Effects of Curcumin and Its Different Formulations in Preclinical and Clinical Studies of Peripheral Neuropathic and Postoperative Pain: A Comprehensive Review

Lesion or disease of the somatosensory system leads to the development of neuropathic pain. Peripheral neuropathic pain encompasses damage or injury of the peripheral nervous system. On the other hand, 10–15% of individuals suffer from acute postoperative pain followed by persistent pain after undergoing surgeries. Antidepressants, anticonvulsants, baclofen, and clonidine are used to treat peripheral neuropathy, whereas opioids are used to treat postoperative pain. The negative effects associated with these drugs emphasize the search for alternative therapeutics with better efficacy and fewer side effects. Curcumin, a polyphenol isolated from the roots of Curcuma longa, possesses antibacterial, antioxidant, and anti-inflammatory properties. Furthermore, the low bioavailability and fast metabolism of curcumin have led to the advent of various curcumin formulations. The present review provides a comprehensive analysis on the effects of curcumin and its formulations in preclinical and clinical studies of neuropathic and postoperative pain. Based on the positive outcomes from both preclinical and clinical studies, curcumin holds the promise of mitigating or preventing neuropathic and postoperative pain conditions. However, more clinical studies with improved curcumin formulations are required to involve its use as adjuvant to neuropathic and postoperative drugs.


Introduction
Neuropathic pain has been defined as a process occurring after a primary lesion or the disease of the somatosensory nervous system [1]. Based on either clinical examination or self-reporting, the prevalence of neuropathic pain is 9.8% and 12.4%, respectively, in the United States. However, due to differences in defining neuropathic pain, and employing different epidemiological assessment methods, it is difficult to provide the accurate estimate of neuropathic pain [2]. Peripheral neuropathic pain refers to damage or injury to the peripheral nerves [3]. According to the Special Interest Group on Neuropathic Pain, gabapentinoids, tricyclic antidepressants, and selective serotonin-norepinephrine reuptake inhibitors have been identified as the first-line drugs for neuropathic pain, whereas lidocaine, capsaicin, and tramadol are considered second-line drugs. Opioids such as morphine, oxycodone, and botulinum toxin-A are included as third-line treatments for peripheral neuropathic pain [4]. However, these drugs are accompanied by several side effects that limit their use in preventing or treating neuropathic pain [4].
On the other hand, acute postoperative pain is followed by persistent pain in 10-15% individuals undergoing surgeries, such as breast, bypass, and thoracic surgery, coronary,

Source and Metabolism
The genus Curcuma is widely cultivated in tropical and sub-tropical regions of Asia, Australia, and South America [44]. Curcumin is obtained from the tuberous rhizomes of C. longa, which is known as "turmeric" worldwide. C. longa is widely cultivated in India, China, and Indonesia [19,45]. The active components of Curcuma rhizomes involve volatile oils and nonvolatile curcuminoids (curcumin, demethoxycurcumin, bisdemethoxycurcumin), which are nontoxic polyphenolic derivatives with several biological activities [46,47]. Curcumin shows unfavorable pharmacokinetic properties (adsorption, distribution, excretion, and metabolism), insolubility in aqueous solutions, instability in neutral and alkaline pH, as well as sensitivity of both solid and solubilized forms to light [48]. Curcumin metabolism mainly takes place in the liver, but also in the intestine by gut microbiota [49]. It is rapidly metabolized either through the phase II conjugation of curcumin-to-curcumin glucuronide and curcumin sulphate in the intestine and hepatic cytosol or phase I enzymatic reduction of curcumin to dihydrocurcumin, tetrahydrocurcumin, hexahydrocurcumin, and hexahydrocurcuminol in the enterocytes and hepatocytes [50][51][52]. Furthermore, glucuronidation occurs on reduced curcumin, leading to formation of curcumin glucuronide, dihydro-curcumin-glucuronide, tetrahydrocurcumin-glucuronide, and curcumin sulfate [50]. Dihydro-ferulic acid and ferulic acid are also formed as the products of secondary biliary metabolism [53,54] (Figure 2). Table 1 summarizes the serum and tissue levels of curcumin in rodents and humans followed by different routes of administration. Despite its efficacy and safety, the poor bioavailability of curcumin undermines its therapeutic potential. Animal studies reported that oral administration [55,56] of curcumin led to its poor absorption, rapid metabolism, and excretion. Oral consumption of curcumin leads to the rapid formation of conjugates, such as curcumin glucuronide and curcumin sulfate in the small intestine, liver, and kidneys. The conjugates undergo rapid excretion in the urine and feces [50,[57][58][59][60][61][62]. In humans, curcumin has poor bioavailability, even when administered at a dose of 12 g/day [63]. Moreover, in humans, the oral bioavailability of curcumin is low because of its low absorption in the small intestine coupled to an extensive reduction and conjugation into metabolites in the liver followed by elimination through the gall bladder [54,64].  Table 1 summarizes the serum and tissue levels of curcumin in rodents and h followed by different routes of administration. Despite its efficacy and safety, th bioavailability of curcumin undermines its therapeutic potential. Animal studies re that oral administration [55,56] of curcumin led to its poor absorption, rapid metab and excretion. Oral consumption of curcumin leads to the rapid formation of conj such as curcumin glucuronide and curcumin sulfate in the small intestine, liver, an neys. The conjugates undergo rapid excretion in the urine and feces [50,[57][58][59][60][61][62]. In hu curcumin has poor bioavailability, even when administered at a dose of 12 g/da Moreover, in humans, the oral bioavailability of curcumin is low because of its l sorption in the small intestine coupled to an extensive reduction and conjugation in tabolites in the liver followed by elimination through the gall bladder [54,64].  X Reduction in MNCV ↓ MDA, neural nitrite, and total calcium content ↓ TNF-α and IL-1β and DNA fragmentation in sciatic nerve [80] Combination Study

Not tested Not tested
Nerve fibers [83]

Chemotherapy-Induced Peripheral Neuropathy (CIPN)
The treatment of cancer with different anticancer agents, including vinca alkaloids, platinum drugs (cisplatin and oxaliplatin), taxanes, and other chemotherapeutic drugs, leads to CIPN, which affects 30-40% of patients [98]. The symptoms of CIPN initiate with the onset of chemotherapy and improve with the completion of the therapy. However, 25-30% patients experience pain or unpleasant paresthesia, which even persists after chemotherapy completion [99]. Moreover, CIPN could potentially lead to a decrease in the dose of chemotherapeutics, change to less effective agents, and even cause cessation of the treatment [100]. In terms of cellular mechanisms, anticancer drugs paclitaxel, vincristine, and oxaliplatin lead to mitochondrial damage of sensory neurons in the dorsal root ganglion (DRG), leading to the increased production of ROS [101][102][103][104]. Chemotherapy leads to the cellular respiration impairment and decreases the production of adenosine triphosphate (ATP). Therefore, promoting mitochondrial respiration and restoring mitochondrial bioenergetics provide protection against CIPN [105,106]. Furthermore, the anticancer drug treatment leads to the reduction in antioxidative enzymes, such as superoxide dismutase (SOD) and catalase (CAT), causing an imbalance between oxidant and antioxidant molecules [101,104,107]. This imbalance promotes the cellular apoptotic pathways, leading to degeneration of peripheral sensory fibers and other inflammatory events [108,109]. Therefore, antioxidant therapy is considered as an effective treatment against CIPN [110]. Table 2 summarizes the effects of curcumin on CIPN. Curcumin improved platinum drug cisplatin or oxaliplatin-induced thermal (heat or cold) and mechanical hypersensitivity [85][86][87], and formalin test [87] in various strains of rodent models. However, Al Moundhri et al. [88] reported that curcumin could not attenuate cisplatin-or oxaliplatininduced painful behavioral outcomes. The study attributed a few factors, such as low number of animals in each treatment group, administration of low concentration of curcumin, and other unknown factors to this effect [88]. Curcumin also did not exert any impairment of neuromuscular coordination, indicating that curcumin did not alter motor coordination [88].
Electrophysiological parameters, such as MNCV and sensory nerve conduction velocity (SNCV) provide important insights into the function of sciatic nerves, showing the severity of nerve injury [111]. In rodents, curcumin increased both MNCV and SNCV, showing its favorable effects on functional deficits caused by the platinum drugs [85,86]. Furthermore, curcumin attenuated alkaloid vincristine-induced sciatic functional loss by increasing level of sciatic functional index (SFI) in male Swiss albino mice [87]. The results further confirm the protective effects of curcumin against chemotherapy-induced neuropathy [87]. The improvement in histopathology of the sciatic nerve, blockade of nuclear, nucleolar atrophy, and neuronal loss supported the protective effects of curcumin against platinum-induced neurotoxicity [86,88]. Al Moundhri et al. [88] also explored coadministration of curcumin with either oxaliplatin or cisplatin and reported an insignificant reduction in the platinum concentration in the sciatic nerve. The result indicates an interesting neuroprotective activity of curcumin in which concomitant treatment of curcumin did not affect the therapeutic efficacy of platinum drugs [88]. However, more research must be conducted to further confirm the neuroprotective and anticancer activities of curcumin. Al Moundhri et al. [88] also reported that curcumin reduced oxaliplatin and cisplatin-induced increase in plasma neurotensin, providing an insight into neurotensin quantification as a biomarker of platinum-based drug neurotoxicity. Furthermore, curcumin exerted its antinociceptive activity against CIPN by modulating several markers of oxidative stress, antioxidant enzymes, and inflammatory cytokines [84,85,87]. Curcumin exerted higher efficacy in decreasing oxidative stress markers and increasing the endogenous antioxidative enzymes compared to standard drugs, including pregabalin selective Cav 2.2 (a2d subunit) channel antagonist [87]. In summary, the antinociceptive activity of curcumin against CIPN could be attributed to its multiple actions, including attenuating pain behaviors, increasing MNCV, SNCV, and SFI, and suppressing inflammatory proteins and cytokines.

Diabetic Painful Neuropathy (DPN)
According to a report by the Centers for Disease Control and Prevention, about 30.3 million people have diabetes, including 9.4% of adults [112]. In the United States, 50% of diabetic patients [113,114] are affected by DPN. Burning, excruciating stabbing pain, numbness, tingling sensation, paresthesia, and hyperesthesia coupled with the aching of feet or hands are some distinguished characteristic features reported in patients with DPN [115,116].
The effects of curcumin on DPN are summarized in Table 2. Curcumin received much attention in treating DPN and its associated complications in rodent models due to its relative safety and inexpensiveness [89][90][91][92][93][94][95][96][97]. Curcumin modulated STZ-induced changes in body weights in two different ways, by either increasing the STZ-induced reduction in body weight [89,95,97] or preventing/decreasing STZ-induced increase in body weight [91,93]. Hyperglycemia is the classical diagnostic marker in both type 1 and type 2 diabetes and is the major cause of diabetic neuropathy [117]. Curcumin significantly reduced elevated blood glucose levels in both mice and rat models of diabetes [93,95,97].
Oxidative stress and inflammation are the two major factors that contribute to the pathophysiology of diabetes and its complications [121,122]. Curcumin ameliorated oxidative stress in DPN models by increasing the key enzymes for antioxidant defense, such as SOD [92], and by increasing total antioxidant capacity (TAS) [94]. TAS provides protection from the neurological damage caused by diabetes-induced oxidative stress [123,124]. It also provides important information on the total antioxidant content in a biological system [123,124]. Curcumin also exerted its antioxidant properties by reducing or scavenging several oxidative stress markers, such as the lipid peroxidation marker MDA [92,94,96], hydrogen peroxide (H 2 O 2 ) [92], nitric oxide (NO) [94][95][96][97], and oxidative stress index (OSI) and total oxidant status (TOS) [94]. OSI and TOS indicate a total concentration of all free radicals generated by diabetes-related oxidative damage [123,125]. Zhao et al. [92] reported that curcumin ameliorated the protein expressions of nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase subunits gp91 phox and p47 phox . The phosphorylation activates NADPH oxidases, leading to the generation of ROS, including H 2 O 2 . Therefore, decreases in gp91phox and p47phox could lead to the decrease in oxidative stress [126][127][128][129]. In addition, curcumin exerted its anti-inflammatory properties by decreasing the production of pro-inflammatory cytokine TNF-α [89,93,[95][96][97] or its receptor 1 (TNF-α receptor 1) [93]. In comparison with a standard antioxidant apocynin, curcumin demonstrated similar antioxidant activity against DPN [92] (Table 2).

Sciatic Nerve Chronic Constriction Injury (CCI)
Animal models of CCI are widely used to study peripheral neuropathic pain. The CCI model of nerve injury possesses two components, inflammatory and nerve injuries, which resemble the pain found in humans [130]. Table 3 summarizes the effects of curcumin on sciatic nerve CCI. Similar to other neuropathic pain models, curcumin alleviated CCI-induced neuropathic pain behaviors, including heat [131][132][133][134][135], mechanical [92,[131][132][133]135,136], and cold [137] hypersensitiv-ities. However, Moini Zanjani et al. [137] reported that low doses (12.5 and 25 mg/kg) of curcumin did not reduce pain behavior but induced mechanical allodynia. However, a high dose (50 mg/kg) of curcumin reduced cold allodynia [137]. The results indicate that different doses of curcumin are effective in alleviating CCI-induced pain behaviors. Curcumin alleviated CCI-induced neuropathic pain by inhibiting the expression of nuclear factor kappa B (NF-κB) in the spinal cord and reducing the expression of CX3C chemokine receptor 1 (CX3CR1) in the dorsal spinal cord and DRG [131] as well as attenuating the messenger RNA (mRNA) or protein expressions [135] of an important inflammatory mediator, cyclooxygenase-2 (Cox-2) [138], and its serum level [137]. Cox-2 is constitutively expressed in the dorsal horn of the spinal cord and is upregulated following injury, leading to the transmission of nociceptive input [139,140]. Besides modulating Cox2, curcumin also reduces the serum level of cortisol by inhibiting the upregulated expression of 11β-hydroxysteroid dehydrogenase type I enzyme (11βHSD1) [132]. The 11βHSD1 is a key enzyme that converts cortisone to cortisol in humans, and 11-dehydrocorticosterone to corticosterone in rodents [141]. These glucocorticoids exert their effects through glucocorticoid receptors that play important roles in the maintenance and development of neuropathic pain by regulating the function and expression of N-methyl-D-aspartate receptor (NMDAR) [142]. Yu et al. [133] reported that curcumin exerted anti-allodynic activity by blocking the immunohistochemical and protein expressions of N-methyl-D-aspartate receptor subunit NR1 (NMDAR NR1) in the spinal cord and DRG. However, Jeon et al. [136] reported that curcumin did not change the protein expression of NR1 in DRG. This discrepancy could be attributed to the dose and duration of curcumin treatment. Yu et al. employed 100 mg/kg of curcumin for 14 days [133], whereas Jeon et al. [136] used 50 mg/kg of curcumin for 7 days in rats. The treatment for 7 days [136] was probably too short to see the curcumin-induced changes at the central sensitization. Therefore, future studies are required to examine the long-term treatment of curcumin on central sensitization in rodent chronic neuropathic pain model. In addition, NMDAR-mediated activation of brain-derived neurotrophic factor (BDNF) is associated with the enrichment of p300/CREBbinding protein (CBP) at the BDNF gene promoter I [143]. Curcumin exerted its therapeutic activity by downregulating the recruitment of p300/CBP and histone acetyltransferase (HAT) (acetyl-Histone H3/acetyl-Histone H4) to the BDNF promoter [135]. Curcumin also downregulated p300/CBP HAT activity-mediated gene expression of Cox-2 [135]. Male Wistar rats 35% (v/v) ethanol 10 g/kg, b.i.d (bis in die, i.e., twice daily), oral, 10 weeks + curcumin: 20, 40 and 80 mg/kg, oral, 10 weeks + 35% (v/v) ethanol (10 g/kg), oral, 10 weeks ↑ Mechanical hyperalgesia threshold (Randall-Selitto paw pressure test) ↓ Mechanical allodynia (von Frey hair test) Thermal hyperalgesia (Tail immersion test) X Reduction in MNCV ↓ MDA, neural nitrite, and total calcium content ↓ TNF-α and IL-1β and DNA fragmentation in sciatic nerve [80] Combination Study Wistar Albino rats of either sex Curcumin per se: 60 mg/kg, i.p. 10 weeks 35% (v/v) ethanol (10 g/kg, twice daily, oral, 10 weeks) + curcumin (30 and 60 mg/kg, oral, 10 weeks) Sildenafil per se: 10 mg/kg, i.p. 10 weeks 35% (v/v) ethanol (10 g/kg, twice daily, oral, 10 weeks) + sildenafil (5 and 10 mg/kg, oral, 10 weeks) 35% (v/v) ethanol (10 g/kg, twice daily, oral, 10 weeks) + curcumin (30 mg/kg, oral, 10 weeks) + sildenafil (5 mg/kg, oral, 10 weeks)
Curcumin turned out to be less efficacious in a chronic constriction injury-chronic constriction release (CCI-CCR) model of neuropathic pain when compared to a neuropathic drug tramadol hydrochloride, a synthetic opioid from the aminocyclohexanol group [145]. However, curcumin was effective in inducing high regeneration and decreasing degeneration of nerve tissues in CCR compared to tramadol [144]. Findings from Ceyhan et al. [144] indicate that long-term use of curcumin in surgical constriction release may exert beneficial effects in ameliorating CCI-induced neuropathic pain.
Zhao et al. [134] explored the underlying mechanisms of antinociceptive action of curcumin in CCI-induced neuropathic pain. The study proposed that descending monoamine system spinal beta2-ARs and delta opioid receptors maintain the anti-allodynic activity of curcumin on mechanical stimuli, whereas descending serotonergic system coupled with spinal 5-HT1A receptors and mu opioid receptors are required for the anti-hyperalgesic activity of curcumin on thermal stimuli [134]. Compression, fracture, crush, wound, and laceration lead to the injury of sciatic nerves [146,147], and to the partial or total autonomic, motor, and sensory function loss [148]. A sciatic nerve crush model in rodents is widely used to represent axonotmesislike moderate peripheral neuropathy (PN) injury and is characterized by myelin sheath destruction and Wallerian degeneration [149]. Table 4 summarizes the effects of curcumin on SNC. Curcumin demonstrated neuroprotective effects on peripheral nerve injury by promoting nerve regeneration [150][151][152] and protecting the injured DRG and sciatic nerve structures [153,154]. In a combination study, curcumin was administered with melatonin, a drug that is used in nerve tissue recovery and repair [155]. Since melatonin is affected by light and dark, the study comparatively evaluated the effects of curcumin and melatonin in light and dark periods [156]. The results showed that curcumin exerted better efficacy in stimulating nerve regeneration compared to melatonin. However, the effects of curcumin did not differ between the light and dark periods of treatments, but melatonin showed significantly better efficacy in the dark compared to light group [151]. Therefore, future studies should explore the effects of curcumin in human nerve regeneration. Furthermore, Ma et al. [152] reported that high doses of curcumin (100 mg/kg and 300 mg/kg) induced similar nerve regeneration effects as mecobalamin, a neuroprotective agent commonly used as a neuroprotective agent against neurodegenerative diseases [157]. All the evidence reinforces the neuroprotective effects of curcumin in promoting nerve regeneration and accelerating motor functional recovery.

Spared Nerve Injury (SNI)
SNI model resembles the stimulus-evoked pain that is observed under clinical settings of neuropathic pain syndrome [162,163]. Table 4 summarizes the effects of curcumin on SNI. Curcumin reduced SNI-induced neuropathic pain behaviors by activating either the tropomyosin receptor kinase A (TrkA) and phosphatidylinositol 3-kinase/Akt protein kinase B (PI3K/Akt) cell survival signaling pathway [158] or the Janus kinase 2-signal transducer and activator of transcription 3 (JAK2-STAT3) signaling pathway [159]. Nerve damage induces neuroinflammation [164], which leads to the upregulation of proinflammatory cytokines [164], including IL-1β, that contribute to the development and maintenance of neuropathic pain [165]. Curcumin downregulated the production of mature IL-1β in the spinal cord and thus attenuated SNI-induced neuropathic pain [159]. Furthermore, curcumin induced the anti-allodynic activity by inhibiting the NAcht leucinerich-repeat protein 1 (NALP1) inflammasome and activating the JAK2-STAT3 pathway in astrocytes [159]. On the other hand, curcumin demonstrated protective effects against injured neurons by stimulating the release of nerve growth factor (NGF) and further activating the TrkA and PI3K/Akt cell survival signaling pathway [158].

Spinal Nerve Ligation (SNL)
Kiso et al. [166] developed a L5/L6 mice spinal nerve ligation model, which is employed in studying neuropathic pain. In this nerve ligation model, mechanical allodynia develops at day 1 and lasts for two months after the surgery. Table 4 summarizes the effects of curcumin on SNL. Lee et al. [161] reported that intrathecal administration of curcumin alleviated SNL-induced allodynia, but they did not explore the underlying mechanisms of action. On the other hand, Pastrana-Quintos et al. [160] reported that both oral and intrathecal curcumin induced anti-allodynic activity in an SNL model of neuropathic pain and that the anti-allodynic effect was mediated via the nitric oxide-cyclic guanosine monophosphate-adenosine triphosphate-sensitive potassium + channels pathway. Furthermore, the highest dose of oral (310 mg/kg) and intrathecal (0.3 mg) curcumin exerted maximal anti-allodynic effects, and intrathecal curcumin even produced significantly higher anti-allodynic activity compared to gabapentin [160].

Postoperative Pain
Patients perceive postoperative pain as one of the most noxious aspects of surgical pain for which effective control measures are lacking [167][168][169]. Table 5 summarizes the effects of curcumin on postoperative pain and preemptive analgesia. Acute treatment of curcumin demonstrated anti-hyperalgesic activity by dose-dependently reversing mechanical hyperalgesia, whereas repeated treatment facilitated the recovery of postoperative pain [170]. However, repeated treatment before surgery did not exert impact on the prevention or reduction in postoperative pain [170]. The results emphasize that acute curcumin treatment may be useful in treating postoperative pain. Curcumin also exerted its analgesic activity by alleviating incision-induced inflammation, spontaneous pain, functional gait abnormalities, and hyperalgesic priming [171]. Although curcumin did not alter the pro-or anti-inflammatory cytokines at the peri incisional level, it augmented transforming growth factor-β (TGF-β), which is implicated to inhibit nociception in both inflammatory and neuropathic pain models [172]. Ju et al. [173] provided important insights into the underlying mechanisms of the antinociceptive activity of curcumin in postoperative pain. The results showed that antagonizing the gamma-aminobutyric acid (GABA) receptors abrogated the curcumin-induced anti-hyperalgesic activity, and curcumin treatment elevated the mRNA expression of GABA-A and GABA-B in the incised spinal cord. On the other hand, antagonizing the opioid receptors reversed the anti-hyperalgesic activity of curcumin but did not alter the mRNA expression of opioid receptors in the spinal cord, indicating the indirect involvement of opioid receptors in mediating curcumin antinociception of postoperative pain [173]. Together, the findings conclude that spinal GABA receptors are important in modulating postoperative pain and that curcumin increases the synthesis of GABA mRNA in the spinal cord, thus mediating the antinociception of postoperative pain. Therefore, postoperative pain can be treated or prevented with spinal GABA receptor agonists.

Preemptive Analgesia
Preemptive analgesia is an antinociceptive treatment that is applied to prevent altered processing of the afferent input that amplifies postoperative pain by preventing central sensitization caused by incisional and inflammatory injuries, and it covers both the period of surgery and the initial postoperative period. The nature of surgery determines the balance between incisional injury and inflammatory injury, with inflammation injury being a dominant factor [177,178]. The application of preemptive analgesia is more effective in reducing surgery-induced nociceptive pain transmission when compared to the application of analgesic treatment provided after surgery [179].
Nurullahoglu et al. [176] suggested the preemptive analgesic effects of curcumin on acute thermal and inflammation-induced pain in female Wistar Albino rats. Furthermore, the study compared the preemptive effects of curcumin with intraperitoneal administration of diclofenac (10 mg/kg), a non-steroidal anti-inflammatory drug [180]. Diclofenac exerts controversial preemptive effects, with some studies, showing no differences in the effects in between pre-and postoperative diclofenac-treated patients undergoing laparoscopic tubal ligation [177], while other studies reported that preoperative administration of diclofenac along with ketorolac and piroxicam reduced postoperative pain in patients undergoing laparoscopy [181,182]. Based on Nurullahoglu et al.'s [176] study, both curcumin and diclofenac exerted preemptive analgesic effects. Bulboacs et al. [175] demonstrated the preemptive effects of curcumin in a rodent migraine model. Curcumin induced analgesic effects in both phase I dominated by vasodilation and phase II dominated by inflammation of formalin test [175]. Moreover, curcumin reduced oxidative stress markers and blood pressure and increased TAC. The study also compared the preemptive analgesic effects of curcumin with a beta-1 blocker, propranolol [183], which is effective in treating migraine patients by increasing the temporal distances between migraine attacks [184]. Another drug, indomethacin, exerts antimigraine effects due to its antinociceptive and anti-inflammatory properties [185]. Bulboacs et al. [175] demonstrated that curcumin had superior activity as compared to propranolol-and indomethacin-treated groups, indicating that curcumin could be used as prophylaxis for migraine. In addition to rodent models, the preemptive analgesic property of curcumin was also effective in a swine model of cardiopulmonary bypass (CPB) and extracorporeal support, resulting in a decrease in TNF-α and intercellular adhesion molecule (ICAM-1) expressions [174]. This study in a swine model provides data for the development of a human translational study [174]. However, further studies are needed to explore the underlying mechanisms of preemptive analgesic effects of curcumin.

Curcumin Formulations and Neuropathic Pain-Preclinical Studies
Preclinical and clinical studies have employed different curcumin formulations synthesized in order to improve the solubility, bioavailability, and pharmacokinetics of curcumin [186][187][188][189][190].For example, in a clinical study, a novel bio-enhanced preparation of curcumin called BCM-95CG (Biocurcumax) showed 6.93-and 6.3-fold higher bioavailability when compared to curcumin and a curcumin-lecithin-piperine formula, respectively [186]. However, Shoba et al. [189] reported that concomitant administration of piperine enhanced the bioavailability, absorption, and serum concentration of curcumin in both rodents and humans with no side effects. Another curcumin formula, Theracurmin, which is curcumin dispersed with colloidal submicron particles, exhibited higher absorption efficiency compared to other curcumin drug-delivery systems, such as BCM-95 (micronized curcumin with turmeric essential oils) and Meriva (curcumin-phospholipid) [187]. A curcumin formulation with a combination of hydrophilic carrier, cellulosic derivatives, and natural antioxidants further showed higher absorption in blood compared to unformulated curcumin [188].

Curcumin and Its Formulations on Neuropathic Pain or Postoperative Pain-Clinical Studies
A vast majority of the studies have reported the antioxidant and anti-inflammatory properties of curcumin and its formulations in clinical settings of chronic inflammatory joint pain, such as osteoarthritis and rheumatoid arthritis [200][201][202][203][204][205][206][207][208]. Only a few clinical studies have focused on the effects of curcumin and/or its formulations in PN and postoperative pain [209][210][211][212][213][214][215]. Table 7 summarizes the effects of curcumin on neuropathic pain and postoperative pain in clinical studies. Diabetic sensorimotor polyneuropathy (DSPN) is one of the most common complications in diabetes mellitus, resulting in impaired motor activity [216]. DSPN affects 25% of individuals with type 2 diabetes mellitus (T2DM) [217,218]. Asadi et al. [211] reported that nano curcumin supplementation decreased the total neuropathy score when assessed by the Toronto Clinical Neuropathy Score. The nano curcumin treatment also reduced the serum levels of fasting blood glucose (FBS) and HbA1c. The study also elucidated that DSPN can be improved by managing hyperglycemia in individuals with T2DM. In another study, patients treated with Meriva (lecithinized curcumin) showed significantly reduced chemotherapy-induced side effects, which was further confirmed by the semiquantitative evaluation of chemotherapy-induced side effects in the control group. Furthermore, patients treated with Meriva had reduced plasma levels of free radicals when compared to the control group [212]. Curcumin is also effective against chronic PN and pain induced by lumbar disc herniation and/or lumbar canal stenosis or carpal tunnel syndrome [215]. A multi-ingredient formula (800 mg dexibuprofen (Dex) + Lipicur (800 mg lipoic acid + 800 mg curcumin phytosome + 8 mg piperine), Dex + 800 mg lipoic acid, and 800 mg Dex only) reduced neuropathic pain in patients with lumbar sciatica and carpal tunnel syndrome. Curcumin efficiently reduced the use of dexibuprofen by 40%, and add-on therapy with lipoic acid exerted no significant results, indicating that Lipicur could be used as an effective alternative therapeutic to treat neuropathic pain [215]. Patients with T2D (n = 80); RCT (placebo-controlled and double-blind) Nano curcumin (72% curcumin, 80 mg) or placebo capsules/day for eight weeks ↓ Score of total neuropathies, reflex score, and temperature in curcumin vs. placebo ↓ HbA1c and FBS in curcumin vs. placebo [211] Chemotherapy-Induced Peripheral Neuropathy (CIPN) Patients undergoing cancer chemo-and radiotherapy (n = 160); RCT (placebo-controlled and double-blind) Lecithinized curcumin (Meriva: 500 mg) or placebo for 60 days from first cycle of chemoor radiotherapy ↓ Local pain rating based on VAS due to radiotherapy in curcumin vs. placebo group ↓ Chemotherapy side effects in curcumin vs. placebo group [212] Peripheral Neuropathy (PN) Patients with chronic PN and lumbar disc herniation and/or lumbar canal stenosis or carpal tunnel syndrome; (n = 135); RCT, open Three formulations as follows: (1) Dex (800 mg) + Lipicur [lipoic acid (800 mg) + curcumin phytosome (800 mg) + piperine (8 mg)]; (2) Dex + lipoic acid (800 mg) and (3) Dex only (800 mg) capsules/day for eight weeks ↓ Neuropathic pain in patients with lumbar sciatica and carpal tunnel syndrome in Lipicur group vs. others ↓ Use of Dex in the Lipicur group vs. others [215] Postoperative Pain Patients undergoing oral surgery for periodontitis (n = 15); RCT (placebo-controlled) Curcumin mucoadhesive film (0.5% extract) or placebo mucoadhesive film placed on gingiva after surgery for seven days ↓ Pain score rating and swelling in curcumin vs. placebo group ↓ Use of oral analgesics in postoperative period in curcumin vs. placebo group [210] Patients following laparoscopic gynecologic surgery (n = 60); RCT, open Curcuminoids extract (1000 mg) or standard analgesia on postoperative days one to three ↓ VAS pain scores following surgery in curcumin vs. standard group N/A [214] Patients undergoing oral surgery for impacted third molars (n = 90); RCT (placebo-controlled) Curcumin (200 mg) + amoxicillin (500 mg) or control (amoxicillin 500 mg + 500 mg mefenamic acid) three times for 24 h ↓ Pain score rating in curcumin vs. placebo group N/A [213] Patients undergoing laparoscopic cholecystectomy (n = 50); RCT (placebo-controlled and double-blind) Curcumin (500 mg) or placebo once every six hours/day for three weeks ↓ Pain score rating in curcumin vs. placebo group ↓ Fatigue score and the use of oral analgesics in postoperative period in curcumin vs. placebo group [209] ↓ = Decrease/lower; CIPN = chemotherapy-induced peripheral neuropathy; Dex = dexibuprofen; DSPN = diabetic sensorimotor polyneuropathy; FBS = fasting blood glucose; HbA1c = glycated hemoglobin; N/A = not applicable; PN = peripheral neuropathy; RCT = randomized controlled trial; T2D = type 2 diabetes; VAS = visual analog scale.
In a pilot randomized trial, curcuminoids extracted from turmeric, containing curcumin, demethoxycurcumin, and bisdemethoxycurcumin [219], reduced postoperative pain severity after laparoscopic gynecologic surgery [214]. In another double-blinded, randomized, placebo-controlled study, curcumin not only reduced postoperative pain but also reduced fatigue based on the patient-reported outcomes following laparoscopic cholecystectomy [209]. Curcumin also reduced intensity of the acute postoperative pain followed by third molar extraction as evaluated by numeric rating scale [213]. Curcumin exerted better efficacy in reducing orofacial pain caused by the postoperative molar extraction-induced inflammation in comparison with mefenamic acid, a non-steroidal anti-inflammatory drug, commonly used to treat inflammatory pain [220][221][222]. Postsurgical removal of the third molar led to the upregulation of inflammatory cytokines, including interleukin 6 (IL-6) and interleukin 8, leading to the development of inflammatory pain [223]. Therefore, in their study, Maulina et al. [213] explained that curcumin demonstrated better anti-inflammatory activity by directly inhibiting the inflammatory cytokines as compared to mefenamic acid that indirectly inhibited or decreased IL-6 by suppressing the secretion of prostaglandin E2, responsible for inducing IL-6 expression [224]. The analgesic activity of curcumin against periodontal surgeries was further confirmed in another study in which curcumin mucoadhesive film reduced postoperative pain and swelling over a period of one week compared to the placebo mucoadhesive film. Therefore, the curcumin mucoadhesive film could become a commercially available phytochemical drug delivery system in the treatment of periodontal postsurgical pain [210]. Taken together, these aforementioned clinical studies conclude that curcumin and its formulations could be used as adjuvants for postoperative care.

Conclusions
The current review provides important information regarding the potential effects of curcumin in treating different peripheral neuropathic conditions, including alcoholic neuropathy, CCI-, CIPN-, DPN-, SNI-, and SNL-induced neuropathic and postoperative pain ( Figure 4). Based on the present review, we identified a few drawbacks in both preclinical and clinical studies. First, only a handful studies have explored the effects of curcumin and its formulations in neuropathic and postoperative pain under clinical settings. Future studies should focus on conducting clinical studies on other PN pain conditions involving curcumin. Second, in most of the clinical studies only a single dose was used. Therefore, dose-related effects remain unknown. Third, only a few preclinical studies have compared the antinociceptive effects of curcumin with standard drugs. In order to enhance the application of curcumin in clinical treatment, it is important to administer clinically used drugs as experimental controls or for a reference comparison. Fourth, most of the animal studies evaluated the anti-hyperalgesic activity of curcumin either by monitoring the behavioral outcomes or by measuring the biochemical paraments. Besides these two parameters, the effects of curcumin on neuropathic pain should also be evaluated by monitoring functional recovery and electrophysiological aspects of pain conditions. Therefore, in the future, it is important to address the aforementioned shortcomings while designing both preclinical and clinical studies. In conclusion, with the advent of these new formulations, including curcuminoids, liposomal encapsulations, nanoparticles, derivatives, and analogs, the multifaceted favorable effects of curcumin will lead to the promising development of therapeutic agents for treating several neuropathic and postoperative pain conditions. functional recovery and electrophysiological aspects of pain conditions. Therefore, in the future, it is important to address the aforementioned shortcomings while designing both preclinical and clinical studies. In conclusion, with the advent of these new formulations, including curcuminoids, liposomal encapsulations, nanoparticles, derivatives, and analogs, the multifaceted favorable effects of curcumin will lead to the promising development of therapeutic agents for treating several neuropathic and postoperative pain conditions.  (3), different peripheral injuries, such as CCI, SNC, SNI, SNL, etc., and/or postoperative pain-induced behaviors in rodent models. Curcumin and its formulations mainly inhibit or reduce mechanical (6A), cold (6B), heat (6C), and chemical-induced (6D) pain behaviors, as well as motor deficits (6E). II. Electrophysiology/Histopathology: Curcumin or its formulations protect injured DRG, decrease neuronal excitability in DRG (1), resulting in attenuation of painful neuropathic behavior. Curcumin or its formulations increase SNCV, decrease loss of DRG neurons, and increase diameter of nerve fibers (2). Furthermore, curcumin and its formulations increase MNCV, decrease neurogenic lesions (3), and atrophy of gastrocnemius muscle (4). The treatments also effectively increase myelin sheath thickness (5A) and prevent demyelination (5B). III. Molecular: Curcumin or its formulations decrease expression of NF-κB, leading to decrease in inflammatory proteins. Furthermore, the treatments increase expressions of Nrf2, leading to increase in levels of antioxidative enzymes that scavenge free radicals and ultimately reduce ROS levels. Moreover, the treatments  (3), different peripheral injuries, such as CCI, SNC, SNI, SNL, etc., and/or postoperative paininduced behaviors in rodent models. Curcumin and its formulations mainly inhibit or reduce mechanical (6A), cold (6B), heat (6C), and chemical-induced (6D) pain behaviors, as well as motor deficits (6E). II. Electrophysiology/Histopathology: Curcumin or its formulations protect injured DRG, decrease neuronal excitability in DRG (1), resulting in attenuation of painful neuropathic behavior. Curcumin or its formulations increase SNCV, decrease loss of DRG neurons, and increase diameter of nerve fibers (2). Furthermore, curcumin and its formulations increase MNCV, decrease neurogenic lesions (3), and atrophy of gastrocnemius muscle (4). The treatments also effectively increase myelin sheath thickness (5A) and prevent demyelination (5B). III. Molecular: Curcumin or its formulations decrease expression of NF-κB, leading to decrease in inflammatory proteins. Furthermore, the treatments increase expressions of Nrf2, leading to increase in levels of antioxidative enzymes that scavenge free radicals and ultimately reduce ROS levels. Moreover, the treatments decrease expressions of Bcl-2 and caspase-3 that lead to reduction in apoptosis and ultimately improve nerve injuries (created with BioRender).