Among the top ten papers cited ( Table 5 ), the paper titled, “Chronic neuropathic pain is accompanied by global changes in gene expression and shares pathobiology with neurodegenerative diseases”, was published by Wang, H et al. in Neuroscience in 2002. This study proposed that NP and neurodegenerative diseases shared common pathophysiological characteristics. In recent years, studies have shown that microglia-mediated neuroinflammation, which is an important pathological basis for diseases including neurodegenerative diseases and NP, is a hot topic of interest for researchers. Interestingly, microglia and neuroinflammation were also found to connect NP to MS, PD, and AD in our keyword co-occurrence map ( Figure 4 ), suggesting a potential link between neurodegenerative diseases and NP ( Table 6 ).

Microglia-mediated neuroinflammation is an important pathological basis for the development of neurodegenerative diseases and is also closely associated with disease progression. Neuroinflammation is an immune response activated by microglia and astrocytes in the central nervous system (brain and spinal cord) and usually associated with direct damage to the nervous system. Neuroinflammation is present in MS, PD, AD and many other neurodegenerative diseases (17). Microglia are a major component of the intrinsic immune system of the brain and spinal cord and can respond rapidly when the body is exposed to injury or infection. Studies have shown that microglia could regulate neuroinflammation associated with neurodegenerative pathologies (18). Neurodegenerative diseases may involve neuronal apoptosis, which stimulates microglia activation and promotes inflammation. Persistent inflammation generates excess free radicals, which further exacerbate oxidative stress thereby generating excess reactive oxygen species and causing irreversible cellular damage. Cellular damage leads to cytokine necrosis, which causes apoptosis and further aggravates neuroinflammation. This forms a recurrent cycle ( Figure 7 ) that eventually induces central and peripheral sensitization, leading to NP (19, 20). According to the keyword analysis, MS, PD, and AD were the three categories of neurodegenerative diseases with the highest attention in this field.

MS is a chronic immune-mediated inflammatory demyelinating disease of the central nervous system and is one of the common neurodegenerative diseases (21). The main symptom of the disease is loss of motor and sensory function, and it is now becoming recognized that chronic pain is also a major problem that affects 50% to 80% of patients with MS. A highly cited systematic review by O’Conner et al. found that the point prevalence of pain in MS patients approached 50%, with approximately 75% of patients reporting pain within one month of assessment (22). Pain is a common complication of MS (23), and NP is a major mechanism of increased risk of pain in patients with MS (24). A systematic review showed an overall prevalence of chronic pain of 52.1% in 274 patients, with the lower extremities being most frequently involved (36.9%). Of these patients, 89 had NP, with an overall prevalence of 23.7%, and was associated with involvement of the sensory function system. Pain intensity was significantly higher in patients with NP than in patients without NP (25). Pain adversely affects family life, ability to work, etc., and pain in MS patients is affected by age, duration of the disease, degree of functional impairment, spasticity, depression, and fatigue (26, 27). Pain in MS patients includes extremity pain, trigeminal neuralgia (TN), Lhermitte’s sign, painful tonic spasms, back pain and headache (26, 28). Pain in MS is central in more than half of patients and is associated with mechanical or thermal nociceptive sensitization (29). In the co-occurrence map of keywords ( Figure 4 ), TN was one of the most important nodes linked to MS. Meanwhile, TN was linked to “neurovascular compression” and “microvascular decompression”. TN is the most characteristic NP in MS. Possible causes of MS-related TN include the destruction of main afferent nerves by pontine plaques, neurovascular compression, and demyelinating lesions affecting the nerves. Other sensory disturbances, including persistent pain and sensory deficits, can be caused by damage to secondary neurons in the spinal trigeminal complex (30–32). Figure 6 shows that “Experimental autoimmune encephalomyelitis” was a research frontier of interest for many researchers in 2018–2019. Because it shares many clinical and neuropathological characteristics with MS, it is widely used to study MS. Olechowski et al. found that inflammation and reactive glial cell proliferation could be key mediators of abnormal pain in female C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein MOG (35–55), and that model could serve as a tool to study NP in MS (33, 34). Other clinical and preclinical model studies also confirmed that demyelination and inflammation played an important role in the pathogenesis of NP in MS, and the progression of MS was associated with abnormal activation of microglia and astrocytes (29).

PD is a multi-system, progressive, incurable neurodegenerative disorder (35), associated with the loss of dopaminergic neurons in the substantia nigra of the brain. As the disease progresses, motor impairment and nonmotor symptoms are a considerable burden of disease. The outbreak graph for keywords ( Figure 6 ) shows that “nonmotor symptom” was one of the latest frontiers of research. Pain has been shown to begin with clinical episodes of PD or follow thereafter as a nonmotor feature of PD (36). Beiske et al. published the study titled, “Pain in Parkinson’s disease: Prevalence and characteristics” in Pain in 2009 (37). They conducted questionnaires, neurological examinations, and structured interviews with 176 family-living Parkinson’s patients, and found that pain was significantly more common in Parkinson’s patients compared to the general population. The prevalence of pain in the PD population is 40% to 85% (38). In patients with PD it is generally described as dystonic pain and non-dystonic pain. Of the non-dystonic sources of pain, there has been less research around central pain (39). Schestatsky et al. found that primary central pain in patients with PD was due to abnormal control of the effects of pain input on autonomic centers and that dysfunction may occur in dopamine-dependent centers that regulated autonomic function and inhibitory regulation of pain input (40, 41). Neuroinflammation is one of the hot spots of NP research in recent years and one of the important immune modulations in PD. It has been found that postmortem PD patients had a significant increase in reactive microglia in the substantia nigra (42) and significant activation of microglia had been observed in various animal models (43).This suggests that abnormal activation of microglia might lead to elevated pro-inflammatory factors and degeneration of dopaminergic neurons in the midbrain region, resulting in pain (44).

AD is also a common neurodegenerative disorder characterized by persistent neuroinflammation leading to overall cognitive decline and progressive loss of memory and reasoning skills (45). The amyloid cascade hypothesis proposes that the misfolded and aggregated β-amyloid protein (Aβ) triggers the pathological characteristics of AD, such as neuronal cell death (46, 47), which requires clearance to maintain normal neuronal function. Many patients with AD suffer from NP, and studies have shown that pain can cause cognitive dysfunction (48, 49), patients with pain in multiple parts of the body have a higher risk of dementia (50). Studies have shown that microglia-regulated neuroinflammation plays a key role in the pathogenesis of AD (51). Activated microglia have a dual role in the clearance of Aβ. Anti-inflammatory microglia activation contributes to Aβ clearance which reduces Aβ accumulation (17, 52), whereas pro-inflammatory microglia activation can induce dysregulated neuroinflammatory responses and leads to synapse loss, neuronal distress, and Aβ production (53, 54). The use of targeting microglia in the central nervous system can provide a new reference for diagnosis and intervention in AD.

The treatment of NP in neurodegenerative diseases is a great challenge due to the heterogeneity of etiology, symptoms, and underlying mechanisms. Treatment of NP can be divided into pharmacological and non-pharmacological treatments. Non-pharmacological treatments can continue to be divided into invasive and non-invasive treatments.

The main drugs currently used to treat NP are nonsteroidal anti-inflammatory drugs, opioids, antidepressants, and anticonvulsants. Anticonvulsants and antidepressants are the recommended first-line treatment drugs. “Gabapentin” and “cannabinoids” were the two drugs that appear on the map of keyword co-occurrence ( Figure 4 ), and “gabapentin” was also a frontier of research during 2001-2012. Among the top ten cited papers ( Table 5 ), there were 4 papers related to “gabapentin” and “cannabinoids”. These four papers are also among the top ten averages citations per year.

Gabapentin is an anticonvulsant. Studies have shown that gabapentin was particularly effective in relieving allergic reactions and nociceptive sensitization in animal models (55). The drug had been clearly shown to be effective in the treatment of NP in diabetic neuropathy (56) and postherpetic neuralgia (57). Its more favorable side effects and lack of drug-drug interactions in different patients (including the elderly) made it an attractive drug (58). Therefore, gabapentin was once considered an important drug for the treatment of NP syndromes (58, 59). Available studies have shown that short-term use (three months) could lead to adverse cardiovascular disease (60) while long-term use of gabapentin could damage musculoskeletal conditions (61–63). Knowing the potential complications can have a considerable impact on the treatment plan given by the clinician. When gabapentin is limited by adverse effects, the cannabinoid is emerging as a promising drug for the treatment of NP. The analgesic effects of exogenous cannabinoids have been extensively demonstrated in experimental models of NP, and there is growing evidence that cannabinoids can provide analgesia in situations that are difficult to treat with other treatments (64–66). However, the duration of treatment and the route of administration that provides better tolerability and safety are still lacking in-depth studies (67). Most guidelines recommend the use of monotherapy as the first and second treatment options (68, 69). Many years ago, researchers have suggested that drug combination therapy is also justified because NP results from multiple mechanisms, but few studies of combination therapy have been documented (70). Combining different medications can sometimes improve analgesia and/or tolerability (71), but the increased use of combination medications also poses some safety concerns. In 2022, Hahn et al. (72) found that opioid-gabapentin combination therapy, despite reducing gastrointestinal adverse effects, may also lead to an increased risk of central nervous system depression and death. A recent meta-analysis (73) compared the efficacy of combinations of two or more drugs with placebo or at least one monotherapy in adults with NP. Their findings failed to demonstrate that the combination of opioid-antidepressants, opioid-gabapentin, and gabapentin-antidepressants was superior to the two monotherapies. Thus, in cases where monotherapy has limited efficacy, combination therapy may be used as a complementary treatment but also requires close monitoring of individual doses to ensure safety.

In the map of keyword co-occurrence ( Figure 4 ), “microvascular decompression,” “gamma knife radiosurgery” were associated with MS and TN, and “deep brain stimulation” was associated with PD, suggesting that microvascular decompression, gamma knife radiosurgery, and deep brain stimulation were common non-pharmacological treatments for NP in neurodegenerative diseases such as MS and PD.

Among invasive treatments, microvascular decompression is considered a safe and effective vascular compression treatment for MS-related TN. It can also be recommended as the preferred procedure in some cases of MS (74). In addition, gamma knife radiosurgery is also an effective surgical treatment for MS-related TN (75–78).

In recent years, a number of non-invasive treatments have become popular with patients. Deep brain stimulation of the subthalamic nucleus has been shown to reduce the incidence of pain and improve the quality of life in patients with idiopathic PD with refractory motor fluctuations (79). In addition, studies have shown that anodal transcranial direct current stimulation reduced pain scores in patients with central chronic pain in MS, and this effect lasted beyond the stimulation period, resulting in long-term clinical effects (80, 81). Other studies have found that transcranial magnetic stimulation could improve motor and other symptoms associated with neurodegenerative processes such as NP, amyotrophic lateral sclerosis, MS, AD, PD, or Huntington’s disease (82).

Besides, exercise has been gaining popularity in recent years as a convenient and low-cost non-invasive treatment with multiple health benefits. In animal models of NP, several studies have found that exercise could reduce mechanical and thermal nociceptive sensitization (83, 84). Human studies have shown that moderate aerobic exercise, combining aerobic and resistance exercise, or high-intensity interval training, could reduce some NP. However, some indicators of NP such as thermal pain thresholds could not be improved (85). Exercise shows beneficial effects on NP in PD. Exercise acts on the muscle activity response, and myokines released during muscle contraction can modulate its activity by interacting with receptors in microglia. On the one hand, it can inhibit the pro-inflammatory mediators induced by microglia activation in PD, thus reducing the level of pro-inflammatory cytokines. On the other hand, it upregulates anti-inflammatory cytokines, which increases the anti-inflammatory level in the central nervous system and exerts neuroprotective activity (86). Exercise prevents cell death of dopaminergic neurons and modulates pain through dopaminergic and non-dopaminergic pain inhibitory pathways. However, it is not clear whether exercise exacerbates pain and impedes neuroplastic changes thereby affecting pain regulation in the central nervous system. In exercise training, there is still a need to avoid acute exacerbation of pain after exercise, while allowing for the establishment of physical activity tolerance (87). The pattern, intensity, frequency, and duration of exercise doses required for NP need to be systematically investigated (88).

The current treatment of NP in neurodegenerative diseases is mainly symptomatic, while mechanism-based treatments are lacking. Highly effective drugs are still lacking in pharmacological treatments.