The increasing concern about pain management in neuropathic pain conditions caused by the absence of specific pharmacological treatment led to an exploration of the possibility of combined therapy between pharmacological and non-pharmacological compounds. When pain is not alleviated by prescribed pharmacologic agents or when those drugs are not easily accessible, researchers and patients look for alternative therapies. In this context, even if their mechanism of action is not completely understood, nutritional supplements were suggested to treat chronic illnesses that are poorly responsive to drugs, such as neuropathic pain, including diabetic neuropathy (DN) and chemotherapy-induced neuropathic pain (CIPN) ^[1][2][9,39]. In recent years, several studies have shown how higher intakes of vegetables and fruit that are rich in antioxidants improve the function of the immune system and fight free radical damage, one of the major molecular actors in neuropathic pain. A supplement can be defined as a product used to support the diet and that contains one or more of the following compounds: vitamins, minerals, herbs or other botanicals, amino acids, live microbials, dietary substances used to increase the total dietary intake or a concentrate, metabolites, constituents, extracts, or combination of any of these ingredients ^[3][40]. To study neuropathic pain and observe the effects of nutritional supplements on pain conditions, several animal models, in particular mice, were developed. Neuropathic pain is induced in mice through peripheral nerve injury carried out via axotomy or chronic constriction injury, through drug-induced injury models administering anti-cancer agents, such as paclitaxel, or through disease-induced models with streptozotocin to induce DN ^[4][5][41,42]. Even so, knowledge about clinical efficacy and mechanism of action is still limited. It is necessary to establish the role of these compounds in neuropathic pain via large randomized controlled trials. The following sections explored the nutritional supplements for the treatment of neuropathic pain, including vitamins (B, C, D), minerals (zinc, magnesium), botanicals (Boswellia serrata, Hypericum perforatum, curcumin, capsaicin, menthol, bromelain), amino acids (acetyl-L-carnitine, acetyl-L-cysteine), fatty acids (ω-3 fatty acids, N-palmitoylethanolamide, α-lipoic acid), and probiotics (Table 1).

Among all the vitamins of B family, thiamine (B1), pyridoxine (B6), folate (B9), and cyanocobalamin (B12) are known to play extremely relevant role in a variety of processes, such as DNA and RNA synthesis, metabolism, immunity and neuroprotection ^[64][65][100,101]. Numerous studies have suggested the protective role of B vitamins in alleviating neuropathic pain, in particular in DN and CIPN. This has been tested in animal and human models of different neuropathic pain conditions. For example, the administration of a cocktail of vitamins B1, B6, and B12 to diabetic rats was found to improve tactile allodynia in diabetic. In the same model, sensory nerve conduction was improved via the administration of vitamin B6 ^[66][102]. Moreover, it was suggested that a stronger reduction in pain caused by DN can be obtained through higher dosages of thiamine and pyridoxine (25 and 50 mg/day) compared with lower doses (1 mg/day of each vitamin) ^[6][43]. This confirms the potential use of combination of B vitamins in the treatment of DN ^[7][8][44,45]. Regarding folate, its role as a methylator in the nervous system led to the exploration of its role in neuropathic pain. In a mouse model of neuropathic pain with spinal cord injury the treatment with folate significantly reduced thermal hyperalgesia compared with control mice. Additionally, a reduction In MMP2 has been found after treatment with folate. MMP2s are involved in the induction of neuropathic pain, so a potential mechanism for the counteracting of pain using folate was suggested ^[9][46]. On the contrary, the decreased level of B vitamins has been hypothesized as risk factor for CIPN. In a double-blinded randomized controlled trial vitamin B6 has been able to reduce CIPN from cisplatin and hexamethylenamin administration. However, further results indicate an alteration in response duration after the administration of high dose of vitamin B6 ^[67][103]. The mechanism of action of vitamin B in treating neuropathic pain is still unclear. A potential role of vitamin B12 has been proposed. It should be implicated in nerve repair and myelination, and thus may improve neuropathy symptoms. However, randomized trials of vitamin B for neuropathic pain are needed to assess the mechanisms and effects of specific type of vitamin B ^[10][11][47,48].

Vitamin C, also called ascorbic acid, plays different relevant roles, from collagen synthesis to improving non-heme iron’s absorption, with immunological function and neuroprotection. Vitamin C is also involved in the maintenance of the integrity of vascular cells. It is synthetized from glucose through the glucuronic acid pathway in animals. Humans lost this biosynthetic ability during evolution. Thus, the intakes of vitamin C in diet are necessary. Vitamin C deficiency causes bleeding knees, wrists and ankles, with arthralgia and myalgia, as manifestations of scurvy disease ^[68][69][104,105]. The use of vitamin C is shown to be effective in several aspects of pain management. In the molecular context of neuropathic pain, vitamin C may play a role in the reduction of reactive oxygen species stimulating the activity of NADPH oxidase and by acting as scavenger of oxidant species ^[65][70][101,106]. Several studies confirm the efficacy of vitamin C in reducing pain derived from neuropathic pain conditions. In particular, a total of 300 patients with type II diabetic and newly diagnosed DN, of either gender, were enrolled in an open-label, parallel-arm, interventional study. Patients were followed up for up to 12 weeks. At the end of the study the reduction in pain in the vitamin-treated group was remarkable ^[17][54]. Again, in a randomized control trial, the supplementation of vitamin C in a smaller group of DN’s patients (75 patients) reduced the pain condition that characterizes DN ^[18][55].

Vitamin D is a hormone that is synthesized in the skin by sunlight and plays a relevant role in calcium homeostasis. It may be involved in a large number of mechanisms underlying pain development. This is suggested by the diffuse localization in central nervous system of vitamin D receptor and 1α-hydroxylase enzyme, which convert the vitamin D’s pro-form into its active form ^[71][72][107,108]. Although there is no clear mechanism of action of vitamin D, one proposed explanation is that vitamin D is involved in the regulation of many processes implicated in pain manifestation: upregulation of Transforming Growth Factor α1, IL-4 and TNF-α; influence on prostaglandin action interacting with Cyclooxygenase 2, 15-Hydroxyprostaglandin dehydrogenase and Prostaglandin E2; neuroprotection via the increment of synthesis of neurotrophins and inhibition of inducible nitric oxide synthase ^[20][73][74][57,109,110]. Treatment with vitamin D has been explored in chronic neuropathic pain conditions, including DN and CIPN. Moreover, these conditions are characterized by vitamin D deficiency ^[20][57]. Vitamin D supplementation has been studied in patients with diabetes mellitus ^[21][22][58,59]. In two different prospective studies, the ability of vitamin D to counteract pain derived from DN caused by diabetes mellitus was observed ^[23][24][60,61]. In a smaller, randomized, placebo-controlled trial of 57 patients with DN, a significant decrease in pain scores in the treatment group compared with the placebo was observed ^[25][62]. Regarding CIPN, the depletion of vitamin D was proposed as risk factor for such condition. The usage of vitamin D as a pre-chemotherapy supplementation with neuroprotective effect in CIPN prophylaxis has been also suggested ^[26][63]. However, the real efficacy of vitamin D for neuropathic pain treatment remains unclear. Randomized controlled trials are needed to test this treatment in order to assess role and mechanisms of vitamin D in the treatment of neuropathic pain conditions.

Zinc is an essential micronutrient used as treatment for different diseases, such as alcohol-related liver disease, sickle cell anemia, macular degeneration, and neuropathic pain ^[75][76][111,112]. Zinc plays a relevant role as an antioxidant compound in the activation of hundreds of genes involved in proliferation and cell growth. The deficiency of this mineral is associated with DNA damage, immune suppression, and apoptosis, ultimately leading to acrodermatitis enteropathica, a fatal condition if untreated ^[76][77][78][112,113,114]. A pain state is usually associated with inflammation, and zinc is a metallothionein with anti-inflammatory properties. Those properties are suggested to be responsible for the therapeutic benefit of zinc ^[79][115]. The efficacy of zinc in reducing pain has been assessed in a variety of animal models. In rats with induced neuropathic pain, the supplementation of zinc induced a reduction in pain. From a molecular point of view, zinc caused a decrease in NGF, involved in sensory hypersensitivity, and IL-1β levels, a marker of inflammation ^[80][81][116,117]. In another study, streptozotocin-induced diabetic rats were treated with zinc in order to establish the role and efficacy of minerals in counteracting DN symptoms. A slight restoration of motor nerve conduction speed, a reduction in tactile response threshold in diabetic rats and the counteraction of oxidative stress were was observed, suggesting the protective role of zinc supplementation in rat models of DN ^[82][118]. Similarly, in a mice model of CIPN treated with paclitaxel, zinc showed a protective role, reducing local allodynia. This is due to the inhibition of the TRPV1 receptor by zinc ^[28][65]. However, clinical studies to assess the role of zinc in treating such conditions are limited. To date, in clinical trials, the role of zinc deficiency has been assessed in various conditions such as DN, where a significant correlation between zinc deficiency, neuropathic pain severity, and CIPN was found, with a delayed pain manifestation ^[29][83][66,119].

Magnesium is an important mineral involved in several intracellular processes. As a metal cation, it is involved in numerous enzyme reactions and in the modulation of signal transduction via the influence of ion transport mediated by pumps, channels and carriers. This activity is principally carried out in excitable tissues ^[84][120]. Here, magnesium is able to antagonize the NMDA receptor, counteracting its activity in neuropathic pain development ^[85][121]. This led to the suggestion of magnesium supplementation as a potential therapeutic strategy against neuropathic pain. In the rat model of DN, magnesium administration caused a downregulation of NMDA receptor phosphorylation. This was followed by a reduction in allodynia ^[86][122]. Several clinical trials have been conducted but they show both negative and positive results ^{[33][34][35][36]}[70,71,72,73]. In fact, neuropathic pain is not always counteracted by magnesium supplementation, either as a single treatment compound or in combination with other drugs.

From the Burseraceae family, Boswellia serrata has gained attention from researchers in recent years due to its numerous properties. Boswellia trees are able to release a resin called “frankincense”. This plant extract is commonly used to reduce swelling and pain caused by inflammatory disease. This is possible due to the composition of the resin. Of all the compounds contained in the Boswellia serrata extract, 3-O-acetyl-11-keto-beta-boswellic acid is responsible for counteracting pain ^[87][123]. The components of Boswellia extract are involved in several processes such as the inhibition of 5-lipoxygenase with a reduced production of leukotrienes involved in inflammatory signaling, the inhibition of NF-κB complex strongly involved in inflammation, and the downregulation or inhibition of pro-inflammatory cytokines, such as IFN-γ, TNF-α and IL-1β ^[88][89][124,125]. Numerous clinical studies have been conducted to assess the potential role of Boswellia serrata extract to counteract inflammation. The extract is a safe and fast acting compound able to exert analgesic properties in a wide spectrum of conditions. However, it is too early to establish clinical practice recommendations ^[39][76].

Hypericum perforatum (or St. John’s Wort) is a plant native to Europe and Asia that has been suggested as an antinociceptive for various conditions related to neuropathic pain ^[90][126]. To assess the role of this plant in neuropathic pain, several rat models have been used. In a rat model of the DN administration of Hypericum perforatum extract from seeds or from the aerial portion of the plant reversed mechanical hyperalgesia with an effect comparable to that of antihyperalgesic drugs ^[91][127]. Similarly, in rat model of CIPN induced with oxaliplatin, the administration of dried extract of this plant highly counteracted mechanical hyperalgesia with an effect comparable to that of antihyperalgesic drugs ^[91][127]. To date, knowledge on the Hypericum perforatum mechanism of action is still unclear, and several theories have been proposed. Firstly, it was shown that the antinociceptive properties are related to hypericin and hyperforin, which can be found in the extract of the plant. Another theory suggests that Hypericum perforatum has a mechanism in common with antihyperalgesic drugs and antidepressants ^[92][128]. In fact, the plant’s extract is primary used to treat depression ^[93][129]. In common with these two types of drugs, Hypericum perforatum may share the ability to inhibit monoamine oxidase and amine reuptake at synapse level ^[94][130]. From a clinical point of view, the administration of Hypericum perforatum extract has been involved in many studies. Despite what has been seen with preclinical data, clinical studies show ambiguous results for the efficacy of Hypericum perforatum in neuropathic pain patients ^[41][42][78,79]. This compound was also well-tolerated. It is clear that the safety of Hypericum perforatum is high when it is used as a monotherapy due to its adverse effects, such as drug interaction and photosensitivity ^[43][90][80,126]. However, solid clinical studies are needed to assess the exact role and mechanism of action of Hypericum perforatum.

Curcumin is a lipophilic polyphenol with antioxidant and anti-inflammatory characteristics. The principal activity of curcumin is the regulation of multiple signaling pathways involved in tumor suppression, cell survival, protein kinase, caspase pathways, and others ^[95][131]. In preclinical studies, mouse models were used to assess the efficacy of curcumin in the treatment of neuropathic pain conditions. For example, in a mouse model of DN a four-week treatment with curcumin led to a reduction in the levels of TNF-α and NO, most likely related to the antinociception observed in the study. This resulted in the attenuation of thermal hyperalgesia ^[96][132]. Similarly, in a rat model of neuropathic pain, curcumin treatment caused a reversion of mechanical allodynia ^[97][133]. Moreover, in a different model, mice treated with curcumin showed a reduction in IL-1β, the JAK2-STAT3 pathway and inflammasome formation ^[98][134]. According to preclinical studies, in clinical trials, curcumin showed similar effects. In a controlled study with 160 patients under chemotherapy, curcumin was administered with an optimized delivery system (MERIVA^®, Indena SpA, Milano, Italy) to assess its ability to prevent or counteract CIPN. This nutraceutical administration led to an overall alleviation of the CIPN condition ^[44][81]. However, the lack of clinical studies is not sufficient to counter the lack of knowledge about curcumin, and thus its role in clinics is not well-defined.

Derived from chili pepper (Capsicum annum), capsaicin is the compound responsible for the burning and irritant effects of chili pepper consumption. Capsaicin is related to pain. Thus, its main role is as an analgesic treatment for various disorders, including neuropathic pain conditions such as DN ^[99][135]. The mechanism in which capsaicin performs its role as an analgesic treatment relies on the ability of this phenolic compound to interact with the receptor TRPV1, directly affecting unmyelinated C-fibers that modulate calcium flux and depleting substance P, a neuropeptide involved in pain perception ^[100][136]. To date, the clinical usage of capsaicin is related to the local treatment with capsaicin-based patches, creams and lotions for daily application ^[101][137]. However, capsules containing chili peppers have been produced to allow capsaicin administration. It is important to precise that a therapeutic dosage for orally administered capsaicin is not well-defined. The available over-the-counter capsules are not for pain treatment. Therefore, a deep exploration of past literature and the creation of solid clinical trials is essential for establish capsaicin dosage in a diet supplementations therapy in order to relieve pain ^[102][138].

From a cooling molecule derived from peppermint to a common analgesic, menthol plays a critical role in pain modulation. Its major analgesic mechanism is related to activation of transient receptor potential cation channel melastatin 8 (TRPM8), involved in the hypersensitivity to cold stimuli in neuropathic pain conditions when co-expressed with TRPV1 ^[103][139]. A peculiar characteristic of TRPM8 is its role in the reduction in pain sensitivity when stimulated. However, several animal models have been used to assess the role of menthol in neuropathic pain. In those models, a reduction in pain conditions was obtained when treating animals with L-menthol isomer ^[104][140]. To date, clinical studies focused on topical administration of menthol. However, research on orally administered menthol in neuropathic pain is rare or altogether absent. An evaluation of the potential usage of menthol as an orally administered nutraceutical could be useful in order to expand the spectrum of these nutraceutical applications.

Bromelain is a safe-to-use nutraceutical that lacks side effects. Hence, its role in neuropathic pain has been assessed in preclinical and clinical studies. For example, in a sciatic-nerve ligation-induced neuropathic pain model, the treatment of rats with bromelain significantly reduced thermal hyperalgesia and mechanical allodynia, with the recovery of sciatic function and structural integrity ^[105][141]. Similarly, in another rat model of neuropathic pain, bromelain administration reduced neuropathic pain characteristic signs ^[105][141]. As for capsaicin, despite numerous preclinical studies, the lack of clinical trials is relevant. Well-defined preclinical results need to be confirmed by clinical trials in neuropathic pain conditions.

Several amino acids have been suggested for the treatment of neuropathic pain conditions, such as acetyl-L-carnitine, N-acetyl-cysteine and glutamine. Acetyl-L-carnitine (ALC) is an endogenous molecule synthesized in the human central and peripheral nervous systems, as well as the kidneys and liver, that has very persistent analgesic effects when supplemented via diet ^[106][142]. Inside cells, this amino acid is involved in intermediary metabolism, protein acetylation, and neuroprotection. A wide range of animal models have been used to assess the neurotrophic and analgesic properties of ALC via the dietary supplementation in neuropathic pain conditions. In preclinical studies, researchers demonstrated the effect of the central anti-nociceptive action on nerve function. Thus, clinical studies tested ALC in patients with several pain conditions, in particular DN and CIPN. In double-blind randomized control trials involving 333 patients with DN, ALC treatment improved the nerve conduction velocity and amplitude ^[49][86]. On the contrary, in two randomized controlled clinical trials only involving patients with DN, no significant changes in the electrophysiology of patients were found after ALC treatment ^[50][87]. Additionally, two open-label studies with CIPN patients showed how ALC treatment may even worsen CIPN symptoms ^[51][88]. So, the results attested both positive and negative effects following ALC administration. However, the negative outcome from clinical studies is surrounded by solid preclinical studies, sustaining the high number of positive outcomes from other clinical studies. This confirms the potentiality of ALC as a dietary supplement for the treatment of neuropathic pain conditions such as DN and CIPN ^[107][143]. Additionally, a better understanding of mechanism of action and dosage focusing on the results about symptoms worsening is needed.