KEY FIGURE

Highlights

• DPN is a heterogeneous condition, but effective treatments are lacking.

• Identifying phenotypes by symptoms can improve diagnosis and guide treatment.

• A phenotype-based approach shows treatment response varies by clinical presentation.

• Personalized care is promising, but biomarkers and large trials remain challenging.

INTRODUCTION

Diabetic peripheral neuropathy (DPN) is one of the most prevalent complications of diabetes mellitus (DM), with a reported prevalence of 15% to 37% in diabetic populations [1]. The incidence of DPN has increased alongside an increasing prevalence of DM [2]. DPN significantly reduces quality of life (QoL) and leads to serious health issues including a higher risk of diabetic foot ulcers (DFUs) and amputations [3]. Despite the availability of various pharmacological treatments, the management of DPN remains a significant challenge. The subjective nature of pain assessment and heterogeneity of sensory deficits among patients contribute to inconsistent treatment outcomes. Commonly prescribed medications such as tricyclic antidepressants (TCAs), anticonvulsants, serotonin-norepinephrine reuptake inhibitors (SNRIs), and topical agents often provide limited relief.

DPN is a heterogeneous disorder that encompasses a variety of sensory phenotypes, ranging from painful to painless forms. These variations stem from complex metabolic and microvascular disruptions driven by chronic hyperglycemia, oxidative stress, and inflammatory pathways. Hyperglycemia and dyslipidemia can trigger multiple metabolic pathways such as polyol, protein kinase C, and advanced glycation end-product (AGE) pathways, leading to oxidative stress and mitochondrial dysfunction [4]. Variations in DM duration, glycemic control, and risk factors for vascular complications among patients, along with differences in pain perception, depression, and sleep disturbances, lead to diverse clinical phenotypes of diabetic neuropathy [5]. Consequently, each clinical phenotype of DPN may be associated with distinct pathophysiological mechanisms and clinical outcomes [6]. Therefore, understanding the pathophysiological basis of the different phenotypes is crucial for developing individualized treatment approaches.

Since the early 1990s, neuropathic pain treatment based on the specific underlying mechanisms rather than on the etiological condition has been recommended, leading to targeted treatment of these mechanisms [7]. However, this approach has associated challenges relating to the difficulties in translating the pathophysiological mechanisms identified in animal studies into clinical practice [8]. Accordingly, a more practical and effective strategy that focuses on the clinically observable manifestations of neuropathic pain through comprehensive symptomatic assessment has been suggested [9]. Specific pain symptoms and their combinations can provide valuable insights into the mechanisms underlying neuropathic pain. These trans-etiological profiles of symptom phenotypes may lead to targeted treatment of the mechanisms [10]. Validated questionnaires such as the Neuropathic Pain Scale (NPS) and Neuropathic Pain Symptom Inventory (NPSI) enable the assessment of pain characteristics [11]. In addition, clinical tests such as quantitative sensory testing (QST) can identify sensory signs [12]. Through several clinical trials, phenotypic profiling has primarily contributed to the characterization of treatment effects on the sensory signs and symptoms of neuropathic pain [13,14].

This review aims to categorize DPN according to clinical phenotypes in order to understand the underlying pathogenesis, describe the rationale for targeted treatment for improving clinical outcomes, and provide insights into the future care of patients with DPN.

DIABETIC PERIPHERAL NEUROPATHY: CLASSIFICATION AND DIAGNOSTIC APPROACH TO PAINFUL DIABETIC PERIPHERAL NEUROPATHY

DPN subtype and phenotype

The terms, subtype and clinical phenotype, although often used interchangeably, have distinct meanings and implications for DPN diagnosis and management. The subtypes of DPN refer to distinct pathological classifications based on the underlying mechanisms and anatomical involvement. These subtypes have primarily been identified through pathophysiological and electrophysiological studies (‘Subtypes’ in Table 1) [15-19].

The common subtypes of DPN include:

(1) Distal symmetric polyneuropathy: This is the most common form of DPN characterized by symmetrical sensory loss and motor involvement, which typically affects the distal extremities. It is the most researched type of DPN, often serving as a prototype for clinical studies.

(2) Focal and multifocal neuropathies: These include conditions such as cranial neuropathies, radiculopathies, and mononeuropathies involving localized nerve damage.

Clinical phenotypes focus on observable symptom patterns and their manifestations. These phenotypes often overlap with subtypes but are defined more by their symptomatic and functional impact. Recent findings suggest that DPN presents heterogeneous phenotypes, broadly categorized into painful, painless, and mixed types (‘Clinical phenotype’ in Table 1). The pain experienced by patients with DPN is a type of neuropathic pain that can feel like burning (a spontaneous, stimulus-independent pain that is common in the feet), tingling (a sensation that can feel like pins and needles), stabbing (a sharp, excruciating pain), electric shock (a sensation that can be described as painful), allodynia (a condition where innocuous stimuli such as clothes or sheets cause pain), hyperesthesia (an increased sensitivity to noxious stimuli), or altered perception (a change in how cold and warm sensations are felt) [15]. Recent studies have indicated that up to 40% of patients with DM experience painful DPN, whereas the remainder exhibit painless sensory deficits [20].

The clinical phenotypes of DPN include:

(1) Painful DPN: This involves chronic pain that is most severe in the feet, but can extend to involve the legs, hands, and arms in a typical ‘glove and stocking distribution.’ The pain can be severe and unremitting and can worsen at night. Pain intensity is consistently associated with QoL, depression, anxiety, and sleep quality. Painful diabetic neuropathy is often inadequately treated, leading to severe sleep deprivation and impaired functioning. Insufficient pain management also results in decreased work productivity and employment challenges [21].

(2) Painless DPN: Painless DPN is often driven by dysfunction of large nerve fibers. Unlike painful forms of neuropathy, this subtype typically progresses without noticeable symptoms, making it challenging to detect in the early stages. Patients may experience a gradual loss of vibration and position sense, as well as diminished proprioception. This can manifest as vague sensations such as ‘walking on wool’ or feeling as if the foot is ‘wrapped in paper.’ As balance becomes impaired, the risk of falls increases significantly. Due to the absence of pain and the subtle onset, many patients do not recognize the sensory decline until substantial nerve damage occurs [22].

(3) Painful DPN with associated sensory loss: In this phenotype, dysfunction of both small and large nerve fibers often coexist, leading to a combination of symptoms including painful sensations that coexist with sensory deficits such as numbness, as well as gait abnormalities and postural instability. Small-fiber involvement typically results in sensory disturbances, whereas large-fiber dysfunction contributes to motor impairment and balance issues [23].

While subtypes guide the understanding of the anatomical and functional extent of nerve damage, often influencing the long-term prognosis, clinical phenotypes assist in symptom management and patient-centered therapeutic strategies. However, combining the knowledge of subtypes and phenotypes enables a comprehensive approach that integrates precision medicine and personalized care.

Clinical phenotypes of painful DPN

Painful DPN is defined as pain directly attributable to abnormalities in the somatosensory system of patients with DM [24]. However, the diagnosis of painful DPN is based on the patient’s description of pain. Symptoms may include burning, shooting, or electric shock-like pain and lancinating, knifelike, or evoked pain, but they may also include tingling (dysesthesia), swelling of the feet, strange sensations such as walking on gravel, or cold or hot sensations. Patients often complain of symmetrical pain or discomfort, often distal, in locations with nocturnal exacerbations [25]. Painful DPN can be further categorized into more specific clinical phenotypes based on the patient’s description of pain.

Although neuropathic pain is characterized by damage to the somatosensory nervous system, its underlying causes and pathogenesis can vary [26]. Moreover, even when the underlying cause of DPN is the same, patients may differ in their perception and recognition of sensory symptoms, as well as in how they express them [27]. Therefore, a comprehensive approach for DPN management is necessary to classify patients or assign phenotypes according to their subjective symptoms and objective test results. There is no gold standard for categorizing DPN based on symptoms. Several studies have introduced methods to categorize patients according to the presence or absence of symptoms, or the characteristics of their symptoms. However, the classification of painful DPN remains unclear because it is based on the patient’s subjective description of pain rather than on precise classification criteria. The heterogeneity of the sensory profile of neuropathic pain may also contribute to the difficulty in classifying painful DPN.

According to Attal et al. [7], painful DPN can manifest in five distinct ways.

(1) Evoked pain (allodynia or hyperalgesia): A heightened sensitivity to stimuli in which light touch or minor mechanical pressure triggers disproportionate pain. It reflects small-fiber dysfunction and central sensitization mechanisms.

(2) Paroxysmal pain (electric shock and sharp): Brief, intermittent episodes of sharp, electric shock-like pain often associated with spontaneous nerve discharge.

(3) Deep pain (compression and tightness): Patients describe this as a deep, aching pain that often resembles the sensation of tightness or pressure. This subtype may be linked to mixed-fiber involvement and central processing abnormalities.

(4) Superficial pain (burning): Burning pain, often localized to the skin, is a hallmark of small-fiber neuropathy and reflects the loss of nociceptive fiber integrity.

(5) Paresthesia and dysesthesia (tingling and brushing): Abnormal sensations such as tingling or discomfort from nonpainful stimuli indicating persistent peripheral nerve irritation.

Although some patients may describe their symptoms using a single pain descriptor, the majority report a combination of multiple pain types or sensory symptoms. Painful and painless features of DPN may coexist within the same individual, underscoring the limitations of conventional classification systems. Patients with DPN often experience complex and overlapping pain sensations, frequently accompanied by sensory loss. Consequently, there has been growing interest in classifying patients based on characteristic clusters of symptoms—referred to as pain phenotypes—to support more precise and personalized therapeutic approaches. To this end, several clinical studies have evaluated pain characteristics using questionnaires or QST, aiming to classify patients into symptom clusters based not only on pain quality or severity of sensory loss, but also on associated features such as sleep disturbances, depressive symptoms, and other coexisting complaints that frequently occur together. Recently, several studies have reported on the classification of DPN patient subgroups based on such analyses; representative findings are summarized below.

In our previous study of patients with DPN in Korea, the clinical impact of DPN on pain, sleep, and QoL was analyzed using cluster analysis along with DPN symptoms; the patients could be divided into three groups [28]. In brief, cluster 1 comprised predominantly asymptomatic patients; cluster 2, moderately symptomatic patients with sleep disturbances; and cluster 3, patients with the most severe pain and lowest QoL, with higher glycosylated hemoglobin levels and a higher proportion of retinopathy or nephropathy. The most important factor for dividing the clusters was pain intensity. Although this was a cross-sectional study, and we were unable to determine differences in response to treatment between each cluster, this comprehensive approach provided a sound rationale for subgrouping patients with DPN in order to individualize their assessment and treatment [28].

In a separate study, 628 patients with neuropathic pain and a douleur neuropathique 4 (DN4) score of ≥4 were asked to describe their pain over the past 24 hours using the NPSI [29]. After normalizing NPSI scores, clustering analysis revealed three groups with different sensory profiles. They were divided into paresthesia/dysesthesia (predominantly pinpointed and evoked pain, but not severe), evoked pain (triggered by brushing, cold or pressure, or electric shock, but not severe), and deep pain (more than an average pressure or squeezing pain) [29].

In another study, brain magnetic resonance imaging (MRI) of 43 patients with painful DPN revealed differences in the regions of the brain with resting-state functional connectivity [30]. Patients with painful DPN were divided into irritable and non-irritable nociceptor phenotypes. In patients in the irritable group, pain severity, as assessed by a questionnaire, was correlated with thalamus-insular cortex functional connectivity, and severe neurological function deficits were associated with lower thalamus-somatosensory cortex functional connectivity. This study presented a new classification method for painful DPN, which may contribute to the understanding of the pathogenesis of painful DPN and individualization of treatment.

There has been an ongoing effort to classify painful DPN, which will allow the development and application of more individualized treatments to patients specific to their pain. The continuation of this research is recommended.

Diagnosis of DPN clinical phenotypes

Understanding distinct clinical phenotypes of DPN is critical for improving diagnostic precision and facilitating personalized therapeutic strategies. The limited efficacy of current pharmacological interventions highlights the need for novel, mechanism-based approaches. Conventional diagnostic modalities, such as nerve conduction studies (NCS), primarily assess large-fiber function and are insufficient to capture the heterogeneity and complexity of DPN phenotypes. Phenotype-specific approaches enable more accurate patient stratification in clinical trials, thereby increasing the likelihood of identifying effective, targeted treatments. Furthermore, the identification of biomarkers associated with specific phenotypes may support earlier diagnosis and guide therapeutic decision-making. Recent advances in neuroimaging have revealed metabolic alterations in the thalamus and peripheral nerves, offering promising tools for patient stratification and prediction of treatment response.

Numerous tools are available for the diagnosis of DPN; however, when it comes to determining clinical phenotypes, the following tools are most commonly utilized to assess the presence or absence of neuropathy and to characterize symptom profiles.

Questionnaires

Questionnaires are one of the most common methods used for characterizing DPN clinical phenotypes. The following questionnaires are not only useful for distinguishing neuropathic pain but also for assessing the clinical characteristics of pain. Among them, except for the Michigan Neuropathy Screening Instrument (MNSI), most tools are primarily designed to evaluate neuropathic pain rather than specifically assess DPN.

1) MNSI

MNSI is a widely used tool for screening the presence of DPN, particularly in outpatient settings by primary care providers. It consists of a 15-item self-administered questionnaire with ‘yes or no’ responses focused on foot sensations such as pain, numbness, and temperature sensitivity [31]. While the MNSI is effective in identifying the presence of neuropathy, it has limitations in evaluating clinical phenotypes. Specifically, it provides only limited insight into symptom characteristics such as numbness, burning pain, hyperalgesia, or prickling sensations.

2) DN4

This was developed by the French Neuropathic Pain Group, it consists of sensory descriptors and signs related to bedside sensory examination [32]. The DN4 and DN4-interview scores show a high diagnostic accuracy for painful diabetic polyneuropathy, with areas under the receiver operating characteristic curve of 0.94 and 0.93, respectively [33].

3) The painDETECT questionnaire

This questionnaire was developed specifically to detect neuropathic pain components in adult patients with low back pain [34]. It comprises seven questions that address the quality of neuropathic pain symptoms and can be completed by the patient without physical examination [35]. This questionnaire is a quick, simple, and reliable screening tool for identifying the likelihood of neuropathic pain. It has been used to identify the sensory profiles of patients with diabetic neuropathy and postherpetic neuralgia (PHN) [36].

4) NPSI

This self-questionnaire was specifically designed to evaluate the different symptoms of neuropathic pain and allows discrimination and quantification of five distinct clinically relevant dimensions of neuropathic pain syndromes that are sensitive to treatment. The psychometric properties of the NPSI suggest that it can be used to characterize subgroups of patients with neuropathic pain and verify whether they respond differentially to various pharmacological agents or other therapeutic interventions [37].

5) Short Form McGill Pain Questionnaire (SF MPQ-2)

This was originally derived from the time-consuming McGill Pain Questionnaire developed in 1975 [38], and has shown excellent validity and reliability in patients with painful DPN. It comprises four components including continuous (throbbing, cramping, gnawing, aching, and heavy pains, and tenderness), intermittent (shooting, stabbing, sharp, splitting, electric shock, and piercing pains), neuropathic (hot-burning and cold-freezing pain, light touch-induced pain, itching, tingling or “pins and needles,” and numbness), and affective (tiring-exhausting, sickening, fearful, and punishing-cruel) subscales.

6) Pain Quality Assessment Scale (PQAS)

This has previously been used to assess patient response to pregabalin (but not to placebo) in a randomized clinical trial (RCT) [39]. Patients who rated their pain as paroxysmal, deep, electrical, or radiating (along with several other descriptors) reported greater analgesic benefits from pregabalin (but there was no association with placebo benefits), highlighting the potential predictive benefits of comprehensively phenotyping patient self-reported pain qualities.

7) Leeds assessment of neuropathic symptoms and signs (LANSS)

This is a pain scale based on the analysis of sensory description and examination of sensory dysfunction (allodynia and pinprick test), with a score of ≥12 out of 24 indicating neuropathic pain. It can be used as an screening tool, but is also sensitive to the treatment effect [40].

QST

QST is a non-invasive psychophysical method used to assess somatosensory function by measuring responses to controlled stimuli such as temperature, vibration, or mechanical pressure, and also patient responses. It comprises a series of standardized tests that can help identify pain phenotypes and diagnose neuropathic pain. It can facilitate in the diagnosis of neuropathies, especially small-fiber neuropathies, which cannot be assessed using conventional electrophysiology [12].

1) Thermal testing

This assesses small-fiber (Aδ and C fibers) function (cold and warm detection thresholds). The cold pain threshold (CPT) and heat pain threshold are used to identify hyperalgesia or loss of pain perception, which is indicative of small-fiber dysfunction. Patients with painful DPN show lower heat pain thresholds due to the hyperexcitability of nociceptive fibers [41].

2) Vibration testing

This evaluates large-fiber (Aβ fiber) function using a tuning fork or a vibratory device; a higher vibration perception threshold suggests progressive large-fiber neuropathy. Painful DPN is often associated with small-fiber dysfunction rather than with large-fiber dysfunction, indicating that vibration testing alone may not effectively differentiate between painful and painless DPN [41].

3) Mechanical and pressure testing

In this test, mechanical hyperalgesia is evaluated by applying increasing pinprick force until pain is perceived. Dynamic mechanical allodynia can be utilized to detect pain in response to light touch using a cotton swab or brush. The pressure pain threshold measures the response to gradual pressure stimulation, identifying deep tissue hyperalgesia. Patients with painful DPN frequently experience mechanical allodynia and hyperalgesia, which differentiates them from patients with painless DPN [42].

4) CPT testing

This is known as the perception threshold test, and is performed using a neurometer (Neurotron, Baltimore, MD, USA) to quantify sensory fiber function. This test evaluates all three major subtypes of sensory nerve fibers:

• Aβ fibers (2,000 Hz): Large myelinated fibers responsible for touch and pressure sensation

• Aδ fibers (250 Hz): Small myelinated fibers involved in pain and temperature sensation

• C fibers (5 Hz): Small unmyelinated fibers associated with slow pain and autonomic function.

CPT testing enables the automated classification of sensory phenotypes such as normoesthesia, hyperesthesia, and hypoesthesia [43]. Patients with hyperesthesia show significantly decreased CPT values, whereas those with hypoesthesia or anesthesia exhibit increased CPT values during nerve damage [44]. Notably, nerve conduction variables in patients with hyperesthesia do not significantly differ from those in patients with normoesthesia, highlighting the unique ability of CPT testing to detect subclinical sensory dysfunction (Fig. 1) [45].

QST is widely used in research and clinical practice to differentiate painful from painless DPN, to quantify sensory deficits, and to identify central and peripheral sensitization mechanisms in neuropathic pain [46]. It assists in the detection of early-stage neuropathy in patients with DM and is particularly useful for diagnosing isolated small-fiber neuropathy, which conventional electrophysiology is unable to achieve because it only assesses large myelinated fibers [47]. For example, the detection of the early stages of subclinical neuropathy in asymptomatic patients with DM can be helpful in optimizing treatment and identifying patients at risk of DFU. QST assesses an individual’s sensory profile and can therefore be valuable in evaluating the underlying pain mechanisms that occur at different frequencies, even in the same neuropathic pain syndromes. In addition, assessing the exact sensory phenotype using QST might be useful for identifying responders to certain treatments in accordance with the underlying pain mechanisms [47]. Furthermore, changes in QST profiles over time can help assess the progression of neuropathy and treatment efficacy [48]. However, QST relies on patient-reported responses, which can be influenced by pain tolerance, cognitive function, and psychological factors, and standardized protocols are required to ensure reproducibility (operator-dependent) [49]. Although it has limitations when combined with other diagnostic modalities, QST enhances diagnostic accuracy and improves patient management. In the future, advancements in automated QST devices and machine learning algorithms may improve diagnostic accuracy and reproducibility, with potential for QST to become a standardized clinical tool for DPN assessment [50].

MRI-based white matter hyperintensities

Advanced imaging techniques, including MRI-based white matter hyperintensity (WMH) quantification, have revealed central neurodegenerative changes in DPN that correlate with disease severity [51]. Identifying phenotype-specific metabolic and structural markers is essential for an accurate diagnosis and targeted therapy.

MRI-based quantification has revealed a higher WMH burden in patients with DPN, especially painful forms, compared to healthy controls [52]. WMHs are correlated with DPN severity, reduced cognitive function, and neurodegenerative changes. The association between central neurodegeneration and peripheral neuropathy underscores the complex interplay between the central and peripheral nervous system involvement in DPN. These findings reveal new avenues for integrated diagnostic and therapeutic strategies.

Nerve/skin biopsy

Nerve and skin biopsies are mainly used for research purposes to examine nerve fiber density and structural changes, especially in cases where the QST results are inconclusive. In 2013, a study investigated differences in skin biopsies of the proximal thigh and distal leg between patients with and without DM neuropathy, and with and without painful DPN [53]. Protein gene product 9.5 was measured by immunohistochemistry to determine the total amount of intraepidermal nerve fibers at each site, and growth-associated protein 43 was measured to assess the amount of regenerating intraepidermal nerve fibers. There was a high growth-associated protein 43/protein gene product ratio in skin biopsy samples from patients with painful DPN, independent of the skin biopsy site, and a high proportion of nerves with axonal swelling per protein gene product in the distal leg. Furthermore, tropomyosin-receptor kinase A and substance P were also detected in areas with axonal swelling, suggesting that they may be involved in nociception in painful DM neuropathy [53].

Corneal confocal microscopy

Corneal confocal microscopy (CCM) is a non‐invasive imaging technique for quantifying corneal nerve fiber integrity. A significant reduction in corneal nerve parameters has been consistently detected in patients with DPN compared to healthy controls and those without DPN [54] and corneal nerve loss is evident even in subclinical cases, allowing early detection of neuropathy [55]. Meta‐analyses and head-to-head studies have shown that CCM‐derived corneal nerve fiber density correlates moderately to strongly with intraepidermal nerve fiber density (IENFD) and with QST measures of small-fiber function, while correlations with large-fiber assessments such as NCS parameters are weaker [56]. CCM also correlates with clinical measures such as the neuropathy disability score, Mc-Gill visual analogue scale (VAS), and neuropathy symptom profile [56]. It meets U.S. Food and Drug Administration criteria as a biomarker across multiple neuropathies and can predict DPN risk—even when glycemic control and low-density lipoprotein cholesterol improve [57,58]. Studies have demonstrated a strong correlation between corneal nerve loss and DPN severity, with the CCM showing high sensitivity and specificity for diagnosing DPN. Additionally, CCM can help predict the risk of developing DPN, making it a valuable tool for early intervention [59]. Despite its strengths, widespread clinical adoption of CCM is limited by the need for specialized equipment and trained personnel, variability in image acquisition and analysis without universally accepted normative databases, and its focus on small-fiber pathology, which does not capture large-fiber or autonomic dysfunction. Further research is needed to clarify CCM’s role in distinguishing between different DPN clinical phenotypes.

Electrodiagnostic studies

Electrodiagnostic studies, primarily NCS and electromyography, play a crucial role in the differential diagnosis of DPN. They help distinguish DPN from other conditions with similar presentations, such as radiculopathy or distal myopathy, and can detect subclinical nerve involvement. Moreover, these studies assist in identifying the predominant pathophysiology mechanism (e.g., axonal vs. demyelinating damage) and assessing disease severity, thereby providing valuable information for prognosis and management. However, their utility in differentiating specific clinical phenotypes or subtypes of DPN remains limited [60].

Other phenotypic domains

Psychological factors

Chronic pain and mood disorders are closely linked, and chronic pain significantly increases the risk of mood disorders such as depression and anxiety. Psychosocial factors such as distress and anxiety are major predictors of the transition from acute to chronic pain, particularly in musculoskeletal conditions [61]. Increased negative effects and pain-specific distress can reduce the effectiveness of pain treatments. Various tools such as the Hospital Anxiety and Depression Scale are used to assess emotional distress and predict treatment outcomes, with high pretreatment scores often linked to poorer pain relief and higher medication misuse [62]. Additionally, pain-related catastrophizing (characterized by magnified pain and feeling helpless) affects treatment efficacy, with patients exhibiting high levels of catastrophizing often showing less benefit from treatments such as opioids, cognitive behavioral therapy, and other interventions [63]. The Pain Catastrophizing Scale is recommended for assessing this cognitive factor because it has strong predictive value for treatment outcomes across various pain conditions [61].

Sleep and fatigue

Sleep disruption has been shown to enhance pain sensitivity, chronic pain severity, and disability [64]. It is a significant risk factor for the development of persistent musculoskeletal pain, with pain and sleep disruption influencing each other bidirectionally [65]. Some studies have indicated that poor sleep quality may result in reduced treatment responses, particularly to opioids [66]. However, sleep disruption may predict better pain reduction with certain treatments such as pregabalin. Self-reporting tools such as the Pittsburgh Sleep Quality Index [67] and the Insomnia Severity Index [68] are commonly used to assess sleep in patients experiencing pain. Additionally, wrist actigraphy and fatigue measures such as the Multidimensional Fatigue Inventory can be helpful in phenotyping patients and predicting treatment outcomes, although pretreatment fatigue as a predictor of pain relief has not been extensively studied [69].

Role of biomarkers

Biomarkers play a crucial role in the diagnosis and management of painful DPN by providing objective measures for assessing nerve damage, inflammation, metabolic alterations, and central sensitization. Traditional diagnoses rely on clinical assessments, NCS, and patient-reported symptoms, which are often subjective and may not fully capture the underlying pathophysiological mechanisms of painful DPN. Biomarkers can enhance diagnostic accuracy, differentiate between painful and painless DPN, and guide personalized treatment strategies.

The metabolic biomarkers of painful DPN reflect metabolic stress and oxidative damage, which contribute to neuronal dysfunction. High AGEs levels have been associated with nerve damage and inflammation [4]. Although not a specific biomarker, glycosylated hemoglobin levels are correlated with DPN progression [70]. Lipid peroxidation markers (e.g., malondialdehyde and 4-hydroxy-2-nonenal) reflect increased oxidative stress due to lipid peroxidation and contribute to pain hypersensitivity [71]. Inflammatory biomarkers such as tumor necrosis factor-alpha (TNF-α), interleukin 1β (IL-1β), and high-sensitivity C-reactive protein, associated with inflammatory pathways, play a crucial role in neuropathic pain by activating nociceptors and sensitizing the nervous system. Elevated levels of these biomarkers are associated with pain severity in patients with painful DPN [72]. Neurotrophic factors regulate nerve regeneration and survival, and their dysregulation has been implicated in painful DPN. Reduced nerve growth factor (NGF) levels impair nerve regeneration and contribute to pain [73], whereas increased brain-derived neurotrophic factor levels are associated with central sensitization and pain persistence [74]. Altered levels of glial cell line-derived neurotrophic factor in patients with DPN suggest its role in peripheral nerve repair [75]. Finally, neurofilament light chain (a marker of axonal damage), is elevated in patients with painful DPN [76].

S100 calcium-binding protein B (associated with Schwann cell damage and pain severity) [77] and total tau protein (increased levels of which are linked to nerve degeneration and diabetic cognitive impairment) [78] have been suggested as neurodegenerative biomarkers of painful DPN. These biomarkers are useful in early detection (neurofilament light chain), pain stratification (NGF, TNF-α, and IL-6 can differentiate painful from painless DPN) and monitoring of treatment response (brain-derived neurotrophic factor, high-sensitivity C-reactive protein, and AGEs can track response to treatments such as gabapentinoids, SNRIs, and anti-inflammatory drugs). Thus, biomarkers can provide objective and quantifiable insights into the mechanisms underlying painful DPN. Metabolic, inflammatory, neurotrophic, and neurodegenerative imaging biomarkers can significantly enhance early diagnosis, pain stratification, and treatment monitoring. While more research is needed to standardize biomarker applications, they have significant potential for the personalized management of painful DPN.

PATHOPHYSIOLOGICAL MECHANISMS UNDERLYING DPN PHENOTYPES

Overview of DPN pathophysiology

DPN is a multifaceted disorder that arises from metabolic, vascular, inflammatory, and neurochemical abnormalities. Persistent hyperglycemia, dyslipidemia, and insulin resistance initiate a cascade of detrimental cellular processes, including mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress, inflammation, and epigenetic modifications, ultimately leading to progressive neuronal and glial cell damage. These cellular and molecular disruptions contribute to the nerve degeneration, altered pain perception, and sensory deficits that typify the disease.

Hyperglycemia is central to the pathogenesis of DPN and activates multiple deleterious biochemical pathways, including the polyol pathway, non-enzymatic glycation, protein kinase C activation, poly (ADP-ribose) polymerase activation, and dysregulation of the hexosamine biosynthetic pathway. Collectively, these pathways drive mitochondrial dysfunction, oxidative stress, and neuronal apoptosis [4]. Chronic hyperglycemia leads to excessive glucose metabolism, which produces reactive oxygen species that induce lipid peroxidation, mitochondrial DNA damage, and oxidative injury in neuronal cells. Oxidative stress impairs mitochondrial adenosine triphosphate (ATP) production, disrupts axonal transport, and triggers inflammatory responses, elevating the levels of pro-inflammatory cytokines such as TNF-α, IL-6, and nuclear factor kappa-light-chain-enhancer of activated B cells, all of which exacerbate neuronal damage [79]. Hyperlipidemia promotes the accumulation of neurotoxic lipid intermediates, further promoting Schwann cell apoptosis and neuronal loss [80].

In DPN, both myelinated and unmyelinated peripheral neurons are affected, with painful DPN primarily involving small Aδ and C fibers, and painless DPN involving large Aβ fiber dysfunction. Microvascular dysfunction exacerbates both conditions, as reduced blood flow contributes to nerve ischemia and pain hypersensitivity [81]. Structural alterations such as myelin degeneration, segmental demyelination, axonal atrophy, and Schwann cell apoptosis further compromise neuronal function and contribute to nerve degeneration [82].

DPN is also associated with central nervous system abnormalities, including increased risk of stroke, cognitive impairment, and depressive symptoms [83]. Structural and functional changes have been observed in the spinal cord, brainstem, thalamus, and somatosensory cortex, suggesting that central sensitization occurs early in the course of the disease [84].

Pathophysiology of painless DPN

Painless DPN is primarily characterized by progressive sensory deficits resulting from axonal degeneration, Schwann cell dysfunction, and mitochondrial abnormalities. One of the earliest signs is reduced thermal sensitivity, attributed to intraepidermal C fiber loss [85]. As the disease progresses, mitochondrial dysfunction leads to insufficient ATP production, impairing axonal transport and contributing to both sensory and motor deficits. Prolonged nerve ischemia and depletion of neurotrophic factors further accelerate nerve fiber loss [86]. Clinically, patients present with diminished perception of vibration and pressure—symptoms associated with large-fiber dysfunction and impaired myelin repair, as well as reduced thermal sensitivity, which is indicative of small-fiber dysfunction [87]. These changes often lead to a delayed diagnosis, as the absence of pain masks disease progression. Structural abnormalities in both the peripheral and central nervous systems, including axonal degeneration and demyelination, are detectable through neuroimaging and are associated with slowed nerve conduction [84]. Ultimately, the loss of protective sensation increases the risk of unrecognized injuries and serious complications such as DFUs [88].

Pathophysiology of painful DPN

Painful DPN develops on a background of chronic hyperglycemia and dyslipidemia, which drive the formation of AGEs, micro-ischemia, oxidative stress, and neuroinflammation [15,24]. These metabolic and vascular insults preferentially injure small Aδ and C fibers, lowering the activation thresholds and producing spontaneous discharges that manifest clinically as burning, shooting, or electric shock-like pain. Peripheral sensitization is reinforced by abnormal ion-channel activity—notably altered sodium, potassium, and calcium currents and overactivity of transient-receptor-potential (TRP) channels such as TRPV1, TRPA1, TRPM8, and P2X3—all of which foster ectopic firing and aberrant nociceptive signaling [77]. Neuroinflammatory mediators and neurotrophic factors such as NGF further amplify nociceptor excitability [89].

Because TRPV1 sits at the intersection of inflammatory and neuropathic pain signaling, it has become a key therapeutic target. Although systemic TRPV1 antagonists are limited by thermoregulatory side effects, repeated low-dose capsaicin can desensitize the channel, and high-dose topical formulations induce reversible terminal atrophy, providing prolonged analgesia [90]. Centrally acting agents that bolster descending inhibition—such as SNRIs and gabapentinoids—also reduce pain intensity and improve QoL in clinical trials [91].

These peripheral changes are paralleled by central sensitization: synaptic plasticity in the dorsal horn, thalamus, and cortex heightens pain gain, while dysfunction of descending noradrenergic and serotonergic inhibitory pathways sustains hypersensitivity [92]. The result is exaggerated responses to noxious stimuli (hyperalgesia) and pain elicited by normally innocuous stimuli (allodynia) that often extend beyond the initial site of nerve injury.

Neuropathic pain in painful DPN is generally confined to regions of sensory dysfunction and can be spontaneous or stimulus-evoked; non-neuropathic musculoskeletal pain may coexist and complicate diagnosis [93]. Altogether, painful DPN represents a highly complex interplay of peripheral and central sensitization, ion-channel dysregulation, oxidative stress, and neuroinflammation. Continued elucidation of these mechanisms is essential for the development of targeted therapies that effectively modulate nociceptive signaling while minimizing adverse effects.

TREATMENT EFFICACY: PROPOSING A FRAMEWORK FOR OPTIMIZING MANAGEMENT STRATEGIES

The primary treatment goal of DPN is to reduce pain intensity, prevent progression, and restore nerve function, with secondary objectives focusing on improving functionality, QoL, sleep, and mood. The initial approach for managing pain, including chronic pain, typically involves pharmacotherapy. However, neuropathic pain such as painful DPN differs significantly from musculoskeletal pain, and commonly used analgesics such as opioids are neither appropriate nor effective for chronic neuropathic pain [94]. Instead, treatment should focus on agents that specifically target neuropathic mechanisms to address the unique underlying causes of pain. Pharmacotherapies for managing painful DPN generally do not include traditional analgesics or opioids, although these can be used ‘as needed.’ Instead, they comprise medications such as anticonvulsants and antidepressants, which must be taken consistently over a period of time to achieve their full therapeutic effect [95].

An etiology-based classification of patients with painful DPN has proven insufficient because first-line treatments fail to provide relief in more than half of the patients. Recently, several promising drugs have failed in late-stage clinical trials. Improved patient stratification strategies may enhance treatment outcomes and the success of future clinical trials [96].

Clinical trials have investigated individualized treatments based on clinical phenotypes (Table 2) [13,97-101]. Despite these advancements, challenges remain in implementing phenotype-specific treatments, including the heterogeneity of DPN presentations, limited availability of targeted therapies, and the need for more comprehensive clinical trials. While significant progress has been made, the following challenges remain: (1) phenotype heterogeneity: clinical diversity complicates standardized treatment protocols; (2) biomarker validation: reliable biomarkers for phenotype-specific diagnoses are lacking; and (3) integrated care models: multidisciplinary approaches are not yet fully implemented in routine practice.

Pharmacological approaches

General treatments (summary of guidelines)

Recent guidelines for the pharmacological treatment of painful DPN recommend a stepwise approach, beginning with firstline agents such as TCAs, SNRIs, and gabapentinoids. Whether these are ineffective or not well tolerated, second-line options such as topical treatments and opioids may be considered. It is essential to tailor the treatment to the individual, considering factors such as efficacy, side effect profiles, and patient preferences.

(1) TCAs: Amitriptyline is a common TCA for the treatment of neuropathic pain. It works by increasing the levels of neurotransmitters such as serotonin and norepinephrine in the brain, which can reduce pain perception. However, TCAs may cause side effects such as dry mouth, constipation, urinary retention, and sedation, which can limit their use, especially in older adults [102].

(2) SNRIs: Drugs such as duloxetine and venlafaxine are effective at treating DPN because they boost the levels of serotonin and norepinephrine, which are neurotransmitters that help manage pain. Common side effects include nausea, dizziness, and sleep disturbances. However, these are often better tolerated than TCAs [103,104].

(3) Gabapentinoids: Gabapentin and pregabalin are anticonvulsants commonly used to treat neuropathic pain. They function by binding to calcium channels in the nervous system, thereby reducing the release of neurotransmitters involved in pain signaling. Although generally effective, these drugs can cause dizziness, somnolence, and peripheral edema, which can affect daily functioning [105,106].

Second-line treatments for painful DPN are generally administered when first-line agents (such as TCAs, SNRIs, or gabapentinoids) are ineffective or cause intolerable side effects. They included opioids, tramadol, topical lidocaine, and capsaicin.

(1) Opioids: Medications such as tramadol and strong opioids (e.g., morphine) are sometimes used when pain is severe and other treatments fail. Opioids bind to opioid receptors in the brain and spinal cord, thereby blocking pain signaling. However, opioids carry a significant risk of dependence, tolerance, and side effects such as constipation, drowsiness, and nausea, making them generally reserved for short-term or severe pain management. Opioid-induced adrenal insufficiency occurs when prolonged opioid use suppresses the hypothalamic-pituitary-adrenal axis, leading to cortisol deficiency [107]. It affects 9% to 29% of long-term opioid users and presents with nonspecific symptoms such as fatigue, musculoskeletal pain, and weight loss, making diagnosis challenging [108]. Treatment involves glucocorticoid replacement and opioid tapering, with many patients recovering their adrenal function after opioid reduction [109]. Increased awareness and further research are required to improve the detection and management of this condition.

(2) Tramadol: Tramadol is a centrally acting analgesic with opioid-like effects that inhibits the reuptake of serotonin and norepinephrine, making it effective against neuropathic pain. However, it can cause side effects such as dizziness, nausea, and a risk of seizures, particularly at higher doses, which limits its use [110].

(3) Topical lidocaine: A patch containing lidocaine (often 5%) can be applied to the skin over painful areas. Lidocaine blocks the sodium channels, which can help reduce the transmission of pain signals. This treatment has the advantage of being localized with minimal systemic side effects but may not be effective for everyone [111].

(4) Capsaicin cream: Capsaicin, derived from chili peppers, can be applied topically to the skin to reduce pain by depleting substance P, a neurotransmitter involved in pain signaling. Although effective in some patients, capsaicin can cause burning, irritation, or discomfort at the site of application [112].

(5) Alpha-lipoic acid (ALA), also known as thioctic acid, and γ-linolenic acid: ALA is the most frequently prescribed monotherapy for DPN in Korea, based on National Health Insurance Service-National Sample Cohort of Korea data [20,113]. It is a potent antioxidant that helps neutralize free radicals, which can cause cellular damage. Its therapeutic mechanism encompasses both symptomatic relief and potential pathophysiological impact. ALA has been shown to improve symptoms of diabetic neuropathy (such as pain, burning, and numbness), with the degree of effectiveness varying among individuals; however, there is limited evidence on its long-term efficacy. It has been suggested as a pathogenesis-oriented treatment for painful DPN [114]. The n-6 polyunsaturated fatty acid, γ-linolenic acid, is an essential component of structural phospholipids in neural cell membranes [115]. In patients with painful DPN (VAS score ≥4.0), it was noninferior to ALA in terms of reducing pain intensity measured over 12 weeks (≥40% reduction in VAS score; △ treatment for the VAS, –0.65 [95% confidence interval, CI, –1.526 to 0.213]: predefined noninferiority margin, δ1=0.51) [113]. Additional long-term RCTs on the differing effects of these antioxidant treatment modalities on the pathophysiology of nerve damage and how they result in different intensities of symptom profiles could further strengthen the rationale for their use in clinical practice.

There is considerable interpatient variability in response to analgesic therapy (even for efficacious treatments), which can be challenging in clinical practice. This has led to calls for ‘precision medicine,’ or personalized pain therapeutics (i.e., empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain, and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or patient subgroups that increase or decrease their response to a specific treatment must be identified [116].

Treatment examples based on clinical phenotypes

Specific pain symptoms and their combinations can provide relevant information regarding the underlying mechanisms [117]. These symptoms can be characterized by pain using validated questionnaires such as the NPS and NPSI. In addition, sensory signs can be identified through clinical testing such as QST [118]. Phenotypic profiling through several clinical trials has contributed to characterization of treatment effects on the sensory signs and symptoms of neuropathic pain (Table 2).

Oxcarbazepine, a sodium channel blocker, has shown promise in the treatment of painful DPN, especially for patients with specific pain characteristics. It is particularly effective in patients with an ‘irritable nociceptor’ phenotype characterized by heightened sodium channel activity [97]. Oxcarbazepine significantly reduced pain in patients with peripheral neuropathic pain in a RCT, especially in those reporting ‘paroxysmal’ or ‘burning’ pain and heat hyperalgesia, as measured by NPSI. Subgroup analysis revealed a statistically significant benefit over placebo (P=0.002) for patients with these symptoms. This evidence highlights the importance of identifying specific pain profiles to optimize treatment and suggests that oxcarbazepine is an effective option for treating neuropathic pain with these distinct features.

A randomized, double-blind comparison of pregabalin and duloxetine in patients with painful DPN suggested that the cluster of patients with the lowest baseline NPSI scores (i.e., the least neuropathic pain symptoms) responded better to duloxetine than to pregabalin (P=0.02 for the comparison of 8-week pain reduction), while the cluster with the highest baseline NPSI scores reported equivalent benefit from the two medications [13].

A recent MRI-based study examined the differences in pain phenotypes between responders and non-responders to intravenous lidocaine treatment in patients with painful DPN using QST. It explored the differences in brain structure and functional connectivity associated with treatment responses. Among the 45 screened patients, 29 met the eligibility criteria (responders, n=14; non-responders, n=15) and along with 26 healthy controls underwent detailed sensory profiling and multimodal brain MRI. A greater proportion of patients with an irritable nociceptor phenotype responded to intravenous lidocaine, with an odds ratio of 8.67 (95% CI, 1.4 to 53.8). Furthermore, responders had a significantly greater mean cortical volume in the primary somatosensory cortex and enhanced functional connectivity between the insular cortex and the corticolimbic circuitry than non-responders. These results provide preliminary evidence to support a mechanism-based approach for individualized therapy for painful DPN [98].

In another study of patients with DPN, a cluster analysis of approximately 900 patients diagnosed with peripheral neuropathy based on their typical QST profile divided the group into three clusters: sensory loss, thermal hyperalgesia, and mechanical hyperalgesia. There were no significant differences in sex, age, or pain intensity among clusters. However, depressive symptoms and TCA use were more common in the sensory loss cluster compared to the other clusters, while anti-convulsant use was more common in the thermal hyperalgesia cluster [119].

Other clinical studies have provided results that can help guide treatment decisions based on clinical phenotype. For example, patients with the greatest degree of pretreatment neuropathic pain symptoms may respond best to pregabalin or topical capsaicin treatment, whereas those reporting the least baseline neuropathic symptoms may benefit the most from duloxetine [116]. A study using botulinum toxin type A also reported that the drug only relieved burning, paroxysmal, and evoked pain among the pain phenotypes assessed using the NPSI and was not effective for deep pain or paresthesia [120]. In addition, preservation of thermal sensation is associated with a better response to botulinum toxin A in patients with peripheral neuropathic pain. In a cluster dominated by mechanical hyperalgesia, oral pregabalin [112], topical lidocaine [121], lamotrigine [122], and intravenous lidocaine [123] showed somewhat superior effects, suggesting that it may be beneficial to divide patients with neuropathy into these subgroups and administer different treatments. Several RCTs have reported that patients with mechanical (static or dynamic) allodynia have responded better to systemic lidocaine or lamotrigine than those without allodynia [123,124].

Although the treatment effect on patients with painless DPN have been less obvious than on those with painful DPN, a cluster with sensory loss as the main feature has shown a relatively superior response to oral opioids [125] and a poorer response to oxcarbamazepine [97].

Emerging pharmacologic treatments

Recent small-cohort clinical trials have investigated various vitamin supplements and novel agents for diabetic neuropathy, including oral ALA [126], vitamin E [127], vitamin D [128], EMA401 (Spinifex Pharmaceuticals, Stamford, CT, USA) [129], and the sodium channel blocker PF-05089771 [130]. However, most of these studies have yielded negative or inconclusive results, Emerging evidence has highlighted the role of inflammation in the pathogenesis of diabetic neuropathy, suggesting that anti-inflammatory treatments may offer new therapeutic options. Resveratrol, a polyphenolic compound with strong antioxidant and anti-inflammatory properties, is a promising therapeutic candidate [131]. Meta-analyses revealed that resveratrol reduced the levels of malondialdehyde, a marker of oxidative stress, while enhancing the activity of key antioxidant enzymes such as superoxide dismutase, catalase, glutathione, and glutathione peroxidase. Additionally, resveratrol effectively lowers levels of pro-inflammatory cytokines such as IL-1β, further supporting its potential to mitigate inflammation-driven nerve damage [132].

Non-pharmacological interventions

Life style modification

Prevention is crucial in patients with DPN owing to the lack of disease-modifying therapies. The American Diabetes Association guidelines for treating DPN recommend the addition of diet and exercise to glycemic control as critical therapeutic interventions for patients with type 2 diabetes mellitus (T2DM) and DPN [133].

Medical weight loss is a promising intervention for improving some DPN symptoms in patients with T2DM. Studies such as the Look Action for Health in Diabetes (Look AHEAD) trial, which followed over 5,000 participants for 9 to 11 years, found that dietary weight loss improved patient-reported outcomes (as measured by the MNSI questionnaire), but did not lead to improvements in clinical examination findings [134]. Similarly, an observational study involving an individual with severe obesity (average body mass index, 40.8 kg/m²) showed improved questionnaire scores but no changes in examination results after dietary weight loss. These findings suggest that although dietary interventions can help manage symptoms, earlier treatment or additional strategies may be needed to achieve more significant benefits [135].

Exercise interventions, although less extensively studied, have shown that patients with T2DM and DPN can experience improvements in IENFD, even with minimal weight loss. This indicates that exercise may benefit nerve health through mechanisms that are independent of weight loss. However, many exercise studies are limited by small sample sizes and lack of randomization, which underscores the need for more robust research in this area [136].

Cognitive behavioral therapy and mindfulness-based therapies may help reduce pain, improve QoL, and alleviate depressive symptoms in patients with DPN. However, current evidence is limited by small sample sizes, methodological weaknesses, and inconsistent findings. Larger, high-quality, multicenter randomized controlled trials are needed to confirm their long-term effectiveness and better tailor treatments to patient needs [137]. These approaches may be particularly beneficial given their success in the management of other chronic pain conditions such as fibromyalgia [138]. For patients who are unresponsive to a single treatment, combination therapy incorporating behavioral, pharmacological, or topical interventions may be more effective.

However, it remains unclear whether these approaches have differential effects depending on the presence or absence of pain in DPN, or according to specific clinical phenotypes within painful DPN, as no studies have yet reported on these distinctions.

Glycemic control

Glycemic control is the most effective disease-modifying therapy for DPN and is recommended as a first-line treatment. The efficacy of glycemic control in reducing DPN risk was most clearly demonstrated in the DM Control and Complications Trial/Epidemiology of DM Interventions and Complications study, which reported a 69% reduction in the incidence of distal symmetric polyneuropathy in patients with type 1 diabetes mellitus (T1DM) over 5 years of intensive glucose monitoring [139]. However, the benefits of glycemic control in reducing the incidence of DPN are limited in patients with T2DM. In the UK Prospective DM Study, which investigated glucose monitoring in patients with T2DM, the rate of DPN was not significantly reduced despite better glycemic control [139]. A Cochrane meta-analysis of 17 RCTs confirmed that glycemic control significantly reduced DPN risk in patients with T1DM (annualized risk difference, 1.84%), but had only a minimal, non-significant effect in those with T2DM (annualized risk difference, 0.58%) [140]. This difference may be due to the additional risk factors in T2DM, although glycemic medications can also target other issues such as hyperlipidemia and impaired insulin signaling [141]. An intervention targeting glucose, cardiovascular factors, lifestyle, and behavior significantly reduced the risk of autonomic neuropathies, but did not significantly affect DPN [142]. Therefore, more emphasis should be placed on developing therapies for T2DM and DPN that simultaneously address multiple risk factors.

Other treatment options

Spinal cord stimulation (SCS) has been developed as a neuromodulation therapy for severe painful DPN; however, its benefits in painless DPN may be limited. The evidence for SCS efficacy in painful DPN is low, with two low-quality multicenter RCTs showing significant pain reduction, but likely biased results [143]. A Cochrane review of 15 RCTs on chronic pain found low-quality evidence for the efficacy of SCS and highlighted serious side effects such as infection and lead displacement, recommending further research into neuromodulation of the dorsal root ganglion [144]. Therefore, the effectiveness of SCS remains controversial.

Nerve blocks using a combination of lidocaine and methylprednisolone were evaluated in 289 patients across two studies, yielding mixed results: one study found no benefit for pudendal neuralgia, whereas the other reported positive effects on pain related to nerve injuries. The overall quality of the evidence was moderate, indicating limited support for its use [145].

Studies on intrathecal methylprednisolone for PHN have shown mixed results; one study faced criticism for its inconsistent findings, whereas another found that combining it with midazolam was more effective [146]. In additional approaches such as central non-invasive neurostimulation [147] and pulsed radiofrequency, which targets the dorsal root ganglion through a catheter needle tip, are being explored for pain management, although further research is needed.

Emerging non-pharmacological therapies

A digital health platform for the remote monitoring of DFUs using smart offloading devices and behavioral metrics demonstrated improved risk stratification and patient adherence to treatment plans [148]. This highlights the potential of integrating digital health tools into DPN management to improve complications such as DFUs. Remote-monitoring platforms enhance patient adherence and improve the outcomes of DFUs.

Conductive hydrogels and advanced wound dressings promote nerve regeneration, modulate the neuroimmune microenvironment, and significantly improve nerve regeneration and wound healing in diabetic models [149]. In addition, studies on the nerve repair effects of hydrogels with biocompatibility, tunable properties, and the ability to create a supportive microenvironment are underway [150], demonstrating the possibility of using hydrogels as a treatment for DPN.

CONCLUSIONS

Interdisciplinary collaboration and innovation are critical for advancing this field and improving patient outcomes. Incorporating phenotype-specific approaches into clinical practice is highly promising for revolutionizing DPN management and ultimately enhancing the QoL patients affected by this complex condition.

Understanding and addressing the distinct phenotypes of DPN are essential for improving patient outcomes. The integration of advanced diagnostic tools and phenotype-specific therapeutic interventions offers a path toward precision medicine for DPN management. Continued research and development of innovative therapeutic measures are critical to address this pervasive complication of DM.

This review highlights the significance of recognizing the clinical phenotypes of DPN to enhance diagnostic accuracy and therapeutic outcomes. Personalized medicine can address the current limitations of DPN management by aligning treatment strategies with the specific characteristics of each phenotype. However, several significant challenges remain unresolved. The lack of robust phenotype-specific biomarkers and the complexity of conducting large-scale clinical trials have hindered the widespread adoption of personalized approaches. Collaborative research efforts are essential to overcome these barriers and validate novel therapies.

Future studies should focus on validating phenotype-specific biomarkers and integrating multidisciplinary approaches to optimize DPN care. This shift toward personalized medicine represents a critical advancement in the management of one of the most challenging complications of DM.

NOTES

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Conception or design: J.C.W.

Acquisition, analysis, or interpretation of data: J.E.L.

Drafting the work or revising: all authors.

Final approval of the manuscript: all authors.

FUNDING

None

ACKNOWLEDGMENTS

None

Fig. 1.

Clinical sensory phenotypes in diabetic peripheral neuropathy (DPN) and suggested phenotype-based treatment approaches. This figure categorizes DPN into three primary clinical sensory phenotypes—normal/subclinical, painful, and painless—based on the pattern of nerve fiber involvement and clinical presentation. The diagram below outlines recommended treatment strategies tailored to each phenotype. Based on findings from previous clinical studies, treatment preferences for each phenotype have also been indicated, reflecting medications shown to be more effective in specific symptom clusters. Painful DPN, typically associated with small-fiber damage, may benefit from agents such as duloxetine, pregabalin, or topical therapies. Painless DPN, more often linked to large-fiber dysfunction, requires vigilant foot care and fall prevention. Subclinical or early-stage presentations highlight the importance of screening and metabolic control. This phenotype-based approach supports more precise and effective management of DPN. TCA, tricyclic antidepressant; SNRI, serotonin-norepinephrine reuptake inhibitor; ALA/GLA, alpha-lipoic acid/gamma-linolenic acid; IV, intravenous.

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About this article

Lee JE, Won JC. Clinical Phenotypes of Diabetic Peripheral Neuropathy: Implications for Phenotypic-Based Therapeutics Strategies. Diabetes Metab J. 2025;49(4):542-564.

Received: Apr 07, 2025; Accepted: Jun 30, 2025

DOI: https://doi.org/10.4093/dmj.2025.0299.

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