This paper is a mini-review on neuropathic pain after limb amputation, with a focus on diabetic patients. Diabetes mellitus is a major cause of lower-limb amputation, and neuropathic pain is among the most disabling sequelae.Peripheral neuropathy affects up to half of diabetic individuals, and 10–34% experience phantom limb pain and up to 59% report residual stump pain after amputation. The pathophysiology involves peripheral nerve injury, diabetes-induced metabolic and vascular toxicity, central sensitization, and glial activation, leading to persistent abnormal pain signaling. Neuropathic pain usually presents as painful diabetic peripheral neuropathy or phantom limb pain. Diagnosis relies on history and neurological examination, aided by tools such as DN4 or LANSS,though their accuracy remains limited. Management is mainly pharmacological, with gabapentinoids, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants as first-line agents, while multimodal and rehabilitative approaches may provide additional benefit. Heterogeneity of patients and lack of longitudinal data hinder standardization, highlighting the need for biomarkers and novel neuromodulatory strategies.

Keywords: diabetes, amputation, neuropathic pain

Amputation has a profound impact on patients’ quality of life, encompassing physical, psychological, and social domains. Functional impairment is often substantial, leading to reduced mobility, greater dependence in activities of daily living, and limited social and professional participation.¹ Psychologically, high rates of depression, anxiety, and dissatisfaction with body image are observed, particularly among individuals undergoing lower-limb amputations.^2,3 Diabetes mellitus remains one of the leading causes of amputation worldwide, largely as a consequence of diabetic foot syndrome, which is characterized by neuropathy, ulceration, infection, and ischemia. The majority of amputations in diabetic patients are preceded by foot ulcers, and the coexistence of infection and peripheral arterial disease (PAD) markedly increases the likelihood of limb loss.^3,4 Neuropathic pain is a frequent and debilitating complication following amputation. This condition has been extensively investigated due to its negative effect on patients’ quality of life.⁵ The most common clinical manifestations include phantom limb pain, residual stump pain, and pain associated with neuroma formation. Evidence indicates that the burden of neuropathic pain after amputation is considerable: meta-analyses report that approximately 34% of patients experience phantom limb pain, while up to 59% suffer from residual stump pain after lower-limb amputation. Painful neuroma formation is a key contributor to these outcomes.^6,7 This review seeks to synthesize current evidence on the pathophysiology of post-amputation pain, with a particular focus on differentiating nociceptive from neuropathic mechanisms, outlining available diagnostic approaches, and summarizing contemporary strategies for clinical management.

Post-amputation neuropathic pain arises from aberrant nerve fiber damage and regeneration, resulting in peripheral and central sensitization, as well as sensory deafferentation phenomena.⁸ Several studies have reported associations between its development and factors such as a more proximal level of amputation, younger age, absence of comorbidities including diabetes and chronic kidney disease, and a history of psychiatric illness; however, these findings remain heterogeneous across different populations.^6,9 The pathophysiology of neuropathic pain in diabetic patients undergoing amputation results from the interplay between peripheral nerve injury, diabetes-induced metabolic alterations, and central sensitization processes. Diabetes promotes metabolic toxicity in peripheral axons, leading to axonal degeneration, inflammatory activation, and changes in the cellular profile of nerves.¹⁰ Moreover, chronic hyperglycemia induces oxidative stress, mitochondrial dysfunction, and reduced autophagic activity in neurons, particularly following nerve injury as occurs in amputation. Experimental evidence suggests that the NR2A–Wnt–TLR2–NF-κB axis is activated in the dorsal horn of the spinal cord, contributing to increased reactive oxygen species (ROS), ATP depletion, and sustained inflammation, thereby facilitating central sensitization and the persistence of neuropathic pain.¹¹ Another important contributor is diabetic vasculopathy, which diminishes vascular supply to the dorsal horn of the spinal cord, resulting in neuronal hypoxia and activation of pathways such as carbonic anhydrase, thereby increasing the excitability of nociceptive neurons and facilitating the development of neuropathic pain.¹² Furthermore, amputation itself, by directly damaging peripheral nerves, amplifies these mechanisms, leading to disorganization of sensory transmission, loss of GABAergic inhibition, and glial activation, which can sustain neuropathic pain even after limb removal.¹³ Given what has been discussed so far, we can see that the pathophysiology of neuropathy in diabetic patients undergoing amputation is multifactorial, involving axonal degeneration, inflammation, mitochondrial dysfunction, central hypoxia and glial sensitization, as evidenced in the current literature.

Peripheral neuropathy is one of the most common complications of both type 1 and type 2 diabetes. Up to half of patients with diabetes develop neuropathy during the course of their disease, which is accompanied by neuropathic pain in 30-40% of cases.¹⁴ In a national database analysis of 29,507 amputees, the incidence of postoperative neuralgia was 4.4%, neuroma 0.4% and phantom limb pain 10.9%; diabetes and diabetic neuropathy were associated with a higher risk of painful complications, although the magnitude of the increase was modest.¹⁵ In the specific case of phantom limb pain, a prospective study showed a prevalence of 82% in diabetics versus 89.4% in non-diabetics, with no statistically significant difference.¹⁶ Neuropathic pain after amputation in diabetic patients generally corresponds to two main diagnoses: diabetic peripheral neuropathic pain (painful DPN) and phantom limb pain.¹⁷ In diabetic patients, DPN is the most common neurological complication, characterized by symptoms such as burning pain, tingling, electric shock, hyperalgesia and allodynia, often in a distal and symmetrical pattern, but which can persist or even appear after amputation, including in the stump or as pain referred to the absent limb.^18,19 Phantom limb pain, on the other hand, is defined as pain perceived in a part of the body that has been amputated. ²⁰ The clinical diagnosis of neuropathic pain is based on a structured approach that includes a detailed anamnesis, neurological physical examination and, when necessary, complementary tests. Neuropathic pain is defined as pain caused by injury or disease of the somatosensory system, and its identification depends on the presence of characteristic symptoms (burning, shock, tingling, allodynia, hyperalgesia) and objective findings of sensory dysfunction in the painful area.²⁰ To increase diagnostic accuracy, validated instruments can be used, such as DN4, LANSS and painDETECT, which assess neuropathic symptoms and signs. However, recent studies show that these instruments have moderate sensitivity and limited specificity, and should be used as aids and not as the sole diagnostic criteria.^21,22

The therapeutic management of neuropathic pain after amputation in patients with diabetes follows the recommendations for peripheral neuropathic pain, with adaptations for the post-amputation context. Treatment is predominantly pharmacological, as there is no robust evidence for the benefit of glycemic control or lifestyle interventions on neuropathic pain in this scenario.¹⁹ For pharmacological treatment, the first line of treatment is gabapentinoids (gabapentin, pregabalin), serotonin and noradrenaline reuptake inhibitors (duloxetine, venlafaxine) or tricyclic antidepressants (amitriptyline, nortriptyline). These agents have similar efficacy and should be chosen according to their comorbidity profile, adverse effects and cost.^23,24 Pregabalin and duloxetine have specific regulatory approval for diabetic neuropathic pain in the USA.¹⁹ The use of a combination of agents from different classes can be considered in refractory cases, with potential benefit and lower risk of adverse effects than increasing the dose of a single.^19,23,24 In a 2015 study, individuals with unilateral lower limb amputation were randomly assigned to receive either a combined intervention of progressive muscle relaxation, mental imagery, and phantom limb exercises or standard residual limb exercises. Both groups also took part in a rehabilitation program that included occupational therapy and prosthesis training. After four weeks of treatment and a follow-up one month later, results showed no significant differences between groups immediately post-treatment. However, at the one-month follow-up, the group that received the combined intervention reported significantly lower pain intensity and reduced phantom limb pain frequency, intensity, and interference, suggesting potential long-term benefits of this multimodal approach.²⁵ Despite advances in understanding post-amputation neuropathic pain in diabetic patients, significant challenges remain. The heterogeneity of patient populations, variability in assessment methods, and limited longitudinal data hinder the development of standardized diagnostic and therapeutic protocols. Looking ahead, research needs to move beyond describing the problem and focus on tools that can guide treatment, such as predictive biomarkers, as well as testing regenerative and neuromodulatory options that may offer patients lasting relief.

None.

The author declare that there are no conflicts of interest.

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