changes associated with PLP.
4 Genetic influences
Previous studies have established the genetic associations with chronic neuropathic pain syndromes, specifically identifying associations within genes coding for voltage-gated ion channels, calcium binding genes, and mitochondrial phosphate caries (178–181). Identification of genetic involvement in neuropathic pain suggests a possible role of genetic predisposition in PLP, which could significantly enhance the clinical management and treatment outcomes of this condition. Devor et al. 2005 demonstrated heritable traits for neuropathic pain in rodents with sciatic nerve ligations, where specific genetic loci on chromosome 15 were linked to pain sensitivity and neuroma-related pain (182). These findings highlight the role of genetic variation in modulating pain responses and provide a framework for understanding the genetic underpinnings of PLP. Human genetic research on PLP is still in its early stages but has shown promising results. Notably, studies by Nissenbaum et al. and Bortsov et al. identified polymorphisms in the CACNG2 gene (calcium voltage-gated channel auxiliary subunit gamma 2) on chromosome 22, which regulates AMPA receptor trafficking (183, 184). Specific polymorphisms in CACNG2 were associated with chronic neuropathic pain, such as postmastectomy pain, suggesting a potential link to PLP (184). This discovery marks one of the first genetic associations with PLP in humans, though further research is needed to confirm these findings.
While a direct link between genetics and PLP remains unestablished, the studies in this area hold promise and could significantly benefit future exploration into the genetic factors contributing to PLP. The exploration of epigenetic mechanisms, such as microRNA regulation, in chronic neuropathic pain also holds promise for PLP research (185–187). These epigenetic factors may offer new insights into how environmental factors and genetic predispositions interact to influence pain perception and could lead to novel therapeutic strategies targeting gene expression (185–187).
5 Conclusion
PLP remains one of the most challenging and poorly understood conditions in the field of amputation, primarily due to the absence of a comprehensive consensus on its underlying pathophysiology. The multifactorial nature of PLP has led to ongoing debate regarding the specific mechanisms involved in its onset. Insights from cerebral, spinal, and peripheral perspectives provide critical evidence, suggesting that PLP likely results from the complex interaction of these diverse systems, rather than from a single etiological cause. Beyond the neurobiological underpinnings, recent advancements in psychology and genetics have shed light on the multifaceted mechanisms contributing to PLP's pathogenesis, further highlighting the intricate nature of the disorder.
This review has aimed to synthesize these diverse lines of research, providing an integrative overview of the physiological, psychological, and genetic factors implicated in PLP. By examining key human and animal studies, we have highlighted recent progress in molecular, psychological, and genetic research that is reshaping our understanding of this condition. A multidimensional approach to PLP, integrating these findings, holds the promise of more personalized treatment strategies that address the diverse and individualized needs of patients. Ultimately, such an approach has the potential to improve treatment outcomes, enhance patient well-being, and drive innovations in both PLP research and therapeutic interventions in the future.
Author contributions
HW: Conceptualization, Methodology, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing. CS: Writing – original draft, Writing – review & editing. RM: Writing – original draft, Writing – review & editing. SH: Writing – original draft, Writing – review & editing. AM: Writing – original draft, Writing – review & editing. KS: Writing – original draft, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1. Erlenwein J, Diers M, Ernst J, Schulz F, Petzke F. Clinical updates on phantom limb pain. Pain Rep. (2021) 6(1):e888. doi: 10.1097/PR9.0000000000000888
2. Hanyu-Deutmeyer AA, Cascella M, Varacallo M. Phantom limb pain. In: Hanyu-Deutmeyer AA, editor. StatPearls. Treasure Island, FL: StatPearls Publishing (2023).
3. Paré A. La méthod de traicter les playes faites par les arquebuses et aultres bastons à feu. Paris (1545).
4. Keil G. Sogenannte Erstbeschreibung des Phantomschmerzes von Ambroise paré. “Chose digne d’admiration et quasi incredible”: die “douleur ès parties mortes et amputées” [so-called initial description of phantom pain by Ambroise Paré. “Chose digne d’admiration et quasi incredible”: the “douleur ès parties mortes et amputées”]. Fortschr Med. (1990) 108(4):62–6.2179086
5. Ellis H. Admiral Nelson’s above elbow amputation. J Perioper Pract. (2014) 24(12):286–7. doi: 10.1177/175045891402401205
6. Mahan AT. The Life of Nelson: The Embodiment of the Sea Power of Great Britain. London: Sampson Low, Marston, & Co. (1897).
7. Mitchell SW, Morehouse GR, Keen WW. Gunshot wounds and other injuries of nerves. 1864. Clin Orthop Relat Res. (2007) 458:35–9. doi: 10.1097/BLO.0b013e31803df02c
9. Avalere Health. Prevalence of Limb Loss and Limb Difference in the United States: Implications for Public Policy. Washington, DC: Avalere (2024). Available online at: https://avalere.com/wp-content/uploads/2024/02/Prevalence-of-Limb-Loss-and-Limb-Difference-in-the-United-States_Implications-for-Public-Policy.pdf
10. Limakatso K, Bedwell GJ, Madden VJ, Parker R. The prevalence and risk factors for phantom limb pain in people with amputations: a systematic review and meta-analysis. PLoS One. (2020) 15(10):e0240431. doi: 10.1371/journal.pone.0240431
11. Ziegler-Graham K, et al. Estimating the prevalence of limb loss in the United States: 2005 to 2050. Arch Phys Med Rehabil. (2008) 89(3):422–9. doi: 10.1016/j.apmr.2007.11.005
12. Padovani MT, Martins MR, Venâncio A, Forni JE. Anxiety, depression and quality of life in individuals with phantom limb pain. Acta Ortop Bras. (2015) 23(2):107–10. doi: 10.1590/1413-78522015230200990
13. Hogan WB, Anderson G, Kovoor M, Alsoof D, McDonald CL, Zhang AS, et al. Phantom limb syndrome: assessment of psychiatric and medical comorbidities associated with phantom pain in 44,028 below knee amputees. Injury. (2022) 53(11):3697–701. doi: 10.1016/j.injury.2022.09.018
14. van der Schans CP, Geertzen JH, Schoppen T, Dijkstra PU. Phantom pain and health-related quality of life in lower limb amputees. J Pain Symptom Manage. (2002) 24(4):429–36. doi: 10.1016/S0885-3924(02)00511-0
17. Grossmann L, Gorodetskaya N, Baron R, Jänig W. Enhancement of ectopic discharge in regenerating A- and C-fibers by inflammatory mediators. J Neurophysiol. (2009) 101(6):2762–74. doi: 10.1152/jn.91091.2008
18. Sun Q, Tu H, Xing GG, Han JS, Wan Y. Ectopic discharges from injured nerve fibers are highly correlated with tactile allodynia only in early, but not late, stage in rats with spinal nerve ligation. Exp Neurol. (2005) 191(1):128–36. doi: 10.1016/j.expneurol.2004.09.008
19. Andoh J, Milde C, Tsao JW, Flor H. Cortical plasticity as a basis of phantom limb pain: fact or fiction? Neuroscience. (2018) 387:85–91. doi: 10.1016/j.neuroscience.2017.11.015
20. Makin TR, Flor H. Brain (re)organisation following amputation: implications for phantom limb pain. Neuroimage. (2020) 218:116943. doi: 10.1016/j.neuroimage.2020.116943
21. Flor H, Elbert T, Mühlnickel W, et al. Cortical reorganization and phantom phenomena in congenital and traumatic upper-extremity amputees. Exp Brain Res. (1998) 119:205–12. doi: 10.1007/s002210050334
22. Subedi B, Grossberg GT. Phantom limb pain: mechanisms and treatment approaches. Pain Res Treat. (2011) 2011:1. doi: 10.1155/2011/864605
23. Harwood DD, Hanumanthu S, Stoudemire A. Pathophysiology and management of phantom limb pain. Gen Hosp Psychiatry. (1992) 14(2):107–18. doi: 10.1016/0163-8343(92)90035-9
24. Postone N. Phantom limb pain: a review. Int J Psychiatry Med. (1988) 17(1):57–70. doi: 10.2190/PKG8-MDUW-URCQ-H2Q2
25. Schone HR, Baker CI, Katz J, et al. Making sense of phantom limb pain. J Neurol Neurosurg Psychiatry. (2022) 93(10):833–43. doi: 10.1136/jnnp-2021-328428
26. Kaur A, Guan Y. Phantom limb pain: a literature review. Chin J Traumatol. (2018) 21(6):366–8. doi: 10.1016/j.cjtee.2018.04.006
27. Hill A. Phantom limb pain: a review of the literature on attributes and potential mechanisms. J Pain Symptom Manage. (1999) 17(2):125–42. doi: 10.1016/S0885-3924(98)00136-5
28. Collins KL, Waters RS, Tsao JW. A review of current theories and treatments for phantom limb pain. J Clin Invest. (2018) 128(6):2168–76. doi: 10.1172/JCI94003
29. Crawford CS. Phantom Limb: Amputation, Embodiment, and Prosthetic Technology. New York, NY: NYU Press (2014). Available online at: http://www.jstor.org/stable/j.ctt9qgc6m
30. Vaso A, Adahan HM, Gjika A, Zahaj S, Zhurda T, Vyshka G, et al. Peripheral nervous system origin of phantom limb pain. Pain. (2014) 155(7):1384–91. doi: 10.1016/j.pain.2014.04.018
33. Black JA, Nikolajsen L, Kroner K, Jensen TS, Waxman SG. Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann Neurol. (2008) 64(6):644–53. doi: 10.1002/ana.21527
34. Devor M. Neuropathic pain and injured nerve: peripheral mechanisms. Br Med Bull. (1991) 47(3):619–30. doi: 10.1093/oxfordjournals.bmb.a072496
35. McMahon SB, Stephen B. Wall and Melzack’s Textbook of Pain. 6th ed. Philadelphia, PA: Elsevier/Saunders (2013).
36. Henderson WR, Smyth GE. Phantom limbs. J Neurol Neurosurg Psychiatr. (1948) 11(2):88–112. doi: 10.1136/jnnp.11.2.88
37. Nordin M, Nyström B, Wallin U, Hagbarth KE. Ectopic sensory discharges and paresthesiae in patients with disorders of peripheral nerves, dorsal roots and dorsal columns. Pain. (1984) 20(3):231–45. doi: 10.1016/0304-3959(84)90013-7
38. Nyström B, Hagbarth KE. Microelectrode recordings from transected nerves in amputees with phantom limb pain. Neurosci Lett. (1981) 27(2):211–6. doi: 10.1016/0304-3940(81)90270-6
39. Sherman RA, Arena JG. Phantom limb pain: mechanisms, incidence, and treatment. Crit Rev Phys Rehabil Med. (1992) 4:1–26.
40. Sherman RA, Griffin VD, Evans CB, Grana AS. Temporal relationships between changes in phantom limb pain intensity and changes in surface electromyogram of the residual limb. Int J Psychophysiol. (1992) 13(1):71–7. doi: 10.1016/0167-8760(92)90022-4
41. Wall PD, Gutnick M. Properties of afferent nerve impulses originating from a neuroma. Nature. (1974) 248(5451):740–3. doi: 10.1038/248740a0
42. Giannini C. Tumors and tumor-like conditions of peripheral nerve. In: Dyck PJ, Thomas PK, editors. Peripheral Neuropathy. 4th ed. W.B. Saunders. (2005). pp. 2585–606. doi: 10.1016/B978-0-7216-9491-7.50118-6
43. Lee SK, Wolfe SW. Peripheral nerve injury and repair. J Am Acad Orthop Surg. (2000) 8(4):243–52. doi: 10.5435/00124635-200007000-00005
44. Wood MD, Mackinnon SE. Pathways regulating modality-specific axonal regeneration in peripheral nerve. Exp Neurol. (2015) 265:171–5. doi: 10.1016/j.expneurol.2015.02.001
45. Faroni A, Mobasseri SA, Kingham PJ, Reid AJ. Peripheral nerve regeneration: experimental strategies and future perspectives. Adv Drug Delivery Rev. (2015) 82-83:160–7. doi: 10.1016/j.addr.2014.11.010
46. Fried K, Govrin-Lippmann R, Rosenthal F, Ellisman MH, Devor M. Ultrastructure of afferent axon endings in a neuroma. J Neurocytol. (1991) 20(8):682–701. doi: 10.1007/BF01187069
47. Oliveira KMC, Pindur L, Han Z, Bhavsar MB, Barker JH, Leppik L. Time course of traumatic neuroma development. PLoS One. (2018) 13(7):e0200548. doi: 10.1371/journal.pone.0200548
48. Fried K, Frisén J. End structure and neuropeptide immunoreactivity of axons in sciatic neuromas following nerve section in neonatal rats. Exp Neurol. (1990) 109(3):286–93. doi: 10.1016/S0014-4886(05)80019-6
49. Fried K, Govrin-Lippmann R, Devor M. Close apposition among neighbouring axonal endings in a neuroma. J Neurocytol. (1993) 22(8):663–81. doi: 10.1007/BF01181491
50. Liu H, Wang HG, Pitt G, Liu Z. Direct observation of compartment-specific localization and dynamics of voltage-gated sodium channels. J Neurosci. (2022) 42(28):5482–98. doi: 10.1523/JNEUROSCI.0086-22.2022
51. Wang W, Atianjoh F, Gauda EB, Yaster M, Li Y, Tao YX. Increased expression of sodium channel subunit Nav1.1 in the injured dorsal root ganglion after peripheral nerve injury. Anat Rec (Hoboken). (2011) 294(8):1406–11. doi: 10.1002/ar.21437
52. Huang ZJ, Song XJ. Differing alterations of sodium currents in small dorsal root ganglion neurons after ganglion compression and peripheral nerve injury. Mol Pain. (2008) 4:20. doi: 10.1186/1744-8069-4-20
53. Black JA, Cummins TR, Plumpton C, Chen YH, Hormuzdiar W, Clare JJ, et al. Upregulation of a silent sodium channel after peripheral, but not central, nerve injury in DRG neurons. J Neurophysiol. (1999) 82(5):2776–85. doi: 10.1152/jn.1999.82.5.2776
54. Wall PD, Devor M, Inbal R, Scadding JW, Schonfeld D, Seltzer Z, et al. Autotomy following peripheral nerve lesions: experimental anaesthesia dolorosa. Pain. (1979) 7(2):103–13. doi: 10.1016/0304-3959(79)90002-2
55. Flor H. Phantom-limb pain: characteristics, causes, and treatment. Lancet Neurol. (2002) 1(3):182–9. doi: 10.1016/S1474-4422(02)00074-1
56. Torebjörk E, Wahren L, Wallin G, Hallin R, Koltzenburg M. Noradrenaline-evoked pain in neuralgia. Pain. (1995) 63(1):11–20. doi: 10.1016/0304-3959(95)00140-N
57. Sherman RA, Bruno GM. Concurrent variation of burning phantom limb and stump pain with near surface blood flow in the stump. Orthopedics. (1987) 10(10):1395–402. doi: 10.3928/0147-7447-19871001-09
58. Devor M, Jänig W, Michaelis M. Modulation of activity in dorsal root ganglion neurons by sympathetic activation in nerve-injured rats. J Neurophysiol. (1994) 71(1):38–47. doi: 10.1152/jn.1994.71.1.38
59. Lin EE, Horasek S, Agarwal S, Wu CL, Raja SN. Local administration of norepinephrine in the stump evokes dose-dependent pain in amputees. Clin J Pain. (2006) 22(5):482–6. doi: 10.1097/01.ajp.0000202980.51786.ae
60. Tegeder I, Costigan M, Griffin RS, Abele A, Belfer I, Schmidt H, et al. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med. (2006) 12(11):1269–77. doi: 10.1038/nm1490
61. Carlen PL, Wall PD, Nadvorna H, Steinbach T. Phantom limbs and related phenomena in recent traumatic amputations. Neurology. (1978) 28(3):211–7. doi: 10.1212/WNL.28.3.211
62. Jensen TS, Finnerup NB. Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. Lancet Neurol. (2014) 13(9):924–35. doi: 10.1016/S1474-4422(14)70102-4
63. Wegner A, Elsenbruch S, Maluck J, Grigoleit JS, Engler H, Jäger M, et al. Inflammation-induced hyperalgesia: effects of timing, dosage, and negative affect on somatic pain sensitivity in human experimental endotoxemia. Brain Behav Immun. (2014) 41:46–54. doi: 10.1016/j.bbi.2014.05.001
64. Benson S, Rebernik L, Wegner A, Kleine-Borgmann J, Engler H, Schlamann M, et al. Neural circuitry mediating inflammation-induced central pain amplification in human experimental endotoxemia. Brain Behav Immun. (2015) 48:222–31. doi: 10.1016/j.bbi.2015.03.017
65. Benson S, Kattoor J, Wegner A, Hammes F, Reidick D, Grigoleit JS, et al. Acute experimental endotoxemia induces visceral hypersensitivity and altered pain evaluation in healthy humans. Pain. (2012) 153(4):794–9. doi: 10.1016/j.pain.2011.12.001
66. Rizzo MA, Kocsis JD, Waxman SG. Selective loss of slow and enhancement of fast na+ currents in cutaneous afferent dorsal root ganglion neurones following axotomy. Neurobiol Dis. (1995) 2(2):87–96. doi: 10.1006/nbdi.1995.0009
67. Cummins TR, Waxman SG. Downregulation of tetrodotoxin-resistant sodium currents and upregulation of a rapidly repriming tetrodotoxin-sensitive sodium current in small spinal sensory neurons after nerve injury. J Neurosci. (1997) 17(10):3503–14. doi: 10.1523/JNEUROSCI.17-10-03503.1997
68. Xie YF, Yang J, Ratté S, Prescott SA. Similar excitability through different sodium channels and implications for the analgesic efficacy of selective drugs. Elife. (2024) 12:RP90960. doi: 10.7554/eLife.90960.3
69. Cregg R, Momin A, Rugiero F, Wood JN, Zhao J. Pain channelopathies. J Physiol. (2010) 588(Pt 11):1897–904. doi: 10.1113/jphysiol.2010.187807
70. Trang T, Beggs S, Wan X, Salter MW. P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation. J Neurosci. (2009) 29(11):3518–28. doi: 10.1523/JNEUROSCI.5714-08.2009
71. Chu J, Yang J, Zhou Y, Chen J, Chen KH, Zhang C, et al. ATP-releasing SWELL1 channel in spinal microglia contributes to neuropathic pain. Sci Adv. (2023) 9(13):eade9931. doi: 10.1126/sciadv.ade9931
72. Vysokov N, McMahon SB, Raouf R. The role of NaV channels in synaptic transmission after axotomy in a microfluidic culture platform. Sci Rep. (2019) 9(1):12915. doi: 10.1038/s41598-019-49214-w
73. Kretschmer T, Happel LT, England JD, Nguyen DH, Tiel RL, Beuerman RW, et al. Accumulation of PN1 and PN3 sodium channels in painful human neuroma-evidence from immunocytochemistry. Acta Neurochir (Wien). (2002) 144(8):803–10. doi: 10.1007/s00701-002-0970-1
74. Kretschmer T, England JD, Happel LT, Liu ZP, Thouron CL, Nguyen DH, et al. Ankyrin G and voltage-gated sodium channels colocalize in human neuroma–key proteins of membrane remodeling after axonal injury. Neurosci Lett. (2002) 323(2):151–5. doi: 10.1016/S0304-3940(02)00021-6
75. Wu CW, Kaas JH. Spinal cord atrophy and reorganization of motoneuron connections following long-standing limb loss in primates. Neuron. (2000) 28(3):967–78. doi: 10.1016/S0896-6273(00)00167-7
76. Fisher KM, Garner JP, Darian-Smith C. Small sensory spinal lesions that affect hand function in monkeys greatly alter primary afferent and motor neuron connections in the cord. J Comp Neurol. (2022) 530(17):3039–55. doi: 10.1002/cne.25395
77. Wu CW, Kaas JH. The effects of long-standing limb loss on anatomical reorganization of the somatosensory afferents in the brainstem and spinal cord. Somatosens Mot Res. (2002) 19(2):153–63. doi: 10.1080/08990220220133261
78. Datta A. The effect of dorsal column lesions in the primary somatosensory cortex and medulla of adult rats. IBRO Neurosci Rep. (2023) 14:466–82. doi: 10.1016/j.ibneur.2023.05.005
79. Flor H, Elbert T, Knecht S, Wienbruch C, Pantev C, Birbaumer N, et al. Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature. (1995) 375(6531):482–4. doi: 10.1038/375482a0
80. Melzack R, Wall PD. Pain mechanisms: a new theory. Science. (1965) 150:971–9. doi: 10.1126/science.150.3699.971
81. Melzack R. From the gate to the neuromatrix. Pain. (1999) (Suppl 6):S121–6. doi: 10.1016/S0304-3959(99)00145-1
82. Karl A, Birbaumer N, Lutzenberger W, Cohen LG, Flor H. Reorganization of motor and somatosensory cortex in upper extremity amputees with phantom limb pain. J Neurosci. (2001) 21:3609–18. doi: 10.1523/JNEUROSCI.21-10-03609.2001
83. Vartiainen N, Kirveskari E, Kallio-Laine K, Kalso E, Forss N. Cortical reorganization in primary somatosensory cortex in patients with unilateral chronic pain. J Pain. (2009) 10(8):854–9. doi: 10.1016/j.jpain.2009.02.006
84. Kaas JH, Merzenich MM, Killackey HP. The reorganization of somatosensory cortex following peripheral nerve damage in adult and developing mammals. Annu Rev Neurosci. (1983) 6:325–56. doi: 10.1146/annurev.ne.06.030183.001545
85. Kaas JH. The reorganization of somatosensory and motor cortex after peripheral nerve or spinal cord injury in primates. Prog Brain Res. (2000) 128:173–9. doi: 10.1016/S0079-6123(00)28015-1
86. Rasmusson DD. Reorganization of raccoon somatosensory cortex following removal of the fifth digit. J Comp Neurol. (1982) 205(4):313–26. doi: 10.1002/cne.902050402
87. Merzenich MM, Nelson RJ, Stryker MP, Cynader MS, Schoppmann A, Zook JM. Somatosensory cortical map changes following digit amputation in adult monkeys. J Comp Neurol. (1984) 224(4):591–605. doi: 10.1002/cne.902240408
88. Merzenich MM, Kaas JH, Wall JT, Nelson RJ, Sur M, Felleman D. Topographic reorganization of somatosensory cortical areas 3b and 1 in adult monkeys following restricted deafferentation. Neuroscience. (1983) 8:33–55. doi: 10.1016/0306-4522(83)90024-6
89. Merzenich MM, Kaas JH, Wall JT, Sur M, Nelson RJ, Felleman DJ. Progression of change following median nerve section in the cortical representation of the hand in areas 3b and 1 in adult owl and squirrel monkeys. Neuroscience. (1983) 10:639–65. doi: 10.1016/0306-4522(83)90208-7
90. Pons TP, Garraghty PE, Ommaya AK, Kaas JH, Taub E, Mishkin M. Massive cortical reorganization after sensory deafferentation in adult macaques. Science. (1991) 252(5014):1857–60. doi: 10.1126/science.1843843
91. Valyear KF, Philip BA, Cirstea CM, Chen PW, Baune NA, Marchal N, et al. Interhemispheric transfer of post-amputation cortical plasticity within the human somatosensory cortex. Neuroimage. (2020) 206:116291. doi: 10.1016/j.neuroimage.2019.116291
92. Makin TR, Krakauer JW. Against cortical reorganisation. Elife. (2023) 12:e84716. doi: 10.7554/eLife.84716
93. Andoh J, Milde C, Diers M, et al. Assessment of cortical reorganization and preserved function in phantom limb pain: a methodological perspective. Sci Rep. (2020) 10:11504. doi: 10.1038/s41598-020-68206-9
94. Makin TR, Scholz J, Filippini N, Henderson Slater D, Tracey I, Johansen-Berg H. Phantom pain is associated with preserved structure and function in the former hand area. Nat Commun. (2013) 4:1570. doi: 10.1038/ncomms2571
95. Ramachandran VS, Rogers-Ramachandran D. Synaesthesia in phantom limbs induced with mirrors. Proc Biol Sci. (1996) 263(1369):377–86. doi: 10.1098/rspb.1996.0058
96. Schwenkreis P, Pleger B, Cornelius B, Weyen U, Dertwinkel R, Zenz M, et al. Reorganization in the ipsilateral motor cortex of patients with lower limb amputation. Neurosci Lett. (2003) 349(3):187–90. doi: 10.1016/S0304-3940(03)00838-3
97. Jerath R, Crawford MW, Jensen M. Etiology of phantom limb syndrome: insights from a 3D default space consciousness model. Med Hypotheses. (2015) 85(2):153–9. doi: 10.1016/j.mehy.2015.04.025
98. Rasmusson DD, Turnbull BG. Immediate effects of digit amputation on SI cortex in the raccoon: unmasking of inhibitory fields. Brain Res. (1983) 288(1–2):368–70. doi: 10.1016/0006-8993(83)90120-8
99. Browne JD, Fraiser R, Cai Y, Leung D, Leung A, Vaninetti M. Unveiling the phantom: what neuroimaging has taught US about phantom limb pain. Brain Behav. (2022) 12(3):e2509. doi: 10.1002/brb3.2509
100. Steeds CE. The anatomy and physiology of pain. Surgery (Oxford). (2009) 27(12):507–11. doi: 10.1016/j.mpsur.2009.10.013
101. Craig AD, Bushnell MC, Zhang ET, Blomqvist A. A thalamic nucleus specific for pain and temperature sensation. Nature. (1994) 372(6508):770–3. doi: 10.1038/372770a0
102. Renn CL, Dorsey SG. The physiology and processing of pain: a review. AACN Clin Issues. (2005) 16(3):277–415. doi: 10.1097/00044067-200507000-00002
103. Leung A. Addressing chronic persistent headaches after MTBI as a neuropathic pain state. J Headache Pain. (2020) 21(1):77. doi: 10.1186/s10194-020-01133-2
104. Albe-Fessard D, Berkley KJ, Kruger L, Ralston HJ 3rd, Willis WD Jr. Diencephalic mechanisms of pain sensation. Brain Res. (1985) 356(3):217–96. doi: 10.1016/0165-0173(85)90013-X
105. Bowsher D, Leijon G, Thuomas KA. Central poststroke pain: correlation of MRI with clinical pain characteristics and sensory abnormalities. Neurology. (1998) 51(5):1352–8. doi: 10.1212/WNL.51.5.1352
106. Florence SL, Hackett TA, Strata F. Thalamic and cortical contributions to neural plasticity after limb amputation. J Neurophysiol. (2000) 83(5):3154–9. doi: 10.1152/jn.2000.83.5.3154
107. Jones EC, Pons TP. Thalamic and brainstem contributions to large-scale plasticity of primate somatosensory cortex. Science. (1998) 282(5391):1121–5. doi: 10.1126/science.282.5391.1121
108. Zhao P, Waxman SG, Hains BC. Sodium channel expression in the ventral posterolateral nucleus of the thalamus after peripheral nerve injury. Mol Pain. (2006) 2:27. doi: 10.1186/1744-8069-2-27
109. Waxman SG, Hains BC. Fire and phantoms after spinal cord injury: na+ channels and central pain. Trends Neurosci. (2006) 29(4):207–15. doi: 10.1016/j.tins.2006.02.003
110. Dostrovsky JO. Immediate and long-term plasticity in human somatosensory thalamus and its involvement in phantom limbs. Pain. (1999) (Suppl 6):S37–43. doi: 10.1016/S0304-3959(99)00136-0
111. Birbaumer N, Lutzenberger W, Montoya P, Larbig W, Unertl K, Töpfner S, et al. Effects of regional anesthesia on phantom limb pain are mirrored in changes in cortical reorganization. J Neurosci. (1997) 17:5503–8. doi: 10.1523/JNEUROSCI.17-14-05503.1997
112. Culp CJ, Abdi S. Current understanding of phantom pain and its treatment. Pain Physician. (2022) 25(7):E941–57.36288580
113. Bushnell MC, Duncan GH, Hofbauer RK, Ha B, Chen JI, Carrier B. Pain perception: is there a role for primary somatosensory cortex? Proc Natl Acad Sci U S A. (1999) 96(14):7705–9. doi: 10.1073/pnas.96.14.7705
114. Lenz FA, Weiss N, Ohara S, Lawson C, Greenspan JD. The role of the thalamus in pain. In: Hallett M, Phillips LH, Schomer DL, Massey JM, editors. Supplements to Clinical Neurophysiology, vol 57. San Francisco, CA: Elsevier. (2004). pp. 50–61. doi: 10.1016/S1567-424X(09)70342-3
115. Ab Aziz CB, Ahmad AH. The role of the thalamus in modulating pain. Malays J Med Sci. (2006) 13(2):11–8.22589599
116. Venkatraman A, Edlow BL, Immordino-Yang MH. The brainstem in emotion: a review. Front Neuroanat. (2017) 11:15. doi: 10.3389/fnana.2017.00015
117. Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci. (2002) 3(8):655–66. doi: 10.1038/nrn894
118. Knotkova H, Cruciani RA, Tronnier VM, Rasche D. Current and future options for the management of phantom-limb pain. J Pain Res. (2012) 5:39–49. doi: 10.2147/JPR.S16733
119. Boomgaardt J, Dastan K, Chan T, Shilling A, Abd-Elsayed A, Kohan L. An algorithm approach to phantom limb pain. J Pain Res. (2022) 15:3349–67. doi: 10.2147/JPR.S355278
120. Bittar RG, Otero S, Carter H, Aziz TZ. Deep brain stimulation for phantom limb pain. J Clin Neurosci. (2005) 12(4):399–404. doi: 10.1016/j.jocn.2004.07.013
121. Pang D, Ashkan K. Deep brain stimulation for phantom limb pain. Eur J Paediatr Neurol. (2022) 39:96–102. doi: 10.1016/j.ejpn.2022.05.009
122. Garcia-Pallero MÁ, Cardona D, Rueda-Ruzafa L, Rodriguez-Arrastia M, Roman P. Central nervous system stimulation therapies in phantom limb pain: a systematic review of clinical trials. Neural Regen Res. (2022) 17(1):59–64. doi: 10.4103/1673-5374.314288
123. Malavera A, Silva FA, Fregni F, Carrillo S, Garcia RG. Repetitive transcranial magnetic stimulation for phantom limb pain in land mine victims: a double-blinded, randomized, sham-controlled trial. J Pain. (2016) 17(8):911–8. doi: 10.1016/j.jpain.2016.05.003
124. Damercheli S, Ramne M, Ortiz-Catalan M. Transcranial direct current stimulation (tDCS) for the treatment and investigation of phantom limb pain (PLP).
125. Herrero JF, Laird JMA, Lopez-Garcia JA. Wind-up of spinal cord neurones and pain sensation: much ado about something? Prog Neurobiol. (2000) 61(2):169–203. doi: 10.1016/S0301-0082(99)00051-9
126. Li J, Simone DA, Larson AA. Windup leads to characteristics of central sensitization. Pain. (1999) 79(1):75–82. doi: 10.1016/S0304-3959(98)00154-7
127. Ma RSY, Kayani K, Whyte-Oshodi D, Whyte-Oshodi A, Nachiappan N, Gnanarajah S, et al. Voltage gated sodium channels as therapeutic targets for chronic pain. J Pain Res. (2019) 12:2709–22. doi: 10.2147/JPR.S207610
128. Dib-Hajj SD, Waxman SG. Diversity of composition and function of sodium channels in peripheral sensory neurons. Pain. (2015) 156(12):2406–7. doi: 10.1097/j.pain.0000000000000353
129. Bennett GJ. Update on the neurophysiology of pain transmission and modulation: focus on the NMDA-receptor. J Pain Symptom Manage. (2000) 19((1 Suppl):2–6. doi: 10.1016/S0885-3924(99)00120-7
130. Inquimbert P, Moll M, Latremoliere A, Tong CK, Whang J, Sheehan GF, et al. NMDA receptor activation underlies the loss of spinal dorsal horn neurons and the transition to persistent pain after peripheral nerve injury. Cell Rep. (2018) 23(9):2678–89. doi: 10.1016/j.celrep.2018.04.107
131. Schwartzman RJ, Grothusen J, Kiefer TR, Rohr P. Neuropathic central pain: epidemiology, etiology, and treatment options. Arch Neurol. (2001) 58(10):1547–50. doi: 10.1001/archneur.58.10.1547
132. Wu L-J, Zhuo M. Targeting the NMDA receptor subunit NR2B for the treatment of neuropathic pain. Neurotherapeutics. (2009) 6(4):693–702. doi: 10.1016/j.nurt.2009.07.008
133. Mendell LM, Wall PD. Responses of single dorsal cord cells to peripheral cutaneous unmyelinated fibers. Nature. (1965) 206:97–9. doi: 10.1038/206097a0
134. Mendell LM. The path to discovery of windup and central sensitization. Front Pain Res (Lausanne). (2022) 3:833104. doi: 10.3389/fpain.2022.833104
135. Wang C, Hao H, He K, An Y, Pu Z, Gamper N, et al. Neuropathic injury-induced plasticity of GABAergic system in peripheral sensory ganglia. Front Pharmacol. (2021) 12:702218. doi: 10.3389/fphar.2021.702218
136. Li C, Lei Y, Tian Y, Xu S, Shen X, Wu H, et al. The etiological contribution of GABAergic plasticity to the pathogenesis of neuropathic pain. Mol Pain. (2019) 15:1744806919847366. doi: 10.1177/1744806919847366
137. Qian X, Zhao X, Yu L, Yin Y, Zhang X-D, Wang L, et al. Current status of GABA receptor subtypes in analgesia. Biomed Pharmacother. (2023) 168:115800. doi: 10.1016/j.biopha.2023.115800
138. Davidoff RA, Aprison MH, Werman R. The effects of strychnine on the inhibition of interneurons by glycine and gamma-aminobutyric acid. Int J Neuropharmacol. (1969) 8:191–4. doi: 10.1016/0028-3908(69)90013-6
139. Polgár E, Hughes ID, Riddell SJ, Maxwell DJ, Puskár Z, Todd AJ. Selective loss of spinal GABAergic or glycinergic neurons is not necessary for development of thermal hyperalgesia in the chronic constriction injury model of neuropathic pain. Pain. (2003) 104:229–39. doi: 10.1016/S0304-3959(03)00011-3
140. Levine ES, Crozier RA, Black IB, Plummer MR. Brain-derived neurotrophic factor modulates hippocampal synaptic transmission by increasing N-methyl-D-aspartic acid receptor activity. Proc Natl Acad Sci U S A. (1998) 95(17):10235–9. doi: 10.1073/pnas.95.17.10235
141. Kerr BJ, Bradbury EJ, Bennett DL, Trivedi PM, Dassan P, French J, et al. Brain-derived neurotrophic factor modulates nociceptive sensory inputs and NMDA-evoked responses in the rat spinal cord. J Neurosci. (1999) 19(12):5138–48. doi: 10.1523/JNEUROSCI.19-12-05138.1999
142. Garraway SM, Huie JR. Spinal plasticity and behavior: BDNF-induced neuromodulation in uninjured and injured spinal cord. Neural Plast. (2016) 2016:9857201. doi: 10.1155/2016/9857201
143. Cirulli F, Berry A, Alleva E. Intracerebroventricular administration of brain-derived neurotrophic factor in adult rats affects analgesia and spontaneous behaviour but not memory retention in a Morris Water Maze task. Neurosci Lett. (2000) 287(3):207–10. doi: 10.1016/S0304-3940(00)01173-3
144. Merighi A, Salio C, Ghirri A, Lossi L, Ferrini F, Betelli C, et al. BDNF as a pain modulator. Prog Neurobiol. (2008) 85(3):297–317. doi: 10.1016/j.pneurobio.2008.04.004
145. Lin YT, Ro LS, Wang HL, Chen JC. Up-regulation of dorsal root ganglia BDNF and trkB receptor in inflammatory pain: an in vivo and in vitro study. J Neuroinflammation. (2011) 8:126. doi: 10.1186/1742-2094-8-126
146. Pezet S, McMahon SB. Neurotrophins: mediators and modulators of pain. Annu Rev Neurosci. (2006) 29:507–38. doi: 10.1146/annurev.neuro.29.051605.112929
147. Anderson-Barnes VC, McAuliffe C, Swanberg KM, Tsao JW. Phantom limb pain–a phenomenon of proprioceptive memory? Med Hypotheses. (2009) 73(4):555–8. doi: 10.1016/j.mehy.2009.05.038
148. Ramachandran VS, Hirstein W. The perception of phantom limbs. The D. O. Hebb lecture. Brain. (1998) 121(Pt 9):1603–30. doi: 10.1093/brain/121.9.1603
149. Melzack R. Phantom limbs and the concept of a neuromatrix. Trends Neurosci. (1990) 13(3):88–92. doi: 10.1016/0166-2236(90)90179-E
150. Di Pino G, Piombino V, Carassiti M, Ortiz-Catalan M. Neurophysiological models of phantom limb pain: what can be learnt. Minerva Anestesiol. (2021) 87(4):481–7. doi: 10.23736/S0375-9393.20.15067-3
151. Gentili ME, Verton C, Kinirons B, Bonnet F. Clinical perception of phantom limb sensation in patients with brachial plexus block. Eur J Anaesthesiol. (2002) 19(2):105–8. doi: 10.1017/S0265021502000182
152. Jensen TS, Krebs B, Nielsen J, Rasmussen P. Phantom limb, phantom pain and stump pain in amputees during the first 6 months following limb amputation. Pain. (1983) 17(3):243–56. doi: 10.1016/0304-3959(83)90097-0
153. Katz J, Melzack R. Pain “memories” in phantom limbs: review and clinical observations. Pain. (1990) 43(3):319–36. doi: 10.1016/0304-3959(90)90029-D
154. Collins KL, Robinson-Freeman KE, O’Conor E, Russell HG, Tsao JW. A survey of frozen phantom limb experiences: are experiences compatible with current theories. Front Neurol. (2018) 9:599. doi: 10.3389/fneur.2018.00599
155. Tung ML, Murphy IC, Griffin SC, Alphonso AL, Hussey-Anderson L, Hughes KE, et al. Observation of limb movements reduces phantom limb pain in bilateral amputees. Ann Clin Transl Neurol. (2014) 1(9):633–8. doi: 10.1002/acn3.89
156. Foell J, Bekrater-Bodmann R, Diers M, Flor H. Mirror therapy for phantom limb pain: brain changes and the role of body representation. Eur J Pain. (2014) 18(5):729–39. doi: 10.1002/j.1532-2149.2013.00433.x
157. Ehrsson HH, Holmes NP, Passingham RE. Touching a rubber hand: feeling of body ownership is associated with activity in multisensory brain areas. J Neurosci. (2005) 25(45):10564–73. doi: 10.1523/JNEUROSCI.0800-05.2005
158. Chiyohara S, Furukawa JI, Noda T, Morimoto J, Imamizu H. Proprioceptive short-term memory in passive motor learning. Sci Rep. (2023) 13(1):20826. doi: 10.1038/s41598-023-48101-9
159. Moseley GL, Olthof N, Venema A, Don S, Wijers M, Gallace A, et al. Psychologically induced cooling of a specific body part caused by the illusory ownership of an artificial counterpart. Proc Natl Acad Sci U S A. (2008) 105(35):13169–73. doi: 10.1073/pnas.0803768105
160. Moseley LG. I can’t find it! Distorted body image and tactile dysfunction in patients with chronic back pain. Pain. (2008) 140(1):239–43. doi: 10.1016/j.pain.2008.08.001
161. Flor H, Nikolajsen L, Staehelin Jensen T. Phantom limb pain: a case of maladaptive CNS plasticity? Nat Rev Neurosci. (2006) 7(11):873–81. doi: 10.1038/nrn1991
162. Lotze M, Flor H, Grodd W, Larbig W, Birbaumer N. Phantom movements and pain: an fMRI study in upper limb amputees. Brain. (2001) 124(Pt 11):2268–77. doi: 10.1093/brain/124.11.2268
163. Arena JG, Sherman RA, Bruno GM, Smith JD. The relationship between situational stress and phantom limb pain: cross-lagged correlational data from six month pain logs. J Psychosom Res. (1990) 34(1):71–7. doi: 10.1016/0022-3999(90)90009-S
164. Angrilli A, Köster U. Psychophysiological stress responses in amputees with and without phantom limb pain. Physiol Behav. (2000) 68(5):699–706. doi: 10.1016/S0031-9384(99)00235-8
165. Sherman RA, Gall N, Gormly J. Treatment of phantom limb pain with muscular relaxation training to disrupt the pain–anxiety–tension cycle. Pain. (1979) 6(1):47–55. doi: 10.1016/0304-3959(79)90139-8
166. Giummarra MJ, Georgiou-Karistianis N, Nicholls ME, Gibson SJ, Chou M, Bradshaw JL. The menacing phantom: what pulls the trigger? Eur J Pain. (2011) 15(7):691.e1–8. doi: 10.1016/j.ejpain.2011.01.005
167. Larbig W, Andoh J, Huse E, Stahl-Corino D, Montoya P, Seltzer Z, et al. Pre- and postoperative predictors of phantom limb pain. Neurosci Lett. (2019) 702:44–50. doi: 10.1016/j.neulet.2018.11.044
168. Ahmed A, Bhatnagar S, Mishra S, Khurana D, Joshi S, Ahmad SM. Prevalence of phantom limb pain, stump pain, and phantom limb sensation among the amputated cancer patients in India: a prospective, observational study. Indian J Palliat Care. (2017) 23(1):24–35. doi: 10.4103/0973-1075.197944
169. Desmond DM, MacLachlan M. Affective distress and amputation-related pain among older men with long-term, traumatic limb amputations. J Pain Symptom Manage. (2006) 31(4):362–8. doi: 10.1016/j.jpainsymman.2005.08.014
170. Hill A. The use of pain coping strategies by patients with phantom limb pain. Pain. (1993) 55(3):347–53. doi: 10.1016/0304-3959(93)90010-M
171. Jensen MP, Ehde DM, Hoffman AJ, Patterson DR, Czerniecki JM, Robinson LR. Cognitions, coping and social environment predict adjustment to phantom limb pain. Pain. (2002) 95(1–2):133–42. doi: 10.1016/S0304-3959(01)00390-6
172. Turk DC. The role of psychological factors in chronic pain. Acta Anaesthesiol Scand. (1999) 43(9):885–8. doi: 10.1034/j.1399-6576.1999.430904.x
173. Hanley MA, Jensen MP, Ehde DM, Hoffman AJ, Patterson DR, Robinson LR. Psychosocial predictors of long-term adjustment to lower-limb amputation and phantom limb pain. Disabil Rehabil. (2004) 26(14–15):882–93. doi: 10.1080/09638280410001708896
174. Richardson C, Glenn S, Horgan M, Nurmikko T. A prospective study of factors associated with the presence of phantom limb pain six months after major lower limb amputation in patients with peripheral vascular disease. J Pain. (2007) 8(10):793–801. doi: 10.1016/j.jpain.2007.05.007
175. Knoerl R, Lavoie Smith EM, Weisberg J. Chronic pain and cognitive behavioral therapy: an integrative review. West J Nurs Res. (2016) 38(5):596–628. doi: 10.1177/0193945915615869
176. Ehde DM, Dillworth TM, Turner JA. Cognitive-behavioral therapy for individuals with chronic pain: efficacy, innovations, and directions for research. Am Psychol. (2014) 69(2):153–66. doi: 10.1037/a0035747
177. Hofmann SG, Asnaani A, Vonk IJ, Sawyer AT, Fang A. The efficacy of cognitive behavioral therapy: a review of meta-analyses. Cogn Ther Res. (2012) 36(5):427–40. doi: 10.1007/s10608-012-9476-1
178. Åkerlund M, Baskozos G, Li W, Themistocleous AC, Pascal MMV, Rayner NW, et al. Genetic associations of neuropathic pain and sensory profile in a deeply phenotyped neuropathy cohort. Pain. (2024):1. doi: 10.1097/j.pain.0000000000003463
179. Veluchamy A, Hébert HL, van Zuydam NR, Pearson ER, Campbell A, Hayward C, et al. Association of genetic variant at chromosome 12q23.1 with neuropathic pain susceptibility. JAMA Netw Open. (2021) 4(12):e2136560. doi: 10.1001/jamanetworkopen.2021.36560
180. Themistocleous AC, Baskozos G, Blesneac I, Comini M, Megy K, Chong S, et al. Investigating genotype-phenotype relationship of extreme neuropathic pain disorders in a UK national cohort. Brain Commun. (2023) 5(2):fcad037. doi: 10.1093/braincomms/fcad037
181. Jergova S, Martinez H, Hernandez M, Schachner B, Gross S, Sagen J. Development of a phantom limb pain model in rats: behavioral and histochemical evaluation. Front Pain Res (Lausanne). (2021) 2:675232. doi: 10.3389/fpain.2021.675232
182. Devor M, Del Canho S, Raber P. Heritability of symptoms in the neuroma model of neuropathic pain: replication and complementation analysis. Pain. (2005) 116(3):294–301. doi: 10.1016/j.pain.2005.04.025
183. Nissenbaum J, Devor M, Seltzer Z, Gebauer M, Michaelis M, Tal M, et al. Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2. Genome Res. (2010) 20(9):1180–90. doi: 10.1101/gr.104976.110
184. Bortsov AV, Devor M, Kaunisto MA, Kalso E, Brufsky A, Kehlet H, et al. CACNG2 polymorphisms associate with chronic pain after mastectomy. Pain. (2019) 160(3):561–8. doi: 10.1097/j.pain.0000000000001432
185. Bali KK, Gandla J, Rangel DR, Castaldi L, Mouritzen P, Agarwal N, et al. A genome-wide screen reveals microRNAs in peripheral sensory neurons driving painful diabetic neuropathy. Pain. (2021) 162(5):1334–51. doi: 10.1097/j.pain.0000000000002159
186. Winkler I, Blotnik S, Shimshoni J, Yagen B, Devor M, Bialer M. Efficacy of antiepileptic isomers of valproic acid and valpromide in a rat model of neuropathic pain. Br J Pharmacol. (2005) 146(2):198–208. doi: 10.1038/sj.bjp.0706310
Keywords: amputation, phantom limb pain, pathophysiology, genetics, central nervous system, peripheral nervous system, psychology
Citation: Wu H, Saini C, Medina R, Hsieh SL, Meshkati A and Sung K (2025) Pain without presence: a narrative review of the pathophysiological landscape of phantom limb pain. Front. Pain Res. 6:1419762. doi: 10.3389/fpain.2025.1419762
Received: 18 April 2024; Accepted: 17 January 2025;
Published: 18 February 2025.
Edited by:
Weibin Shi, Penn State Health, United StatesReviewed by:
Jeffrey C. Petruska, University of Louisville, United StatesEva Lendaro, Massachusetts Institute of Technology, United States
Oksana Sayko, Medical College of Wisconsin, United States
Copyright: © 2025 Wu, Saini, Medina, Hsieh, Meshkati and Sung. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Hong Wu, SG9uZ19XdUBydXNoLmVkdQ==