The IASP formally established the terms NcP and NeP, and their definitions have evolved over time (1). In 1994, NeP was defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system (2), and, in 2011, as pain caused by a lesion or disease of the somatosensory nervous system (3). In 1994, the term NcP did not appear in the book published by the IASP (2). In 2001, NcP was defined as pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptor (3). In 2016, the IASP first introduced the term NpP (1) and, in 2017, formally adopted it (4).

Currently, the IASP defines NcP, NeP, and NpP as follows (5).

NcP is pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors (5). This term is designed to contrast with NeP (5). The term is used to describe pain occurring with a normally functioning somatosensory nervous system to contrast with the abnormal function seen in NeP (5).

NeP is pain caused by a lesion or disease of the somatosensory nervous system (5). NeP is a clinical description (and not a diagnosis) which requires a demonstrable lesion or a disease that satisfies the established neurological diagnostic criteria (5). The term lesion is commonly used when the diagnostic investigations (e.g., imaging, neurophysiology, biopsies, lab tests) reveal an abnormality or when there was obvious trauma (5). The term disease is commonly used when the underlying etiology of the lesion is known (e.g., stroke, vasculitis, diabetes mellitus, genetic abnormality) (5).

NpP is pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain (5). Patients can have a combination of NcP and NpP (5).

Several conceptual challenges remain. First, there is currently no evidence-based method to diagnose NpP as defined by the IASP. Second, the distinction between NeP and NpP depends largely on whether lesions can be detected using current diagnostic technologies, which may change in the future. Third, the coexistence of the unified NeP and the separate NeP, both merely labeled as “NeP,” represents a previously unrecognized academic ambiguity. Details are discussed in Sections 4.1 and 4.5.

Thapa et al. (6) and many others present specific conditions corresponding to NcP, NeP, and NpP. Table 1 lists the specific conditions that are generally recognized as typical conditions of each pain type. It is estimated that the typical conditions of NcP are post-traumatic pain and osteoarthritis, those of NeP are diabetic neuropathy and postherpetic neuralgia (PHN), and that of NpP is fibromyalgia (FM).

Kosek et al. emphasized that the proposal to introduce a third pain mechanism should itself be subject to debate (1). This “third mechanism” refers to the concept later proposed as NpP.

The three aforementioned types of pain are defined based on their etiology. NcP can be generally identified based on pain etiology. According to the IASP definition, NeP is diagnosed when a lesion or disease of the somatosensory nervous system accounts for the pain in cases not classified as NcP. Among pain that is not NcP, pain lacking such a lesion or disease is classified as NpP. Specifically, the level of medical knowledge and diagnostic technology at the time of diagnosis determines whether a lesion or disease can be identified to explain the etiology of pain. Whether such a lesion or disease is identified or not distinguishes NeP from NpP. Caution is warranted when relying on this method of classification.

For example, in ancient times, no lesions could be identified in Parkinson's disease. Ancient medical theories (e.g., demonic possession or ancestral curses) based on the inability to identify lesions have been rejected by current medical evidence. Lesions in Parkinson's disease have been identified using current advanced medical technologies. Similarly, any medical theories based on the inability to detect lesions with current technology—which is far less advanced than what may be available 100 years from now—may also become obsolete.

FM is generally considered a typical NpP. At present, no cerebral abnormalities suitable as diagnostic criteria have been identified; however, various cerebral abnormalities have been reported (7, 8). Many of those studies have been conducted using research-grade brain examination methods rather than those commonly used in clinical practice. Due to variability in the locations of abnormalities across studies, the specific brain region responsible for FM has not been determined. In the future, advancements in diagnostic technologies (including diagnostic equipment) may enable the detection of lesions that explain the etiology of pain. Therefore, FM may eventually be reclassified from NpP to NeP. Such a retransition could result in conceptual inconsistencies and contradictions.

NeP is typically divided into central NeP, arising from lesions in the central nervous system (CNS), and peripheral NeP, which arises from lesions in the peripheral nervous system. Traditionally, most cases of NeP have been considered peripheral NeP, whereas conditions currently described as NpP may share some features with central NeP.

Because NcP and NeP require markedly different treatments, distinguishing between the two types of pain is essential from both diagnostic and therapeutic perspectives. Pharmacological treatments for NcP include non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, whereas NeP is typically managed with serotonin–norepinephrine reuptake inhibitors (SNRIs), amitriptyline, and gabapentinoids (77). There is currently no established guideline for either the pharmacological or the non-pharmacological treatment of NpP. The treatment of FM, a typical NpP, closely resembles that of NeP. Kosek reported that the pharmacological treatment of NpP closely resembles that of NeP but differed from NcP (78).

Several medications have demonstrated efficacy in treating NeP associated with diabetic neuropathy and PHN, and these medications are also often used to treat NeP associated with other conditions (79). While the pharmacological and non-pharmacological treatments for diabetic neuropathy, PHN, post-stroke pain, spinal cord injury pain, and other NeP conditions differ in certain respects, the overall treatment strategies are largely similar. Likewise, while small distinctions exist between the treatment strategies for FM (a typical NpP) and various forms of NeP, from a practical perspective, they may be considered largely interchangeable. For clinicians specializing in pain treatment, especially those focusing on the pharmacological treatment of chronic pain, memorizing specific treatments for each pain subtype can be considered somewhat impractical. For physicians who are not pain specialists, remembering the distinctions between treatment strategies may be even more challenging. Antidepressants (SNRIs and amitriptyline) and gabapentinoids have shown efficacy in both NeP and FM (80, 81). Similarly, the non-pharmacological treatments such as exercise (82, 83), cognitive behavioral therapy (CBT) (84, 85), transcranial direct current stimulation (tDCS) (86, 87), and mindfulness-based interventions (88, 89) have shown efficacy in both NeP and FM. In clinical practice, treatments effective for FM have also been applied to NeP, and vice versa. This cross-application has broadened treatment strategies and may have contributed to improved clinical outcomes in both conditions. Placing emphasis on the subtle differences between treatments for NpP (or FM) and NeP is questionable in terms of clinical value, as the treatment strategies are largely similar, if not virtually identical. Because the treatments for NpP (or FM) and NeP are very similar, the clinical value of distinguishing between them is questionable.

The conceptual framework that emphasizes minor distinctions between treatments for NpP and NeP may complicate the overall approach to pain treatment. Pain is classified into seven categories (NpP + NeP + NcP, NpP + NeP, NpP + NcP, NeP + NcP, NpP, NeP, and NcP) based on the combinations of the three types of pain (see Figure 1). Even among clinicians specializing in pain treatment, particularly in the pharmacological treatment of chronic pain, making distinctions among these seven categories in clinical practice can be challenging. Moreover, clearly distinguished treatment strategies for each category have not been well established. From a treatment perspective, a clear distinction between NpP and NeP is often unnecessary. Non-specialist clinicians are likely to find pain diagnosis and treatment too complex, making it difficult for them to provide appropriate care. From both diagnostic and therapeutic perspectives, the distinction between NpP and NeP may be of limited clinical relevance.

Most questionnaires, as well as objective diagnostic methods, were developed before the IASP officially adopted NpP in 2017. Therefore, they cannot reliably distinguish between NpP and NeP. This challenge is particularly pronounced for questionnaires, which are used more frequently. Because NpP shares many clinical features with NeP, it is likely that some cases of NpP are classified as NeP in the context of these questionnaires. This challenge is discussed in greater detail later. As discussed later, FM, a typical example of NpP, is often classified as NeP by these questionnaires.

Therefore, caution is warranted when interpreting the results of these questionnaires as evidence of NeP in such contexts.

There are two conceptualizations of NeP: the unified NeP and the separate NeP. Currently, the same term NeP is used with different meanings. The term NeP in papers published before 2017 likely included the current NpP (i.e., the unified NeP). Therefore, the term NeP in papers published before 2017 thus differs from the current definition of NeP (i.e., the separate NeP). Caution should be exercised when interpreting the term NeP in papers published after 2017. If both NeP and NpP are mentioned in the same paper (90), the term NeP is generally the separate NeP. However, if only NeP is used in a paper, it is often difficult to determine whether the term NeP is the unified NeP or the separate NeP. As noted above, NeP in articles that use questionnaires to identify NeP is highly likely to represent the unified NeP (91). As a result, evidence regarding the prevalence, diagnosis, and treatment of NeP may be developed based on different conceptual frameworks, causing difficulties in accurate interpretation and comparison among studies. This confusion tends to be further exacerbated in narrative reviews, systematic reviews, and meta-analyses citing original papers. Similarly, the confusion tends to gradually worsen over time. This confusion is difficult to detect, and it is extremely challenging for non-specialist clinicians to recognize it. To the best of the author's knowledge, no published study has explicitly described the conceptual uncertainty arising from the simultaneous use of the unified NeP and the separate NeP. The most serious concern is that this conceptual uncertainty may go unrecognized, resulting in the continued accumulation of erroneous evidence and the entrenchment of an erroneous foundation for clinical medicine and basic research.

In this Section 4.6, a CSI score of 40 or higher is used as a diagnostic criterion for CS or CSS.

Iwasaki et al. reported that there was an association between NeP and CSS in patients with preoperative lumbar spinal stenosis using the painDETECT and CSI questionnaires (92). Feng et al. reported that CS was commonly seen in chronic pain disorders, including NeP (93). Mesci et al. reported that significantly higher NeP scores were found in patients with CS compared to those without CS (94). Thus, NeP and CS (or CSS) are closely associated.

Alp et al. reported that among 114 patients with psoriatic arthritis, 16 (66.7%) of the 24 patients with NeP also had CS, while 18 (36.7%) of the 49 patients with CS also had NeP (95). Kim et al. reported that among 316 patients who underwent primary unilateral total knee arthroplasty for end-stage osteoarthritis, 55 (17.4%) had both CS and NeP, 68 (21.5%) had CS only, 35 (11.1%) had NeP only, and 158 (50.0%) had neither condition (96). Among the 103 patients with CS (CSI ≥40), 68 (66.0%) also had NeP. Goldoni et al. reported that among 125 participants with knee osteoarthritis, 33 (26.4%) had both neuropathic-like symptoms (NS) and CS, 18 (14.4%) had NS only, 27 (21.6%) had CS only, and 47 (37.6%) had neither condition with NS assessed using the same diagnostic criteria as NeP (97). Among the 60 patients with CS (CSI ≥40), 33 (55.0%) also had NeP.

Leerling et al. reported that among 80 adult patients with chronic nonbacterial osteitis (CNO), 23 patients (29%) had pure NcP (NcP only, no NeP or NpP components), 2 patients (3%) had a combination of NcP and NeP, 32 patients (40%) had a combination of NcP and NpP, and 23 patients (29%) had a combination of NcP, NeP, and NpP (98). All patients with CNO naturally had NcP. Among the 55 patients with CS (CSI ≥40), 23 (41.8%) also had NeP. They used a CSI score ≥40 as one of the diagnostic criteria for NpP. Their diagnostic criteria for NpP differ from the conventional ones. In other words, NpP diagnosed using different criteria can coexist.

While only specialists need to understand leukemia treatment, all clinicians should understand pain treatment. Nearly all clinicians encounter and manage pain in their routine practice. Therefore, simplifying the diagnostic framework and treatment strategies—such as integrating NpP into NeP—could improve non-specialist clinicians' ability to provide more effective care.

Integrating NpP into NeP may streamline the pain classification framework. In this model, pain would be categorized into two primary types: NcP and NeP. Practically, because mixed pain states frequently occur, pain may be classified into three clinical categories: pure NcP, pure NeP, and mixed pain involving both NcP and NeP (see Figure 3). This simplified classification may facilitate both diagnosis and treatment planning.

Moreover, by unifying NpP with NeP, evidence related to treatment and epidemiology for each can be shared and applied across both conditions, potentially expanding treatment strategies. Broader treatment strategies may result in better treatment outcomes. As described in Section 4.3 Therapeutic Challenges, treatment for non-NcP pain is generally similar. These approaches are also applied to pain with an unknown diagnosis. Exceptions include the pharmacological treatment of trigeminal neuralgia (100), migraine [symptomatic medications (101) and preventive medications (102)], complex regional pain syndrome (103), and others. If exceptional diseases are excluded, there are three possible approaches: NcP treatment, NeP treatment, or a combination of the two. From both diagnostic and therapeutic perspectives, the distinction between NpP and NeP may be of limited clinical relevance.

When differing medical theories exist, it is reasonable to evaluate their utility from a therapeutic outcome perspective. Generally, a greater variety of treatment options can provide more opportunities for individualized and effective care. If treatment strategies traditionally associated with both NeP and NpP are applied within a unified framework, treatment options may be broadened, potentially contributing to better treatment outcomes.

The proposed integration of NpP into NeP also has another important implication. The term “psychogenic pain” is still occasionally used in papers (104–107), and in some cases, is used almost synonymously with NpP (107). For example, one recent study suggests that the CSI score is now thought to assess psychogenic pain (107). It is likely that most forms of pain, including NcP, are influenced by psychological states; however, this influence is distinct from the concept of psychogenic pain. According to the IASP definition, psychogenic elements are not included in the concept of NpP (5). Although the use of the term psychogenic pain appears to be gradually declining, it may still be more commonly encountered in actual clinical practice than in peer-reviewed papers, as it is often altered during the editorial review. Based on clinical experience in Japan, the term “psychogenic pain” is occasionally used, and such a diagnosis is sometimes made (104, 107). In particular, patients labeled as having psychogenic pain are often subjected to psychosocial burden and may be deprived of opportunities to receive appropriate care, raising serious concerns. The proposed reclassification may help reduce the use of this term, ultimately resulting in improved patient care.

In addition to clinical benefits, integrating NpP into NeP may also provide benefits for the scientific community. At present, basic research on NpP and NeP is often conducted separately, resulting in fragmented data and difficulties in comparing findings. In particular, the distinction between CS and NpP remains a major unresolved issue. A unified terminology would facilitate the integration of basic research and promote closer alignment with clinical diagnostic frameworks. Such consistency could accelerate the translation of basic science into clinical applications, ultimately benefiting both research progress and patient care.

Historically, pain research has focused on NcP, whereas NeP research focused on peripheral mechanisms. Because pure NcP is rare and NcP–NeP mixed pain and pure NeP are increasingly relevant, integrating NpP into NeP will likely focus future research on NeP, particularly central NeP. In this framework, FM may be recognized as a prototypical central NeP, due to its high prevalence, including incomplete forms, affecting over 20% of the population (108, 109). In acute pain (<3 months), pure NcP is present in a small proportion of cases (see Figure 4A). In chronic pain (≥3 months), it is nearly absent or may disappear entirely (see Figure 4B).