Molecular Mechanisms of Chronic Pain and Therapeutic Interventions.

One has to consider that pain is rarely exclusively nociceptive or neuropathic. This highlights the need for a continuum‐based classification system for pain [ 7 ]. Mixed pain involves a complex interplay between nociceptive, neuropathic, and nociplastic pain types, occurring simultaneously or concurrently within the same anatomical region. The relative dominance of each mechanism may vary over time, leading to either acute or chronic mixed pain [ 16 ]. However, some mixed pain may also indicate the existence of an entirely distinct pathophysiological mechanism [ 303 ]. It is increasingly recognized that many pain conditions, particularly those related to cancer and spine pain, exhibit a mixed pain phenotype. A large study estimated that the prevalence of mixed pain among patients with chronic pain is over 50% [ 16 , 304 ]. Many professionals believe that the various forms of pain exist on a temporal continuum, with the main distinction between neuropathic and non‐NP being the lack of transduction in cases of NP [ 7 ]. This framework may provide an explanation for the occasional improvement of NP by NSAIDs, despite their primary efficacy in nociceptive pain [ 7 , 305 ]. Currently, the identification of mixed pain relies on clinical assessment through a comprehensive evaluation of patient's medical background and detailed physical examination, rather than relying on explicit screening or diagnostic criteria. This absence of standardized screening or diagnostic criteria for mixed pain poses challenges for primary care physicians who frequently come across patients exhibiting potential mixed pain conditions in their everyday practice [ 303 ]. Furthermore, its pathophysiology remains elusive, resulting in the absence of established treatment guidelines at present. There is a growing interest within the medical community regarding the subject of mixed pain. Each patient exhibits unique responses to various situations, interventions, surgeries, and medications. This holds particularly true in cases involving mixed pain scenarios, where distinct pain pathways are implicated. The adjustment of treatments and diagnosis for each individual is therefore crucial. A personalized combination of the aforementioned treatments, tailored to meet the specific needs of each patient, should be implemented. [ 306 ]

Zhen Li, Xing Li, Jieqiong Liu, Rao Sun, Yingze Ye, Hongbing Xiang, Fang Luo, Shiyong Li, and Ailin Luo made significant contributions to the content discussion and actively participated in writing, reviewing, and editing the manuscript prior to its submission. The final version of the manuscript was approved by all authors.

No ethical approval was required for this study.

Chronic pain persists beyond the anticipated period of tissue healing and can be further categorized into nociceptive pain, neuropathic pain (NP), and nociplastic pain (as shown in Figure  1 ) [ 7 , 12 ]. Nociceptive, neuropathic, and nociplastic pain result from diverse mechanisms [ 7 ]. Nociceptive pain refers to pain that results from the activation of primary afferent neurons’ peripheral terminals by noxious stimuli, or from damage or threat of damage to non‐neural tissue, and is proportional to the nociceptive input (Table  1 ) [ 2 , 7 , 10 ]. The nociceptive pain can be classified into two distinct categories: somatic nociceptive pain, which is typically localized precisely at the dermal level and characterized as pungent, lacerating, and burning; and visceral pain, which commonly manifests as a diffuse and indistinct sensation perceived in the body's mid‐line, specifically around the lower sternum or upper abdomen [ 13 ]. Chronic inflammatory pain is a form of nociceptive pain that arises from the hypersensitivity of nociceptors due to the activation of the immune system following tissue injury or infection, leading to the release of inflammatory mediators [ 9 , 14 ]. Significantly, studies showed that pure nociceptive pain is rare. The longer the duration of nociceptive pain, the higher the proportion of NP [ 15 , 16 ]. Illustrative drawing showing the various manifestations of nociceptive, neuropathic, and nociplastic pain, along with molecular mechanisms. Classification of chronic pain. Abbreviations: HIV, human immunodeficiency virus; IBS, irritable bowel syndrome. Chronic NP refers to persistent pain resulting from a lesion or disorder affecting the somatosensory nervous system (Table  1 ) [ 17 ]. It can arise due to conditions like diabetes and multiple sclerosis, physical trauma caused by injury or surgery, viral infections such as Herpes and human immunodeficiency virus (HIV), as well as chemotherapy medications like paclitaxel that impact the peripheral and/or central nervous system (CNS) [ 18 ]. The pain can occur spontaneously (without any external stimulus) or be triggered by an increased response to a painful stimulus (hyperalgesia) or a painful reaction to a normally nonpainful stimulus (allodynia) [ 19 , 20 ]. Common descriptors for nociceptive pain often include words like dull and pulsating, while NP is commonly characterized by adjectives such as piercing and radiating [ 7 ]. NP arises from persistent pathological changes in the functioning of the damaged nervous system. The diagnosis of NP necessitates a history of injury or disease affecting the nervous system, along with a neuroanatomically plausible distribution pattern for the experienced pain [ 18 , 20 ]. In the recently published ICD11 classification, NP is categorized into either peripheral or central NP depending on whether the lesion or disease affects the somatosensory nervous system in the periphery or centrally [ 20 , 21 ]. Statistically, approximately 15–25% of chronic pain is neuropathic, with the most prevalent conditions being diabetic neuropathy (DN), radiculopathy, and postherpetic neuralgia [ 22 ]. The term nociplastic pain was introduced in 2016 to delineate a distinct pain mechanism, separate from both nociceptive and NP [ 23 ]. According to the IASP, nociplastic pain is defined as “pain that arises from altered nociception despite the absence of clear evidence indicating actual or potential tissue damage activating peripheral nociceptors, or any indication of disease or lesion within the somatosensory system causing the pain” (Table  1 ) [ 23 ]. Nociplastic pain is characterized by diffuse body discomfort, often accompanied by fatigue and disturbances in sleep, mood, and cognition, as well as multisensory hypersensitivity. This type of pain is widely believed to be prevalent and influential in various chronic pain conditions such as fibromyalgia, low back pain, and headache. Although the precise etiology (or etiologies) of nociplastic pain remains elusive, factors such as female gender, trauma exposure, disrupted sleep patterns, early‐life stressors, heightened somatic awareness, and sedentary lifestyle contribute to an increased susceptibility to nociplastic pain [ 24 , 25 ]. While the suggested definition implies that nociplastic pain is a separate category devoid of any existing or potential tissue or somatosensory harm, available evidence suggests a potential overlap of nociceptive, neuropathic, and nociplastic pain. This suggests that rather than being a distinct entity, nociplastic pain should be considered as part of a chronic pain continuum [ 23 , 24 , 25 ]. The term mixed pain, for instance, has been employed to characterize conditions such as cancer pain that may involve nociceptive, neuropathic, and nociplastic elements [ 26 ]. This phenomenon is observed in individuals who experience both nociceptive pain (e.g., rheumatic disorders) and NP (e.g., small fiber neuropathy), where the presence of comorbid fibromyalgia is often identified as concurrent nociplastic mechanisms [ 27 ].

The mechanisms underlying nociplastic pain remain incompletely understood; however, it is believed that increased sensitivity to pain in CNS and sensory information, coupled with changes in pain regulation, are considered significant factors [ 25 ]. Central sensitization pertains to the enhancement of nociceptive transmission in the dorsal horn of the spinal cord, leading to subthreshold sensory stimuli acquiring the capability to generate APs along pain pathways [ 24 , 246 ]. Undoubtedly, central sensitization provides a mechanistic rationale for the manifestation of pain symptoms like allodynia and hyperalgesia in individuals experiencing nociplastic pain [ 24 , 246 ]. The pathophysiology of central sensitization is characterized by enhanced excitatory signaling through glutamate and reduced GABA expression (as shown in Figure  4 ). Imbalances in excitatory and inhibitory neurotransmitters within spinal and brain regions have been demonstrated to be closely associated with the development of nociplastic pain in both animal models and patients experiencing this condition [ 24 , 246 ]. A recent study has also demonstrated that an increased excitatory tone in the anterior insula, compared with inhibitory tone, is associated with hyperalgesia and clinical pain in patients with fibromyalgia [ 247 ]. Moreover, microglia release proinflammatory cytokines and pronociceptive neurotrophic factors into the CNS, thereby promoting the development of neuroinflammation and central sensitization (delayed rectifier) [ 246 , 248 ]. Neuroimmune mechanisms relevant to nociplastic pain syndromes in both the peripheral and CNS. Nociplastic pain syndromes involve a variety of complex pathophysiological mechanisms, primary including neuroimmune interactions, central sensitization, monoaminergic unbalance, and peripheral sensitization. The increased neutrophils and SGCs in sensory ganglia is crucial for the promotion of heightened pain sensitivity and sensitization of dorsal horn cells to harmful stimulation in nociplastic pain. The upregulation of pronociceptive molecules, such as TNF‐α, IL‐1β, and HMGB1, released from glial cells enhance neuroinflammation and pain signaling in CNS. For example, microglia TLR4 activation by HMGB1 contributes to microglia stimulation and neuroinflammation leading to the development of chronic nociplastic pain. Activation of TLR4 and TLR7 has been shown to enhance the activity of TRPV1 and TRPA1 channels, respectively, thereby facilitating neuronal excitability through enhancing Ca 2+ influx, substance P as well as CGRP release. Enhanced excitatory signaling through glutamate and reduced GABA expression in the CNS contributes to central sensitization. Moreover, microglia release proinflammatory cytokines and pronociceptive neurotrophic factors into the CNS, thereby promoting the development of neuroinflammation and central sensitization. The descending pain modulatory system, involving endogenous opioids, noradrenaline, serotonin, dopamine, and endocannabinoid, plays an important role in the development of nociplastic pain. AMPA indicates a‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor; BDNF, brain‐derived neurotrophic factor; CGRP, calcitonin gene‐related peptide; CNS, central nervous system; GABA, gamma‐aminobutyric acid; α5‐GABA, α5 subunit containing GABA type A; HMGB1, high‐mobility group box 1 protein; IL‐1β, interleukin‐1 beta; NGF, nerve growth factor; NMDA, N‐methyl‐D‐aspartate receptor; PAG, periaqueductal grey; RVM, rostral ventromedial medulla; TNF‐α, tumor necrosis factor alpha; TLR, Toll‐like receptor; TRPV1, transient receptor potential vanilloid 1. The red arrow signifies an increase or decrease, while other‐colored arrows indicate secretion. The plus sign (+) signifies promotion. The excitatory neurotransmitter plays a crucial role in the mechanisms underlying nociplastic pain [ 246 ]. Numerous investigations have demonstrated elevated levels of glutamate and glutamine, especially in the insula and posterior cingulate regions, which are commonly linked to increased severity of clinical pain in patients with fibromyalgia [ 249 , 250 ]. A recent meta‐analysis found indications of increased levels of glutamate and glutamine in the insula and posterior cingulate regions among different types of chronic pain conditions, including migraine, fibromyalgia, temporomandibular disorder, irritable bowel syndrome (IBS), cLBP, and pelvic pain, when compared with control groups [ 24 , 251 ]. Additionally, the effectiveness of ketamine in alleviating pain is apparent through both preclinical and clinical research [ 252 , 253 ]. This collective evidence presented further supports the crucial role of glutamate in the establishment and maintenance of nociplastic pain [ 24 , 246 ]. Disturbance of equilibrium between excitatory and inhibitory inputs in central sensitization highlights the pivotal role of GABA in the dysfunction of pain pathways. In this context, GABA levels exhibit a reduction in the brains of mice and rats experiencing pain resembling fibromyalgia [ 254 , 255 ]. Clinical investigations support this narrative, as evidenced by the observed decrease in GABA levels in the anterior insular cortex of 16 patients with fibromyalgia [ 256 ]. However, the expression of α5‐GABA A receptor, which is an extra synaptic receptor for GABA, shows an increase in a pain model resembling fibromyalgia [ 257 ]. Additionally, alleviation of reserpine‐induced fibromyalgia in rats can be achieved through the blockade of spinal α5‐GABA A receptors [ 257 ]. These findings reinforce the key role of impaired GABAergic tone in nociplastic pain conditions. The descending pain modulatory system (DPMS) governs neural activity within the spinal dorsal horn and exerts an impact on the transmission of nociceptive signals from peripheral regions to the CNS [ 24 ]. The DPMS comprises the ACC (Anterior Cingulate Cortex), hypothalamus, amygdala, periaqueductal grey (PAG), and RVM. Research has demonstrated that individuals with nociplastic pain exhibit impairments in DPMS‐mediated pain modulation, as indicated by decreased activity and functional connectivity within these brain regions [ 24 ]. The key neurotransmitters implicated in the DPMS involve endogenous opioids, noradrenaline, serotonin, and dopamine (as shown in Figure  4 ) [ 24 , 246 ]. Patients with nociplastic pain exhibit reduced levels of noradrenaline, serotonin, and dopamine in the CSF [ 258 ], while the levels of endogenous opioids in the CSF are increased [ 259 ]. Additionally, individuals with fibromyalgia exhibit a reduction in the number or availability of μ‐opioid receptors in the brain [ 260 ]. These data suggest that those experiencing nociplastic pain may have elevated levels of endogenous opioids, consequently leading to hyperalgesia induced by endogenous opioids [ 260 ]. The biochemistry results align with clinical observations indicating the inefficacy or potential exacerbation of nociplastic pain by opioids [ 261 ]. Supporting this hypothesis further, preliminary findings indicate that the use of low doses of naltrexone, an antagonist for the μ‐opioid receptor, can effectively alleviate fibromyalgia [ 262 ]. The decrease in serotoninergic neurons corresponds to a reduction in serotonin levels observed in nociplastic pain paradigms within the spinal cord, highlighting the crucial involvement of serotonin in modulating nociplastic pain [ 263 ]. In reality, the administration of serotonin reuptake inhibitors results in an increase in serotonin levels and subsequently elicits analgesic effects in a fibromyalgia model [ 264 ]. Furthermore, administration of 5‐HT(2C) receptor agonists systemically demonstrates effective alleviation of muscular hyperalgesia in a myalgia model induced by reserpine [ 265 ]. These results accentuate the therapeutic potential of serotonin reuptake inhibitors and serotonin agonists in nociplastic pain [ 246 ]. It is worth noting that serotonin has both pain‐relieving and pain‐promoting effects in chronic pain, with its actions dependent on the specific receptors activated. This highlights the complex role of the serotonergic system in regulating pain [ 266 ]. The nociceptive information is also facilitated by noradrenaline through the descending pain pathways [ 267 ]. Various clinical studies highlighted the variations in noradrenaline levels detected in both serum and CSF among individuals with fibromyalgia, indicating its substantial role in the pathophysiology of nociplastic pain [ 258 , 268 , 269 ]. In line with this, animal models have presented additional findings indicating decreased levels of noradrenaline in the spinal cord and specific regions of the brain in experimental fibromyalgia models [ 263 ]. Notably, the effectiveness of dual reuptake inhibitors that act on both noradrenaline and serotonin systems (e.g., atomoxetine, duloxetine, and milnacipran) has been shown to relieve heightened sensitivity of muscles [ 270 ]. Additionally, a clinical study revealed that daily administration of duloxetine resulted in a reduction in pain severity among patients with IBS [ 271 ]. The disrupted reward circuitry in chronic pain states has been demonstrated by numerous studies. Individuals with fibromyalgia exhibit an abnormal dopamine response to pain in the striatum [ 272 ], which aligns with similar findings observed in individuals with cLBP [ 273 ]. Consistent findings from diverse investigations consistently highlight a decrease in dopamine concentrations in CSF and serum, accompanied by impaired functioning of presynaptic dopamine receptors among individuals with fibromyalgia [ 274 ]. Moreover, pharmacological manipulation of dopamine receptors leads to a reduction in hypersensitivity within a pain model resembling fibromyalgia [ 275 , 276 ]. Additionally, it has been reported that the activation of dopamine D2 receptors effectively suppresses chronic migraine by inhibiting the positive feedback loop involving GluA2/ROS in both in vivo and in vitro experiments conducted on rats [ 277 ]. Retrograde signaling involves the generation of an endocannabinoid in response to postsynaptic activity, which then travels backward across the synapse and attaches to presynaptic CB1 receptors (CB1Rs), ultimately regulating the release of neurotransmitters through inhibition. As a result, this binding process usually leads to a reduction in pain pathway signaling within nociceptive neurons [ 278 ]. In addition, cannabinoids have the potential to facilitate the release of GABA and glutamate neurotransmitters in the PAG, leading to direct stimulation of descending inhibitory pain pathways and enhancing their antinociceptive properties [ 279 , 280 ]. Reduced levels of anandamide in the CSF of migraine patients may also indicate an impairment of the endocannabinoid system within these patients [ 281 ]. However, there is evidence supporting elevated levels of circulating endocannabinoids among fibromyalgia patients [ 282 ]. In summary, nociplastic pain patients and animal models consistently exhibit elevated levels of opioids and decreased levels of serotonin, noradrenaline, and dopamine. Manipulating these neurotransmitters through various receptors shows promising therapeutic effects [ 24 , 246 ]. While nociplastic pain may not exhibit any discernible injury or inflammation, recent findings highlight the substantial involvement of immune system components in its underlying mechanisms [ 24 , 246 ]. For instance, mice with reserpine‐induced fibromyalgia exhibited a significant rise in proinflammatory cytokines like TNF‐α and IL‐1β in their bloodstream, which correlated with the increased activity of NLRP3 inflammasome [ 254 , 283 ]. In similar, in the acid saline‐induced fibromyalgia model, there was an elevation observed in levels of IL‐1β and IL‐6 [ 284 ]. Furthermore, administering IL‐10 into the muscles effectively reduced hyperalgesia after acid saline injections [ 285 ]. Despite this preclinical evidence, traditional treatments such as anti‐inflammatory or immunosuppressive therapies have proven ineffective in addressing classic nociplastic pain conditions like fibromyalgia, IBS, tension headache, and interstitial cystitis/bladder pain syndrome [ 246 ]. On the contrary, research on CSF samples from individuals with fibromyalgia indicates that inflammatory molecules and signaling pathways exhibit heightened activity in the CNS during nociplastic pain compared with healthy individuals [ 286 , 287 ]. These findings indicate that sensitization through inflammatory signaling in CSF and CNS may serve as a potential pathophysiological mechanism for nociplastic pain conditions (as shown in Figure  4 ) [ 24 , 288 ]. Microglial polarization and microgliosis are the primary hallmarks of neuroinflammation and serve as drivers of nociplastic pain [ 248 ]. Evidence from positron emission tomography studies suggests dysregulation of microglia and astrocytes in nociplastic pain conditions [ 289 ]. Indeed, activation of microglia through various neuromolecules, including ATP and Substance P, plays a vital part in the development of nociplastic pain [ 248 , 290 , 291 ]. The activation of microglial TLR has also been demonstrated to contribute to the stimulation of microglia and neuroinflammation, ultimately leading to nociplastic pain [ 292 ]. Increased glial activity in nociplastic pain is a potential mechanism by which TLR4 antagonists (like naltrexone) relieve pain in fibromyalgia, although regulation of endogenous opioidergic tone is also a plausible hypothesis [ 262 ]. TLR4 is typically found on sentinel immune cells, as well as astrocytes and microglia in the brain and spinal cord [ 246 , 293 ]. TLR4 has been suggested to play a significant role in the development of nociplastic pain syndromes, such as fibromyalgia, stress‐induced, and sleep deprivation‐induced pain [ 246 ]. Reactive activation of microglia TLR plays a role in stimulating microglia and promoting neuroinflammation, ultimately resulting in the emergence of persistent nociplastic pain [ 248 ]. Indeed, the activation of TLR4 and TRL7 has been shown to enhance the activity of TRPV1 and TRPA1 channels, respectively, thereby facilitating neuronal excitability in individuals with fibromyalgia [ 246 , 294 ]. The stimulation of TLR4 in whole blood is associated with elevated release of cytokines and chemokines in various pain syndromes, such as chronic fatigue syndrome, endometriosis, fibromyalgia, IBS, migraine, and low back pain [ 295 , 296 ]. In addition, the activation of TRPA1 channels leads to the secretion of substance P and CGRP from peripheral terminals, thereby facilitating neurogenic inflammatory responses [ 297 ], which is presently acknowledged as a prominent mechanism underlying migraine [ 298 ]. Peripheral mechanisms likely play a role in nociplastic pain, but their specific contribution to its development is still debated [ 24 ]. Injection of IgG from individuals with fibromyalgia into mice induced hyperalgesia and enhanced nociceptor responsiveness [ 299 ], although an independent research group failed to replicate this effect [ 300 ]. The results of subsequent investigations have demonstrated that IgG specifically attaches to anti‐SGCs in patients with fibromyalgia, and the extent of this attachment is correlated with the severity of the disease [ 301 ]. Meanwhile, a recent investigation has revealed that the presence of neutrophils in sensory ganglia is crucial for the promotion of heightened pain sensitivity and sensitization of dorsal horn cells to harmful stimulation in fibromyalgia. These effects were found to be reversible upon depletion of neutrophils, providing evidence for a mechanism in which CNS sensitization depends on neutrophil activity [ 300 ]. The consensus among these studies is that the DRG plays a potentially significant role in contributing to pain hypersensitivity observed in nociplastic pain models. Additionally, the involvement of sodium channel proliferation has been proposed to have a substantial impact on the development of nociplastic pain [ 7 ]. Furthermore, it is commonly observed that the sympathetic nervous system exhibits increased activity in conditions characterized by diffuse pain such as fibromyalgia and IBS [ 7 ]. Consistent with this, the interaction between inflammation and the autonomic nervous system can exacerbate endometriosis and is closely correlated with endometriosis‐associated pain [ 302 ].

The guidelines for managing chronic pain may vary depending on whether they pertain to symptom treatment (such as neuropathic or back pain) or a specific condition (like knee OA). Additionally, the perspective of the authors and their respective specialties (surgical or nonsurgical) can influence the content of guidelines [ 7 , 307 ]. The optimal approach to pain treatment is mechanism‐based; however, in clinical practice, it can be challenging or even impossible to identify the underlying mechanisms of pain. Therefore, the management usually depends on approaches that target symptoms or diseases (as showed in Tables  2 and  3 ). For many patients, therapy goals should be individualized to focus on enhancing quality of life, which may be more attainable than achieving significant pain reduction [ 7 ]. Pain is a complex outcome resulting from various biological, psychological, and social factors; therefore, interdisciplinary treatment has been recommended in guidelines to optimize outcomes. Ideally, this approach should incorporate personalized strategies within a shared decision model [ 308 , 309 ]. Recommended medications for different types of pain. Abbreviations: ASICs, acid‐sensing ion channels; CGRP, calcitonin gene‐related peptide; COX, cyclooxygenase; CPPP, chronic postoperative pain; CRPS, complex regional pain syndrome; DN, diabetic neuropathy; DPMS, descending pain modulatory system; mTOR, mammalian target of rapamycin receptor; NMDAR, N‐methyl‐D‐aspartic acid receptors; NP, neuropathic pain; OA, osteoarthritis; SNRIs, serotonin–norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TRPA1, transient receptor potential A1; TRPV1, transient receptor potential vanilloid 1; VGSCs, voltage‐gated sodium channel. Recommended nonpharmacological therapies for different types of pain. Abbreviations: CIN, chemotherapy‐induced neuropathy; cLBP, chronic low back pain; CPPP, chronic postoperative pain; CRPS, complex regional pain syndrome; DN, diabetic neuropathy; DPMS, descending pain modulatory system; IBS, irritable bowel syndrome; OA, osteoarthritis. The first‐line treatments for nociceptive pain include topical and oral NSAIDs. Compared with NSAIDs, acetaminophen (paracetamol) does not possess anti‐inflammatory properties. The efficacy of muscle relaxants has been demonstrated in the treatment of acute spinal pain, but there is limited evidence supporting their use for chronic neck or back pain [ 347 ]. Scant evidence exists regarding the effectiveness of benzodiazepines among different muscle relaxants [ 347 ], as they can lead to physical dependence and elevate the likelihood of complications associated with opioids [ 348 ]. The analgesic antidepressants have demonstrated efficacy in the treatment of low back pain, despite being specifically indicated for NP [ 347 ]. Among the numerous available NSAIDs, ibuprofen, diclofenac, and ketoprofen continue to be the most commonly utilized [ 349 , 350 ]. Primary indications for the use of NSAIDs include CPPP, acute arthritis, traumatic pain, RA, and various other disorders affecting the joints and connective tissues. It should be noted that not all NSAIDs possess identical characteristics. Specifically, when selecting the appropriate NSAIDs for an individual patient, it is crucial to consider medication‐related factors (such as pharmacokinetic properties) as well as patient‐related characteristics (including comorbidities, and potential adverse effects) [ 349 ]. Corticosteroids are frequently used in the treatment of inflammatory pain [ 351 ]. According to the EULAR guidelines, corticosteroids are recommended as a viable and efficient option for pain management associated with crystal‐induced arthritic conditions in cases where NSAIDs are poorly tolerated [ 352 , 353 ]. Furthermore, platelet‐rich plasma therapy has been demonstrated to effectively alleviate various types of OA pain by promoting chondrocyte proliferation and facilitating the development of cartilage matrix, while inhibiting the production of inflammatory factors [ 354 , 355 ]. Biologic drugs may be beneficial in the management of nociceptive pain. Anakirna, an antagonist of IL‐1 receptors, demonstrated a significant reduction in gout pain [ 356 ]. The IL‐1 inhibitors rilonacept and canakinumab have also demonstrated efficacy in reducing the inflammatory pain associated with gout [ 357 ]. The involvement of NGF in pain signaling associated with OA has been observed, suggesting its potential role [ 349 ]. Furthermore, the United States Food and Drug Administration (US FDA) has granted approval for tanezumab, a humanized monoclonal IgG2 antibody that effectively inhibits the binding between NGF and TrkA receptors, specifically for treating OA and lower back discomfort [ 358 ]. The recombinant fully human anti‐NGF antibody, fasinumab, is currently undergoing clinical trials and holds promising potential as a therapeutic intervention for OA [ 352 ]. NTP is commercially available for the management of chronic painful conditions related to inflammation in Asia. Its mechanism involves the suppression of descending pain pathways and inhibition of inflammatory signaling and cell death pathways [ 349 , 359 ]. The natural antimitotic alkaloid, colchicine, is widely utilized in the treatment of gout [ 349 ]. Colchicine can effectively alleviate pain and inflammation associated with crystal‐induced arthritis, which is characterized by intense inflammatory processes triggered by the deposition of crystals in synovial tissues [ 360 , 361 , 362 ]. Overall, the treatment of nociceptive pain needs to take into account the type of pain, the specific situation of the patient, and the degree of inflammatory response to formulate an individualized treatment plan. Furthermore, treatment strategies should be continuously updated and optimized as our understanding of the mechanisms behind nociceptive pain deepens. The management of NP primarily focuses on symptomatic treatment due to the limited efficacy in addressing the underlying cause; moreover, addressing etiological conditions such as diabetes mellitus often fails to provide adequate relief from NP. Patients with NP typically exhibit poor responsiveness to analgesics like acetaminophen, NSAIDs, or weak opioids. The conventional approach to managing NP in patients involves commencing treatment with conservative pharmacological and complementary therapies prior to considering the implementation of interventional techniques like nerve blocks and neuromodulation [ 18 ]. The first‐line medications for NP are analgesic antidepressants and antiepileptic drugs. Pregabalin and gabapentin have emerged as the preferred treatment options and have received US FDA approval for managing NP associated with DN, spinal cord injury, and postherpetic neuralgia [ 18 , 329 , 330 ]. Gabapentinoids have demonstrated efficacy primarily in two distinct types of NP: postherpetic neuralgia (with a minimum 50% reduction in pain reported by 41% of patients for pregabalin and 32% of patients for gabapentin) and DN pain (with a minimum 50% decrease in pain reported by 41% of patients for pregabalin and 38% of patients for gabapentin) [ 363 , 364 ]. Other studies have demonstrated a moderate impact of gabapentinoids on alleviating NP caused by spinal cord injury, while their impact on central NP and HIV‐induced NP remains contradictory [ 364 , 365 ]. However, limited research has been conducted to evaluate their efficacy in other forms of NP [ 366 ]. Pregabalin also demonstrates superior effectiveness in managing post‐total joint arthroplasty compared with gabapentin [ 331 ]. In contrast, the PROSPECT guidelines suggest caution or limited endorsement for gabapentinoids in managing various other forms of postoperative pain due to their unfavorable risk‐benefit ratio [ 367 ]. Among the various classes of antidepressant medications, TCAs (such as nortriptyline hydrochloride and amitriptyline hydrochloride), as well as SNRIs (such as duloxetine hydrochloride and venlafaxine hydrochloride) are indicated for the treatment of NP [ 7 , 330 , 368 ]. Among TCAs, amitriptyline is the most commonly prescribed medication for the treatment of postherpetic neuralgia, DN pain, and central NP [ 369 ]. Among SNRIs, duloxetine and venlafaxine are primarily utilized for DN and are endorsed by the NeuPSIG and European Federation of Neurological Societies as first‐line therapies for NP [ 366 ]. The overall effect of SSRIs is to suppress pain; however, clinical trials have demonstrated that the efficacy of SSRIs is comparatively lower than that of TCAs or SNRIs, potentially due to receptor interactions counteracting their effects [ 370 ]. According to the research, SSRIs only alleviate pain in approximately 14% of patients suffering from chronic NP [ 322 ]. Their extensive pharmacological effects increase the likelihood of potential adverse reactions. As a result, SSRIs are generally not used as the primary medications in clinical pain management [ 2 ]. Oxcarbazepine and carbamazepine are considered effective in treating NP, particularly as a first‐line treatment for trigeminal neuralgia. Studies have shown that carbamazepine can reduce pain by at least 30% in 88.3% of patients, while oxcarbazepine achieves similar results in 90.9% of patients [ 371 , 372 ]. They are inhibitors of Nav channels and have demonstrated the ability to suppress spontaneous ectopic activity triggered by nerve injuries [ 366 ]. Botulinum toxin type A (BoNT/A), a protein known for its neurotoxic properties, is employed as a tertiary treatment option for NP in patients who exhibit resistance to other therapeutic options. Both single and repeated subcutaneous administrations of BoNT/A are utilized to manage conditions such as trigeminal neuralgia, postherpetic neuralgia, DN, and refractory NP including poststroke pain and spinal cord injury [ 373 ]. There is a rising interest in immunomodulation as an innovative therapeutic approach for individuals suffering from NP [ 195 ]. In certain circumstances, intravenous immunoglobulin treatment, which dampens immune responses, may provide relief for individuals suffering from chronic inflammatory demyelinating polyneuropathy‐associated pain [ 374 ]; however, it does not provide relief for those experiencing pain related to postpolio syndrome [ 375 ]. Moreover, supplementation of omega‐3 fatty acids resulted in a reduction in pain sensitivity and inhibited the functioning of inflammatory and oxidative stress pathways among patients with type 2 diabetes [ 376 , 377 ]. Patients with different NP conditions, including cervical radiculopathy, thoracic outlet syndrome, carpal tunnel syndrome, fibromyalgia, and burn injuries, also experienced significant pain reduction for a duration of up to 19 months after starting daily omega‐3 supplementation. No adverse effects were observed during the treatment period [ 378 ]. Multiple clinical trials have also demonstrated the efficacy of IL‐6 receptor inhibitors like tocilizumab, and TNF inhibitors including adalimumab, etanercept, and infliximab in alleviating pain among individuals diagnosed with lumbosacral radiculopathy and sciatica [ 379 , 380 , 381 ]. However, a comprehensive examination and meta‐analysis revealed that the existing data were inadequate to endorse the utilization of anti‐TNF agents in individuals suffering from sciatica [ 382 ]. In all, these results underscore the positive impact of immunomodulatory therapies in certain NP syndromes but not universally across all types [ 195 ]. An increasing number of clinical studies have been focusing on novel pharmacological targets, such as ion channels and glutamatergic receptors. With respect to Nav1.8, new substances have been discovered that exhibit selective inhibition of this target to address NP. A clinical study further corroborated these findings by demonstrating the analgesic effects of a selective Nav1.8 inhibitor, VX 150 (Phase I), in patients with NP [ 366 , 383 ]. A TRPA1 antagonist, GRC 17356, also demonstrated promising results in a Phase II clinical trial for the treatment of DN [ 384 ]. In addition, various P2X receptor antagonists have undergone or are presently undergoing clinical assessment for various forms of NP. For instance, clinical trials are currently underway to investigate the efficacy of P2X4 receptor antagonists like NP‐1815‐PX and NC‐2600 in addressing NP conditions [ 366 ]. Consequently, the effective management of NP requires a holistic approach that integrates diverse therapeutic interventions. Opioids, such as morphine and oxycodone, are typically reserved for severe cases; however, their use is associated with certain risks [ 385 , 386 ]. Tramadol and tapentadol are analgesics that act on the CNS and are commonly used to alleviate moderate to severe NP [ 387 ]. Each of these therapeutic options presents distinct advantages and considerations, and the selection of second‐line treatments should be guided by individual patient factors [ 320 ]. Recommending a multimodal and stepwise approach based on severity, similar to the one suggested by the US Veteran's Health Administration, is considered ideal for addressing nociplastic pain. This involves starting with education and self‐care interventions, gradually advancing to more sophisticated therapies if deemed essential [ 25 , 388 ]. The management strategies for nociplastic pain aim to attenuate symptoms rather than eradicate them, with a primary focus on nonpharmacological treatments as the preferred initial approach that can be tailored individually (precision medicine). The treatment goals should not only focus on pain relief but also include improvement of function and other indicators related to quality of life [ 24 , 25 ]. To date, there is a lack of established recommendations for managing nociplastic pain. The efficacy of traditional analgesic medications, such as NSAIDs and paracetamol, is typically limited in individuals with nociplastic pain. Opioids should be avoided in these cases [ 25 ]. The use of NSAIDs is warranted solely when there is clinical evidence of inflammation [ 279 ]. More potent medications include SNRIs like duloxetine and milnacipran, tricyclic compounds like cyclobenzaprine, noradrenaline reuptake inhibitors like esreboxetine, and gabapentinoids. The efficacy of duloxetine as a treatment for various chronic pain conditions, such as fibromyalgia and chronic headaches, has been demonstrated [ 389 , 390 ]. The overall evidence regarding the efficacy of cannabinoids for musculoskeletal pain treatment remains inconclusive, whereas available data strongly support their use in managing fibromyalgia pain [ 279 ]. Studies indicate that ketamine treatment demonstrated a significant reduction in short‐term pain among patients suffering from chronic noncancer pain conditions, such as migraine, fibromyalgia, and complex regional pain syndrome. However, the long‐term effectiveness of ketamine in pain management remains uncertain [ 391 ]. The use of opioid analgesics is strongly discouraged [ 25 , 392 ]. In addition to the recognized hazards linked with opioid treatment, individuals experiencing nociplastic pain may exhibit reduced sensitivity toward opioids due to elevated levels of naturally occurring opiates, exacerbation of hyperalgesia, and disruption in sleep patterns [ 393 , 394 ]. In fact, the effectiveness of low‐dose naltrexone, an opioid antagonist that may increase the number of opioid receptors and improve the body's reaction to natural pain‐relieving substances, has been proven in the treatment of complex regional pain, chronic back pain, and fibromyalgia [ 262 ]. Opioids are analgesic medications commonly employed across all age groups. These drugs play a crucial role in clinical symptomatic and palliative therapies. Opioids act as agonists on μ, κ, and δ receptors, exhibiting diminishing effects across these receptor subtypes. The clinical and social issues arising from opioids are primarily attributed to their adverse effects, such as tolerance, hyperalgesia, respiratory depression, and gastrointestinal response [ 2 ]. The current consensus is that opioids are no longer recommended as the initial treatment option for any form of persistent pain, and in certain populations (such as young individuals with noncancer pain), many guidelines do not recommend their use at all [ 337 ]. The VA/DoD guideline development group asserted that the potential for severe opioid‐related harms and significant adverse incidents, particularly in cases of prolonged usage, outweighed any potential benefits derived from temporary improvements in pain severity and functional status among patients with chronic pain [ 337 , 395 ]. The weak opioid agonist tramadol is widely used for pain management, particularly in cases of postoperative and chronic musculoskeletal pain. Both CPS and EFNS guidelines also recommend tramadol as a secondary treatment option for NP [ 329 , 338 ]. Furthermore, it can be employed with utmost safety and efficacy for pain relief without any adverse impact on the respiratory function of the neonate. Recently, a chewable tablet has been developed and employed for pediatric use, further substantiating its safety [ 396 ]. The updated 2022 VA/DoD guideline recommends prescribing buprenorphine as an alternative to full opioid agonists for individuals who are currently receiving daily opioids for the management of persistent pain [ 337 ]. The primary appeal of buprenorphine lies in its pharmacological properties, specifically its partial opioid agonism, and frequent coformulation with naloxone. This unique combination enhances safety by reducing the risk of misuse and overdose compared with full opioid agonists [ 397 ]. However, the recommendation for buprenorphine is based on evidence of limited quality [ 337 ]. Accumulating evidence suggests the existence of a complex network of interconnections between gut microbiota and the CNS, known as the gut microbiota‐brain axis [ 398 , 399 ]. The gut microbiota is capable of producing neurotransmitters (including GABA, serotonin, noradrenaline, and dopamine), metabolites (like short‐chain fatty acids [SCFAs] and bile acids), as well as PAMPs (such as lipopolysaccharide [LPS] and peptidoglycans). These products exert an impact on resident neuronal and immune cells in the gastrointestinal tract, thereby modulating signal transmission within vagal afferent pathways. They also traverse the intestinal barrier, gain access to the systemic circulation, and penetrate the CNS to interact with immune and glial cells. This interaction leads to the secretion of cytokines and chemokines to regulate nociceptive signaling in both peripheral and CNS [ 195 , 398 ]. Currently, there are mainly preclinical animal studies suggesting that gut microbiota could potentially have a significant impact on nociceptive pain. Inflammatory hypernociception was observed to be attenuated in germ‐free mice. Reduction of hypernociception was associated with a decrease in tissue inflammation and could be reversed through the repositioning of the microbiota or subcutaneous injection of LPS. Importantly, observed reduction in pain hypersensitivity among germ‐free mice was linked to an increased expression of IL‐10 and could be reversed by using an anti‐IL‐10 neutralizing antibody [ 400 ]. Additionally, injection of monosodium urate monohydrate crystals resulted in joint inflammation, hyperalgesia, and increased levels of IL‐1β and CXCL1. These effects were significantly reduced in germ‐free mice and mice subjected to antibiotic treatment [ 401 ]. These findings suggest that targeting the gut microbiota or applying specific probiotics holds promise in mitigating pain hypersensitivity across various inflammatory conditions. In fact, probiotics containing lactic acid‐producing bacteria have been shown to alleviate pain in RA patients, concurrently leading to a reduction in proinflammatory cytokine levels within the serum [ 402 , 403 ]. In nerve‐injured rodents with NP, dysbiosis of the microbiota was found to be correlated with altered levels of various metabolites in both serum and spinal cord. These metabolites primarily play a role in regulating lipid metabolism and the inflammatory response [ 195 , 404 ]. The mediators derived from the microbiota have the ability to impact innate immune cells residing in the DRG and spinal cord, thereby exerting regulatory control over neuronal excitability and pain perception [ 398 , 405 ]. The resolution of CINP may be attributed to the reduction of inflammatory factors via the LPS–TLR4 pathway in macrophages, which is facilitated by antibiotic treatment targeting gut microbiota eradication [ 406 , 407 ]. Gut microbiota has also been implicated in regulating microglia in models of NP. Depletion of gut microbiota can alleviate thermal hyperalgesia by inhibiting the activation of spinal glial cells in animals with nerve injury or DN [ 406 ]. A separate investigation found that SCFAs derived from microbiota were involved in the regulation of microglial activation and the promotion of proinflammatory microglial polarization in mice with nerve injury. Antibiotic administration reversed pain sensitivity, reduced microgliosis, and suppressed the secretion of proinflammatory cytokines in the spinal cord and hippocampus following nerve injury. Interestingly, these beneficial effects were blocked when SCFAs were administered [ 408 ]. However, there is currently a limited repertoire of validated clinical approaches available for manipulating the gut microbiota in patients suffering from NP. The involvement of gut microbiota in the pathogenesis of nociplastic pain, such as IBS, migraine, and fibromyalgia, has been established through preclinical studies. For instance, alteration of gut microbiota composition by means of antibiotic usage is correlated with an elevated susceptibility to IBS [ 409 ]. Additionally, it has been demonstrated that fecal transplantation from a human suffering from migraines induces nitroglycerin hyperalgesia in mice, thereby suggesting a potential association between the gut microbiota and susceptibility to migraines [ 410 ]. These studies have provided valuable insights into the mechanisms underlying the regulation of nociplastic pain by gut microbiota. Findings from clinical studies further support the notion. The antibiotic rifaximin effectively alleviates abdominal pain in patients suffering from IBS [ 411 ]. Specific probiotics demonstrated efficacy in alleviating abdominal pain among both adult and pediatric patients with IBS [ 412 , 413 ]. Supplementation with probiotics demonstrated an improvement in the quality‐of‐life scores among migraine patients [ 414 ]. Additionally, foods low in monosaccharides, fermentable oligosaccharides, disaccharides, and polyols have been shown to alleviate visceral nociception in patients with IBS caused by gut dysbiosis and TLR4‐dependent mast cell activation triggered by LPS [ 415 , 416 ]. A clinical case study of gut microbiota transplantation in patients with fibromyalgia also demonstrated significant symptom improvement and notable alterations of the enteric microbiota [ 417 ]. Nanomedicine involves the use of nanocarriers, specifically nanoparticles, to facilitate targeted drug delivery within the human body to previously inaccessible locations. At present, organic materials such as liposomes represent the primary application of nanoparticles in medical practice [ 352 ]. Nanomedicine has demonstrated enhanced efficacy of poorly soluble drugs with reduced dosages, attributed to the particles’ ability to enhance drug bioavailability [ 418 ]. These drug delivery systems employ specific parameters to optimize the circulation time of a drug and enhance its tissue/organ specificity [ 419 ]. Additionally, nanomedicine nanomedicine also showcases its potential to safely administer therapeutic doses of typically toxic substances with minimal local or systemic harm [ 352 , 420 , 421 ]. The utilization of nanomedicine for precise targeting of sodium channels represents an innovative and highly significant approach in the field of pain management [ 422 ]. Indeed, through the utilization of nanoscale carriers such as liposomes, adeno‐associated viral (AAV) vectors, and polymeric or lipid nanoparticles, NaV blockers can be precisely delivered to specific nerves or tissues with unparalleled precision [ 422 ]. Currently, nanomedicines targeting VGSCs have primarily been confined to local infiltration analgesia and peripheral nerve block for localized or regional anesthesia in surgical interventions as well as for the management of pain following surgery [ 422 ]. In addition, the versatility of nanomedicine also allows for the development of combination therapies that simultaneously target multiple pain pathways [ 423 , 424 ]. For instance, it is possible to design nanoparticles that can transport both an anti‐inflammatory and an analgesic substance, effectively managing inflammation and pain in a complementary way. This strategy exhibits significant promise for improving pain alleviation in intricate conditions [ 422 , 424 ]. The field of stem cell therapy is a crucial component within the realm of regenerative medicine. Adult stem cells can be classified based on their source tissue, such as those obtained from the hematopoietic stem cells, placenta and umbilical cord, mesenchymal cells (MSCs) derived from bone marrow, and adipose tissue‐derived MSCs [ 421 ]. Their general mechanisms underlying the modulation of chronic pain include the following three aspects. The direct approach involves the rapid division of lesions and preparation of injured tissues. Stem cells also secrete a variety of trophic factors such as VEGF, transforming growth factor, and other anti‐inflammatory cytokines. Additionally, stem cells can globally modulate the immune system, including suppressing the differentiation of monocytes into dendritic cells, inhibiting T cell maturation, and regulating NK cell activity [ 2 ]. In preclinical studies, stem cells obtained from bone marrow, adipose tissue, and peripheral nerves have demonstrated significant attenuation of NP, such as sciatic nerve injury and DN [ 421 , 425 ]. Transplantation of stem cells effectively reverses opioid tolerance [ 426 ]. VEGF serves as a potent regulator in the modulation of complex neuropathy. Enhanced pain relief is observed in patients with Parkinson's disease when treated with bioengineered stem cells that express VEGF [ 427 ]. The limited number of human trials notwithstanding, the available evidence effectively showcases the advantageous facets of stem cell applications. For example, treatment with MSCs has been shown to significantly alleviate pain in patients suffering from spinal cord injury and neuropathic facial pain [ 428 , 429 ]. MSC therapy could also potentially serve as a viable alternative treatment option for individuals suffering from chronic back pain. After undergoing autologous expanded bone marrow MSC injection treatment, patients diagnosed with lumbar disc degeneration and suffering from chronic back pain experienced rapid improvement in both pain and disability, reaching 85% maximum improvement within a period of 3 months [ 430 ]. With the European Medicines Agency and the US FDA approving more than a dozen gene therapy programs out of over 800 in development, personalized medicine for various diseases has been significantly enhanced by the emergence of gene therapy [ 431 , 432 ]. The methodologies of gene therapy can be classified into two categories according to the delivery systems: viral infection and nonviral vectors [ 2 ]. Ion channels are the main targets in gene therapy by viral delivery systems. Pain responses in mice were attenuated through the suppression of NaV1.7 in nociceptors mediated by clustered regularly interspaced short palindromic repeats (CRISPR)–dCas9 [ 433 ]. The study demonstrated that intrathecal infusion of CRISPR–dCas9 adeno‐associated virus 9 (AAV9) effectively attenuated inflammatory pain and NP [ 433 ]. A study was conducted to investigate the genetic variations of TRPV1, where a K710N missense variant of TRPV1 was introduced using CRISPR/dCas9 technology. This resulted in a reduction in calcium influx and a decrease in neuronal excitability, thereby suppressing nociceptive and NP [ 434 ]. In a mouse model of inflammatory hyperalgesia, the CRISPR–Cas9 editing of the PKC phosphorylation residue S801 in TRPV1 effectively alleviated masseter muscle inflammation‐induced pain, while preserving the physiological functions of TRPV1 [ 435 ]. In addition, delivery of the gene encoding CBD3 via AAV in DRG effectively alleviates NP through inhibiting the activity of Cav2.2 [ 436 ]. Naked plasmids offer a potent therapeutic strategy for the treatment of ischemic diseases [ 2 ]. Topical application of naked HGF plasmids effectively mitigates macrophage infiltration in the DRG, thereby reducing the secretion of proinflammatory factors, such as TNF‐α, IL‐1β, and IL‐6 [ 437 , 438 ]. This pain relief strategy has successfully completed phase III clinical trials for DN [ 439 ], making it the most advanced gene therapy approach currently available for clinical application. Similarly, administration of naked plasmids containing anti‐inflammatory IL‐10 induces long‐lasting NP and OA‐pain suppression [ 440 , 441 ]. Taken together, the concurrent development of dual‐track gene therapies has paved the way for future investigations in a novel direction.

The current therapy of assessment and management for chronic pain still falls significantly short of adopting a mechanism‐oriented or precision medicine strategy. The newly introduced 2021 IASP clinical criteria and grading system for nociplastic pain facilitate prompt recognition and categorization of individuals according to their unique pain characteristics, representing a crucial advancement in the field of precision pain medicine [ 11 , 442 ]. The present review elucidates the fundamental molecular mechanisms underlying nociceptive, neuropathic, and nociplastic pain, respectively. Immune responses and alterations in ion channels play a crucial role in the development of nociceptive and NP. Epigenetic modifications and endoplasmic reticular stress can further exacerbate NP, while the emergence of nociplastic pain is likely influenced by central sensitization, impairments in descending pain modulation, and neuroinflammation. Significantly, despite the emphasis on precision medicine, there is a lack of practical frameworks for integrating molecular profiling—such as biomarkers and genetic testing—into clinical workflows. Overlapping molecular pathways among various pain subtypes (e.g., shared neuroinflammation in neuropathic and nociplastic pain) affect therapeutic approaches. A thorough analysis of these cross‐subtype interactions is essential for refining the application of precision medicine. In the part of therapeutic strategies, we reviewed some recent advancements in both pharmaceutical and nonpharmaceutical approaches to managing chronic pain. The first‐line treatments for nociceptive pain include topical and oral NSAIDs. In order to devise a personalized treatment plan, it is imperative to consider the type of pain, the specific circumstances of the patient, and the extent of inflammatory response. The conventional approach to managing NP in patients entails initiating treatment with conservative pharmacological and complementary therapies prior to employing interventional strategies. The management strategies for nociplastic pain primarily focus on individualized nonpharmacological treatments as the preferred initial approach. All in all, the guidelines for managing chronic pain may vary depending on whether they pertain to symptom management or a specific medical condition, ultimately leading to diverse approaches to treatment. Emerging treatment strategies, such as microbial intervention, nanomedicine, stem cell therapy, and gene therapy, have the potential to enhance the precision of chronic pain management. Meanwhile, tracking the ongoing clinical trials related to chronic pain treatment targeting ion channels will provide further direction for therapeutic management (Table  4 ). Clinical updates of potential ion channels modulators for chronic pain management. Abbreviations: ASICs, acid‐sensing ion channels; Cavs, voltage‐gated calcium channels; CINP, chemotherapy‐induced neuropathic pain; cLBP, chronic low back pain; CPPP, chronic postoperative pain; DN, diabetic neuropathy; IBS, irritable bowel syndrome; NP, neuropathic pain; P2X, ionotropic purinergic receptors; PN, postherpetic neuralgia; TRPA1, transient receptor potential A1; TRPM8, transient receptor potential (TRP) transient receptor potential melastatin 8.; TRPV, transient receptor potential vanilloid. To sum up, we have examined some innovative and contentious advancements in mechanical and therapeutic strategies that may offer new perspectives for the future management of chronic pain. The majority of recent preclinical and clinical investigations within the pain field have primarily centered around elucidating its underlying mechanisms and exploring therapeutic interventions. However, there are certain limitations that need to be addressed, such as insufficient research evidence, limited accuracy in experimental models, underutilization of omics data, and slow progress in the clinical translation of pain research [ 2 ]. The improvement and validation of reproducibility and predictability in animal models and outcome measures should be explored for the translation of preclinical findings to human pain conditions. A more comprehensive comprehension of the ligand‐binding sites, protein structure, and precise mechanisms of action of different analgesics has the potential to expedite pharmaceutical discovery. In this regard, the utilization of the AlphaFold Protein Structure Database and other artificial intelligence methodologies presents opportunities for drug innovation, as well as the selection and prioritization of drug target combinations. Moreover, it has the potential to improve the design of clinical trials and offer valuable perspectives on individualized treatment approaches [ 444 , 445 ]. Herein, we propose several future perspectives for pain research, including the development of advanced experimental models, comprehensive application of omics, identification of biomarkers for chronic pain, elucidation of the mechanisms underlying the transition from acute to chronic pain, the development of nonopioid analgesics, and the exploration of brain mechanisms based on pain resilience.

Pain is defined by the International Association for the Study of Pain (IASP) as an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage [ 1 ]. Indeed, acute pain acts as a defense mechanism against noxious stimuli and is a significant adaptive and protective mechanism under normal physiological conditions [ 2 ]. Chronic pain is defined as pain that persists or recurs for more than 3 months [ 3 ]. The global impact of this issue is substantial, making it a significant public concern due to its high morbidity rates, increased mortality rates, and significant healthcare expenses [ 4 ]. According to estimates from the recent Global Burden of Disease study, chronic low back pain (cLBP) is one of the most prevalent conditions that affects 619 million individuals worldwide in 2020; this number is expected to escalate to 843 million by 2050 [ 5 , 6 ]. Among the four primary contributors to years lost to disability, three of them (namely, back pain, neck pain, and musculoskeletal disorders) are chronic pain conditions [ 6 , 7 ]. The primary motivation for seeking medical care is pain, with osteoarthritis (OA), back pain, and headaches ranking among the top 10 reasons [ 8 ]. Pain relief has been a requisite and a crucial index for clinical treatment [ 2 ]. Despite advancements in therapy, the management of chronic pain remains challenging due to the progressive nature of the condition. Currently available pharmacological and nonpharmacological interventions solely provide symptomatic relief, often with limited efficacy and significant adverse effects [ 9 ]. Therefore, it is imperative to develop more effective and secure therapies that focus on addressing the fundamental causes of persistent pain. Precision medicine pertains to the capacity of categorizing patients into distinct groups based on their varying vulnerability, biology, or prognosis associated with a specific ailment, as well as their unique reaction to a particular therapy. Consequently, treatment can be customized according to individual patient attributes [ 9 , 10 ]. Applying this to chronic pain, there is a growing need to accurately classify chronic pain into its three major phenotypes (nociceptive, neuropathic, and nociplastic pain) in order to customize appropriate treatment strategies [ 1 ]. The 2021 IASP clinical criteria and grading system for nociplastic pain emphasize on the importance of early identification and accurate classification of patients based on their pain phenotype during treatment [ 11 ]. These criteria represent a crucial advancement in the pursuit of precision pain medicine, holding immense potential for the field of pain management. Our comprehension of the phenotypic characteristics, as well as the underlying etiology and pathophysiology, of nociceptive, neuropathic, and nociplastic pain is advancing. Recent studies have further investigated the molecular mechanisms involved in chronic pain. However, in most cases, due to the absence of detailed classification of pain types and their mechanisms, the current assessment and management of chronic pain still significantly fall short of adopting a mechanism‐oriented or precision medicine strategy. This review presents an overview of the distinctive molecular mechanisms underlying nociceptive, neuropathic, and nociplastic pain, with an emphasis on the immune responses, ion channels, monoaminergic imbalance, and neuroinflammation. We delineate the status quo of nociceptive, neuropathic, and nociplastic pain management. A comprehensive overview was also given on a range of enhanced and innovative pain management strategies, including microbial intervention, nanomedicine, stem cell therapy, and gene therapy.

The authors declare no conflicts of interest.