Analgesia and silymarin: What are the opportunities and challenges?

Abstract

Pain is an unpleasant sensory and emotional sensation about actual or possible tissue damage that can cause remarkable health and economic problems. For pain relief, analgesic drugs are commonly utilized; however, their prolonged use can cause different side effects from mild to severe stages. Therefore, discovering new and alternative choices for analgesic purposes is of importance. Hopeful evidence has shown that flavonoid compounds have various therapeutic and pharmacological potentials. Among these, silymarin, obtained from the milk thistle plant Silybum marianum, has addressed its competence in medicine, as demonstrated by its capacity against metabolic diseases, malignancies, inflammatory-related disorders, and organ toxicities. In the recent decade, some documents have stated the analgesic influences of silymarin, especially in some pathological situations like rheumatoid arthritis and neuropathic pain. Also, there is promising information regarding the possible synergistic effects of silymarin and some pharmacological or bioactive compounds. For these reasons, this narrative literature review aims to summarize and discuss the analgesic abilities of this flavonoid agent in pathological and nonpathological conditions and its interactions with other drugs with a focus on the involved mechanisms.

Introduction

Pain, as defined by the International Association for the Study of Pain (IASP), is an annoying perceptual and emotional sensation that stems from real or potential tissue damage. ¹ Reportedly, pain influences over 20% of people throughout the world, making major public health and socioeconomic challenges. ² Detection, processing, and responding to pain is attributable to pain-related neural networks encompassing peripheral neurons, peripheral receptive elements associating the spinal cord (dorsal horn) with spinal-to-brain relay pathways, and integrative neurons regulating nociceptive signals by inhibitive or excitatory effects at spinal, subcortical, and cortical levels. ³ Nociception has four stages, including transduction, transmission, modulation, and perception. Transduction is related to chemical or physical stimuli converted into transmittable electrical signals. Transmission means the conduction of neuronal electrical activity. Modulation refers to the change in neuronal function by transmission pathways. Eventually, perception is a subjective experience of pain arising from somatosensory transmission.^4–6 Pain is classified based on diverse landmarks, including anatomical location, mechanism, and etiology, and acute and chronic types are two main categories related to pain. ⁷ Acute pain is severe, initiates promptly, and lasts a short time following the improvement of injury. On the contrary, chronic pain remains for 3 months or more and can manifest symptoms from slight to severe stage. ⁸ Analgesic drugs are often utilized for pain alleviation; however, continuous use of these medications causes side effects ranging from mild (e.g., allergic reactions) to severe (e.g., gastric bleeding, vomiting, nausea, dyspepsia, and gastrointestinal problems). ⁹ Therefore, discovering an ideal and alternative approach for analgesic purposes is of great importance. These days, natural compounds have gained much attention in medical sciences due to their diverse therapeutic and pharmacological features, like analgesic influences. The importance of herbal products in pain control can be highlighted by their role as effective alternatives or complements to conventional analgesic drugs, which often have side effects ranging from mild to severe. Herbal medicines are valued for their ability to reduce pain and inflammation, especially in mild to moderate cases, with typically fewer adverse effects. They offer therapeutic benefits in managing various pain conditions, including arthritis, migraines, neuropathic pain, and inflammatory pain. Herbal remedies are known to provide natural pain relief by mechanisms like anti-inflammatory effects, desensitization of nerve receptors, and modulation of pain signaling pathways. Additionally, some herbal compounds show promise for neuroprotection and immunoregulation, which can support pain control in chronic pain conditions.^10,11

Among these, the analgesic potential of silymarin is getting in the spotlight of scientists. Silymarin is extracted from the milk thistle plant Silybum marianum, and its health benefits in neuroprotection, immunoregulation, cardioprotection, and anti-cancer effects have been demonstrated. ¹² It has been selected for pain control research due to its multiple pharmacological properties, particularly its strong anti-inflammatory and antioxidant effects, which play a significant role in alleviating pain and related symptoms in various conditions. Studies showed that silymarin reduced pain responses in animal models, including formalin-induced pain and cisplatin-induced hyperalgesia, possibly through mechanisms involving histaminergic system interaction and oxidative stress reduction.^13,14 There is also evidence highlighting the analgesic capacity of silymarin in some conditions, like arthritis and neuropathic pain (Table 1). Ergo, the aim of this narrative literature review is to summarize and discuss the analgesic effects of this natural compound in these conditions with a mechanistic insight.

Table 1.

The current evidence regarding the analgesic potential of silymarin based on the clinical and experimental evidence.

Condition (s)	Dose (s)	Rout	Effect/mechanism (s)	Model	Ref.
Neuropathic pain	25, 50, and 100 mg/kg	Intraperitoneally	Decreasing inflammatory pain similar to diclofenac	In vivo (mice)	(15)
Diabetic neuropathy	50 and 100 mg/kg	Oral/Intraperitoneal	Attenuation of mechanical and thermal hyperalgesia through anti-inflammatory and antioxidative effects, modulation of oxidative stress markers	In vivo (rats)	(16)
Rheumatoid arthritis	280 mg/day for 2 months	Orally	Decreasing clinical manifestation of pain, liver toxicity, liver enzymes, and renal problems	Human	(17)
Inflammatory and thermal pain	5, 10, and 25 mg/kg	Subcutaneously	Decreasing writhing response time- and dose-dependently, increasing latency time comparable to morphine, elevating serum thiol levels and DPPH radical scavenging	In vivo (mice)	(18)
Thermal and inflammatory nociception	40–100 mg/kg	Intraperitoneally	decreasing writhing numbers compared with single therapies with silymarin and ketamine	In vivo (mice)	(19)
Inflammatory pain	1–10 μM and 50 mg/kg	Intraperitoneally	Attenuating calcium signaling through phospholipase C signaling and Orai channels in nociceptors and inhibiting thermal hyperalgesia	In vitro and in vivo (mice)	(20)
Cisplatin-induced neuropathic pain	25, 50, and 100 mg/kg	Intraperitoneal	Reduced hyperalgesia and neuropathic pain behaviors possibly via histaminergic system mediation	In vivo (mice)	(21)
Formalin-induced inflammatory pain	50 and 100 mg/kg	Intraperitoneal	Significant reduction of licking/biting behaviors in early and late phases through anti-inflammatory and antioxidant pathways	In vivo (rat)	(22)
Inflammatory pain	50, 100, 200, and 400 mg/kg	Intraperitoneally	Decreasing pain sensitivity in the first and second phases of the formalin-caused pain model	In vivo (rat)	(23)

Silymarin and chemistry

For the first time, silymarin was isolated and discovered by Wagner et al. in 1968. ²⁴ This lipophilic flavonoid compound is obtained from milk thistle seeds, and its composition comprises seven isomeric flavonolignans (i.e., silychristin A, silychristin B, silybin A, silybin B, isosilybin A, isosilybin B, and silydianin) as well as the flavonoid taxifolin. ²⁵ Flavonolignans are existed in the mixture of a flavonoid unit covalently linked to a lignin-originated moiety. The molecular formula and weight of the flavonolignan skeleton are C₂₅H₂₂O₁₀ (Figure 1) and 482 g/mol, respectively. ²⁶ Structurally, it has been stated that the existence of 2,3-double bonds in the C-ring of flavonoids is responsible for elevating antioxidant capacity. ²⁷ Silybin, accounting for 50%–70% of silymarin, possesses the highest biological function among silymarin components. Milk thistle seeds are composed of low levels of taxifolin (as a flavonoid) and approximately 20%–35% fatty acids, besides other phenolic constituents. ²⁸ Also, some other flavonolignans have been detected in the seeds, encompassing dehydrosilybin, desoxysilycristin, silandrin, silybinome, isosilybin, desoxysilydianin, neosilyhermin, and silyhermin. ²⁷

Figure 1.

Chemical formula of silymarin.

Silymarin and pharmacology

The pharmacological benefits of silymarin in a wide range of diseases, such as non-alcoholic steatohepatitis, ²⁹ breast cancer, ³⁰ acute hepatitis, ³¹ ulcerative colitis, ³² type 2 diabetes mellitus, ³³ nephrotoxicity, ³⁴ hepatotoxicity ³⁵ have been demonstrated in the clinical settings. Moreover. The obtained results from preclinical and clinical research have approved the anti-inflammatory, ³⁶ anti-oxidative, ³⁷ anti-cancer, ³⁸ anti-viral, ³⁷ immunomodulatory, ³⁹ and pro-apoptotic ⁴⁰ properties of this natural agent (Figure 2). Toxicological studies have shown that tolerability of silymarin is suitable, and its adverse effects mainly is limited to negligible allergic reactions, gastrointestinal disorders, headache, nausea, itching, and urticarial. ⁴¹ According to reports, silymarin has no potential to be teratogenic and toxic after death. In animal investigations, the safe doses of silymarin have been implicated at 2500 and 5000 mg/kg orally. ⁴² Because of its hydrophobicity, giving rise to bioavailability, silymarin is usually formulated in capsule form as a standardized extract, including 70%–80% active components. Also, silymarin formulation in self-emulsifying pellets causes elevation of pharmacokinetic absorption of its main active molecules.^43,44 Silymarin is typically absorbed orally and subsequently distributed in the gastrointestinal system, comprising the stomach, liver, pancreas, and intestine. Its metabolites are eliminated in the bile and exposed to enterohepatic circulation. ⁴⁵ It has been documented that the administration of silymarin can promote the bioactivity of a number of drugs whose biological functions are mitigated by the liver, for instance, amitriptyline, celecoxib, diclofenac, fluvastatin, ibuprofen, zileuton, losartan, glipizide, piroxicam, torsemide, tolbutamide, phenytoin, and tamoxifen. ⁴⁶ In a clinical trial in 2012, Moltó et al. assessed pharmacokinetic interactions between silymarin and antiretroviral drugs (i.e., darunavir and ritonavir) in HIV-positive individuals. Their outcomes reflected considerable reductions in AUC (area under the curve) and Cmax (peak concentration) indices once silymarin was co-used with the antiretroviral combination compared to the drugs prescribed without silymarin. ⁴⁷ Similarly, another study showed that the co-prescription of losartan with various sources of silymarin remarkably enhanced the circulatory concentration of losartan. ⁴⁸

Figure 2.

Different pharmacological and biological benefits of silymarin.

ROS, reactive oxygen species.

Silymarin and analgesic effects

Neuropathic pain

Hassani et al. have investigated the possible alleviating role of silymarin in formalin-induced nociception (as an inflammatory pain model) and neuropathic pain modeled by sciatic nerve ligation in vivo. In inflammatory pain-related groups, formalin (0.5%) was injected into the paw of mice, and nociceptive behaviors (licking/biting) were assessed. ¹⁵ The authors found that silymarin administration intraperitoneally at the doses of 25, 50, and 100 mg/kg 120 min before the intraplantar injection of formalin repressed the nociceptive reactions significantly during the inflammatory phase of the formalin test. Interestingly, it was shown that all used doses were effective in exerting antinociceptive effects. ¹⁵ This report can be expected due to the anti-inflammatory features of silymarin, especially by its inhibitive role in neutrophil infiltration and production of prostaglandin E2 (PGE2), interleukin (IL)-1β, and tumor necrosis factor-α (TNF-α). ⁴¹ However, the findings of the hot plate test indicated that silymarin therapy, 2 weeks following sciatic nerve ligation, could not decrease thermal hyperalgesia in animals, in contrast to imipramine, which exhibited strong analgesic influences. ¹⁵ Silymarin inefficiency in this context may be related to its inability to regulate vital pathways engaged in neuropathic pain, particularly β₂-adrenergic receptors (β2-AR). One of the main mechanisms of analgesic drugs is attributed to their functionality to induce β2-AR activation because the instigation of β2-AR can repress degranulation mast cells and dwindle the secretion of serotonin and histamine, which are known as amplifiers of peripheral nociception.^49–51 In another project, the pain-relief effects of oral administration of silymarin and rutin, one of the members of important flavonoids, alone (60 mg/kg/day silymarin and 100 mg/kg/day rutin) or in combination (30 mg/kg/day silymarin + 50 mg/kg rutin) for 6 weeks on streptozotocin (STZ)-caused diabetic neuropathy (DN) was scrutinized. ⁵² The mechanical and thermal hyperalgesia were monitored by paw pressure withdrawal test and tail flick test, respectively. The outcomes revealed that the combination therapy was superior to monotherapies by enhancing mechanical and thermal analgesia through exerting anti-inflammatory and antioxidative influences, as demonstrated by restored levels or activity of thiobarbituric acid reactive substances (TBARS; a lipid peroxidation marker), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione reductase (GR), and glutathione-S-transferase (GST). ⁵²

Arthritis

Appealingly, the analgesic effects of silymarin in rheumatoid arthritis patients who received methotrexate, a standard drug for these cases, have been evaluated in a double-blind randomized clinical trial. ¹⁷ In this work, 58 related patients in two distinct groups were included. In Group 1, patients received only methotrexate (2.5 mg for 6 months), and in Group 2, alongside methotrexate, silymarin (280 mg/day for 2 months) was administrated. Pain evaluation was done using the visual analog scale (VAS) questionnaire. Finally, it was observed that silymarin, without exerting a detrimental effect on blood parameters (e.g., platelets and WBC), can significantly decrease VAS scores in group 2 (p < 0.0001), addressing its role in pain relief in cases with rheumatoid arthritis. Another finding of this research showed the liver protective role, as evidence by a considerable reduction in alanine transaminase, aspartate aminotransferase, and alkaline phosphatase (p < 0.0001), and the ability of silymarin to abate inflammatory and renal parameters of these patients (i.e., erythrocyte sedimentation rate, blood urea nitrogen, and creatinine) in these patients. ¹⁷

Other findings regarding the antinociceptive and analgesic effects

Recently, silymarin has been identified using calcium imaging as a novel suppressor of intracellular pathways related to the sensitization of sensory neurons, a key inducer of pathological pain. ²⁰ Pathological pain mainly stems from excessive sensory neuron activity caused by several factors, such as neuronal stress, inflammatory responses, and axon damage.^20,53 This hyperexcitability is promoted through G-protein coupled receptor (GPCR) signaling, which in turn regulates voltage-gated ion channels and TRP-family ion channels.^54,55 In line with this notion, DuBreuil et al. have scrutinized new approaches to neutralize this sensitization using calcium imaging to monitor compounds repressing the intracellular pathways accountable for increased neuronal activity. This study has exhibited that a combination of two agonists, including CYM5541 (targeting S1PR3) and L-054,264 (targeting SSTR2), instigated calcium responses in sensory neurons in vitro and caused thermal hypersensitivity and pain in vivo. ²⁰ By monitoring a library of 906 bioactive substances, 24 repressors of this calcium signaling were discovered. Interestingly, one prominent compound was silymarin, which dramatically inhibited neuronal activation not only by inducing a cocktail but also by a different inflammatory cocktail comprising PGE2 and bradykinin. Of note, silymarin did not change baseline neuronal excitability; however, it particularly decreased calcium influx through Orai channels and downstream phospholipase C signaling (Figure 3). Another important point is that pretreatment with silymarin in animal models limited thermal hypersensitivity development conferred by inflammatory adjuvants, revealing its capacity as a targeted anti-inflammatory analgesic agent. ²⁰

Figure 3.

A schematic presentation regarding the analgesic mechanisms of silymarin.

Synergistic effects with ketamine and morphine

A preclinical study has focused on the antinociceptive influences of silymarin and its interaction with morphine, an opioid painkiller, in mice. In this work, there were five groups, including control (normal saline), silymarin (5, 10, and 25 mg/kg, subcutaneously), morphine (1, 5, and 10 mg/kg), silymarin+ morphine (10 mg/kg silymarin and 5 mg/kg morphine), and a group pretreated with an opioid antagonist (naloxone 2 mg/kg). ¹⁸ The antinociceptive actions were evaluated using the writhing test and tail flick test, referring to abdominal constrictions caused by acetic acid and tail withdrawal latency in reaction to thermal stimulus, respectively. ¹⁸ Silymarin could divulge antinociception dose-dependently in thermal (tail flick) and visceral (writhing) pain models. Also, this natural compound promoted morphine’s impact on nociception, addressing synergistic interaction. On the other hand, naloxone therapy limited the antinociceptive effects of silymarin, revealing opioid receptor engagement in antinociception mechanisms of silymarin. Moreover, other results of this research raised the possibility of the involvement of an enhanced antioxidant defense system, as evidenced by increased serum levels of total thiol molecules (TTM) and 2,2-Diphenyl-1-picrylhydrazy (DPPH) scavenging in the pain relief effects of silymarin. ¹⁸ Another study has explored the analgesic impacts of the intraperitoneal application of this flavonoid and ketamine, an anesthetic drug with analgesic features, once used singly or together on central (hot plate test) and visceral (acetic acid-conferred writhing test) pain and pharmacological interactions using isobolographic analysis in mice. ¹⁹ This scientific document showed that ED₅₀ values (median effective dose for analgesia according to hot plate test) for silymarin and ketamine are 57.22and 1.96 mg/kg, respectively; however, their combination use exhibited antagonistic interactions. Surprisingly, data from the writhing test indicated that concurrent use of silymarin and ketamine at doses of 120 and 4 mg/kg, respectively, remarkably decreased writhing numbers compared with these monotherapies. Collectively, these findings manifested the antagonistic interactions in the combination approach in the pathways related to central pain and synergistic interactions in combination therapy in visceral pain. ¹⁹ Regarding the writhing test, it is stated that following acetic acid injection, levels of PGE2 in the peritoneal cavity are considerably increased, so silymarin’s analgesic influences may be related to its ability to suppress prostaglandin synthesis. ²¹ Also, ketamine can serve as an analgesic agent in animals and humans by blocking NMDA receptors. ²² The reason behind the counteractive effects of the combination of these two therapeutic choices, as observed in the hot plate test, may be related to the restriction of silymarin to penetrating CNS or its interference with the central impacts of ketamine. Despite this, the anti-inflammatory features of silymarin may be the main reason for the promotion of the analgesic effects of ketamine based on the writhing test.

Conclusion

Pain is known as the most prevalent reported experience by subjects in alarming or pathological conditions, posing significant health and financial challenges. These years, bioactive compounds such as silymarin have acquired much attention in the medicinal and pharmacological arena. In this respect, the anti-inflammatory, anti-oxidative, anti-cancer, anti-viral, immunomodulatory, and pro-apoptotic characteristics of this flavonoid compound have been demonstrated. The diverse therapeutic and pharmacological benefits of silymarin have encouraged scientists to explore its analgesic potential in different conditions, like rheumatoid arthritis and neuropathic pain. The experimental evidence has shown that silymarin can serve as an analgesic agent through diverse mechanisms, such as decreasing calcium influx through Orai channels and downstream phospholipase C signaling and regulating opioid receptors. Also, in the two pathological conditions, data obtained from paw licking/biting scores, hot plate test, and VAS questionnaire approved the analgesic effects of silymarin mainly in light of its suppressive function in neutrophil infiltration and formation of inflammatory mediators, like PGE2, IL-1β, and TNF-α. Notably, the synergistic effects of silymarin with some analgesic pharmacological (e.g., morphine) or bioactive agents (e.g., rutin) have also been expressed by promoting the antioxidant defense system, as shown by elevated TTM and DPPH scavenging and restored TBARS, GSH, SOD, CAT, GPx, GR, and GST, and anti-inflammatory features. Despite these promising outcomes, more in-depth research is required to validate these reports. Also, more information is needed to find drug interactions of silymarin with other drugs to improve patient safety, therapeutic effectiveness, and better decide in clinical assessments.