Global use of Ethnomedicinal Plants to Treat Toothache

Toothache is one of the most common global health problems, and medicinal plants are widely used to relieve the associated pain and inflammation. Several studies have been conducted on the use of plants to treat toothache, but no study has comprehensively assessed the types of plants and the mechanisms of action of the phytochemical compounds involved in their analgesic effect. This review aims to bridge this gap. This is the first review to collect a large volume of data on the global use of medicinal plants used in the treatment of toothache. It presents the relevant information for dentists, researchers, and academics on using medicinal plants to treat toothache. We found that preclinical studies and state-of-the-art technology hold promise for furthering our knowledge of this important topic. In total, 21 species of medicinal plants used to treat toothache were found in America, 29 in Europe, 192 in Africa, 112 in Asia, and 10 in Oceania. The most common species were Allium sativum, Allium cepa, Acmella oleracea, Jatropha curcas, Jatropha gossypiifolia, and Syzygium aromaticum. The most commonly found family of medicinal plants was Asteraceae, followed by Solanaceae, Fabaceae, Lamiaceae, Euphorbiaceae, Rutaceae, and Myrtaceae. The most common phytochemicals found were flavonoids, terpenes, polyphenols, and alkaloids. The reported mechanisms of action involved in toothache analgesia were antioxidant effects, effects mediated by transient receptor potential channels, the ?-aminobutyric acid mechanism, and the cyclooxygenase/lipoxygenase anti-inflammatory mechanism.

Toothache is an unpleasant sensory and emotional experience 1 . originating in the tooth or adjacent structures and is caused by factors such as caries, periodontal disease, trauma, or dentoalveolar abscess 2 . It is one of the most common health problems worldwide 3 . Toothache has a higher prevalence in lower socioeconomic groups, in whom this disease is not always adequately treated 4 ., and in developing countries, where access to healthcare is limited. This has led many local communities to resort to using alternatives for toothache relief, such as medicinal plants 3 .
Medicinal plants are widely used in dental practices. The World Health Organization has reported that between 65% and 80% of the population in developing countries use them to reduce inflammation, inhibit oral pathogen growth, and trigger anti-inflammatory, antiseptic, antioxidant, and analgesic effects 3,4 . Several phytochemical studies conducted on these plants have identified compounds such as flavonoids, alkaloids, and terpenes, which reduce toothache through their mechanism of action 3,[5][6][7] .
Phytotherapy is the use of plants to treat diseases or as health-promoting agents. When used for this purpose, their original composition and integrity are generally preserved, so that an entire plant or a desired percentage of its components may be used for medicinal purposes, fulfilling a specific mechanism of action, generally, a specific pathway to relieve pain [8.. However, to our knowledge, no study has comprehensively tackled the mechanisms of action of the phytochemical compounds contained in medicinal plants used to treat toothache. This integrative review aimed to bridge this gap by compiling and analyzing the different studies available in the literature.

Materials and Methods
The available literature in PubMed, PMC, and Scopus databases was searched to identify relevant articles on medicinal plants used to relieve toothache, published in English until July 31, 2021, using the search terms toothache, dental pain, medicinal plants, medicinal herbs, and phytochemicals. Articles unrelated to the use of plants that relieved toothache or lacking data for at least one of the following characteristics were excluded: family, scientific name, plant parts used, and method of preparation.
Of a total of 300 articles, 80 met the inclusion criteria and were comprehensively analyzed for this review. In addition, we performed a manual search of the reference lists of the initially selected articles to complement the available information and found 294 additional articles. Ten books with relevant information were also included. Regional medicinal plant types retrieved from the articles and books were summarized by continents. Finally, owing to length restrictions, this review did not include information related to the possible adverse reactions and drug interactions resulting from the use of the plants included in this review.

Medicinal plants for toothache treatment
For several millennia, plants have been used in traditional dentistry to treat toothache, periodontal disease, herpetic ulcers, stomatitis, maxillary sinusitis, and other ailments 6 . In recent years, advances in science and technology have identified the phytochemical compounds in some of these plants and their mechanisms of action 3 . Phytochemicals are a large group of plant-derived chemical substances that have various biochemical and physiological effects that are beneficial for human health and nutrition 6, 9 . Phytochemicals found in plants vary greatly in number, structural heterogeneity, and distribution, and they are classified into polyphenols, carotenoids, alkaloids, terpenes, and terpenoids 10,11 . All the tables in this review outline the phytochemicals described in previous reports on medicinal plants used to treat toothache, focusing on their analgesic mechanisms of action.

Plant parts and preparation method
As mentioned above, plants are used to treat diseases through phytotherapy, using either the entire plant or a desired percentage of its components [8.. The most commonly used parts of medicinal plants are the leaves, seeds, flowers, and roots. The roots, in particular, are highly important because they are higher in bioactive compound content than other plant parts 3,[12][13][14] .
Leaves contain high concentrations of secondary metabolites, phytochemicals, and essential oils that have various health benefits [14.. Hence, most of the research studies support the use of leaves instead of roots because root extraction threatens the conservation of several plant species, especially those that are widely used 3,14 .
There is considerable variation in the preparation methods of plants used to treat toothache, and the most common methods of administration are: using the plant extract, chewing, crushing, and drinking a decoction 3 .

Mechanisms of action of phytochemical compounds
Phytochemicals such as flavonoids, alkaloids, and terpenes 3,5 . are biologically active compounds found in plants that work through various mechanisms of action 15,16 . Based on the information gathered in this review, the most salient mechanisms of action of phytochemicals used to treat toothache were antioxidant activity 9,17 ., action on transient receptor potential channels (TRP) 18 , ã-aminobutyric acid (GABA) mechanism 19,20 , and anti-inflammatory mechanisms (cyclooxygenase (COX) and lipoxygenase (LOX) pathways) 21 .

antioxidant activity
In living organisms, reactive oxygen species (ROS) are generated during metabolism and do not generally cause oxidative damage to cellular components due to the action of antioxidants present in these organisms 22 .
Natural antioxidants are found in various plants and play a key role in stopping the generation of free radicals by preventing the oxidation of biomolecules in the body. Therefore, they are valuable therapeutic agents for preventing diseases caused by oxidative stress. The latter causes an imbalance that favors the production of prooxidants, represented by ROS, such as superoxide anions (O 2 -), hydrogen peroxide (H 2 O 2 ), and hydroxyl radicals (OH -) 23 , which damage key cellular components, such as DNA, proteins, and membrane lipids, and can even trigger cell death 17,[24][25][26][27] .
Conversely, during inflammatory processes, free radicals balance themselves by attacking the nearest stable molecule and "stealing" an electron. The attacked molecule then becomes a free radical by losing its electron and initiating a cascade of cell-damaging reactions 24 . Additionally, leukocytes present in damaged regions cause a "respiratory burst" from enhanced oxygen uptake, and inflammatory cells generate inflammatory mediators that act on the infection site to release more reactive species 24,28,29 .
Therefore, the role of antioxidants is to delay, prevent, or eliminate oxidative damage of target molecules by controlling the levels of free radicals and other reactive species 30 . Plants are responsible for our oxygenated environment, and because they are exposed to high intracellular levels of oxygen and ROS, they have developed specialized defense systems (antioxidants) to protect their structures and tissues. Antioxidant activity is inherent to all plants as they act to prevent, destroy, or neutralize free radicals 17 .
These antioxidant defense systems can be enzymatic complexes and non-enzymatic systems. Some enzymatic complexes are superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR). Non-enzymatic systems consist of lowmolecular-weight antioxidants such as ascorbic acid, glutathione, proline, carotenoids, phenolic acids, and flavonoids; and high-molecularweight secondary metabolites, such as tannins, which efficiently prevent the toxic effects of free radicals 31,32 .
The phytochemicals in plants can act as antioxidants by directly eliminating ROS, chelating metals (Fe, Zn, Mg, and Mn), quenching the mitochondrial respiratory chain, and increasing the levels of endogenous antioxidant enzymes, such as SOD, CAT, and GPx 9, 31 .
ROS and reactive nitrogen species (RNS) are key players in various types of pain 33 . Evidence suggests that tissue injury induces the production of both ROS and RNS, which cause pain by promoting neuronal excitability in pain pathways through neural interactions and by triggering mitochondrial dysfunction and neuro-inflammation 26,34 .
Peroxynitrite (ONOO -) (PN) and its precursor superoxide (SO) are critical in the development of chronic pain and in the transition from acute to chronic pain [35.. An increase in SO/PN production triggers thermal hyperalgesia associated with acute and chronic inflammation in response to the activation of the N-methyld-aspartate receptor (NMDAR), leading to the development of orofacial pain 36 .
PN improves protein kinase C (PKC) activity. This kinase is activated by peripheral and central sensitization and optimizes the translocation of regulatory subunits of NADPH oxidase to the cell membrane to increase the production of SO derived from NADPH oxidase. These two mechanisms together amplify the formation of SOderived PN, leading to the development of central sensitization 35 .
Thus, antioxidants can be administered for pain management to prevent the negative impact of ROS and RNS on nociception, both of which play key roles in neuro-inflammatory processes both at the central and peripheral levels, leading to increased nociceptive and inflammatory responses 26,33,37,38 .
In addition to their antioxidant activity, flavonoids and phenolic compounds exhibit effective anti-inflammatory biological properties by blocking two main signaling pathways, NF-5ØßB and mitogen-activated protein kinase (MAPK) 24 . These pathways initiate a cascade of phosphorylation events and result in the production of several pro-inflammatory mediators that mediate the transmission of extracellular signals from the membrane to the nucleus 24,27,39 . action on trP channels TRP channels are involved in various homeostatic and sensory functions, such as nociception and temperature sensation, and are expressed in both neuronal and non-neuronal cells. They are grouped into six subfamilies: TRP ankyrin (TRPA), TRP canonical (TRPC), TRP melastatin (TRPM), TRP mucolipin (TRPML), TRP polycystin (TRPP), and TRP vanilloid (TRPV). They are mostly non-selective cation channels expressed on the cell membrane, including the TRPA1 channel, a Ca 2+ -permeable channel expressed in sensory neurons and is activated by phytochemicals and multiple products of oxidative stress 18 .
The Ca 2+ -permeable TRP channels of presynaptic terminals can modulate synaptic transmission independent of action potentials. Thus, the TRP channels, TRPV1, and TRPA1 can cause the release of neurotransmitters at sensory nerve terminals where these channels are highly co-expressed and participate in inflammatory hyperalgesia 18,40 . Capsaicin (hot pepper), allicin (garlic), camphor (Cinnamomum camphora), rosemary, and menthol (peppermint) are all analgesics that excite and desensitize nociceptive sensory neurons by acting on the TRPA1 and TRPV1 channels [41][42][43] .
Other phytochemicals also activate the TRP channels. For example, curcumin (Curcuma longa) activates TRPA1 channels; eugenol activates the TRPV1 and TRPV3 channels; menthol activates TRPM8 channels; ginger components activate the TRPV1 and TRPA1 channels; and the thymol and linalool compounds of thyme (Thymus vulgaris) activate the TRPV3 and TRPA1 channels 18 . GaBa mechanism G A B A i s a m a j o r i n h i b i t o r y neurotransmitter 44 . involved in most inhibitory actions in the central and peripheral nervous systems (CNS and PNS). GABA exerts its action through two types of receptors: ionotropic (GABAA and GABAC) and metabotropic (GABAB) receptors. GABAA and GABAC are ion channels found in CNS neurons that are permeable to chloride ions when activated by GABA. GABAB receptors belong to the superfamily of G protein-coupled   receptors and are present at different levels of the  pain neuraxis where they regulate nociceptive  transmission and pain 19,45,46 .
Some phytochemicals, including flavonoids and terpenes, modulate the function of ionotropic GABA receptors and can act as positive, negative, and neutralizing allosteric modulators. Thus, herbal preparations such as Heliopsis longipes, Acmella caulirhiza, Ginkgo biloba, Panax ginseng, and Scutellaria lateriflora may help modulate toothache by crossing the blood-brain barrier and influencing brain function. Past research has suggested that an increase in GABAergic activity in the rostral agranular insular cortex may induce analgesia by enhancing the descending inhibition of spinal cord nociceptive neurons 19,47 .
Spilanthes acmella is a flowering herb species, also known as the "toothache plant" [48][49][50] . It has been used for centuries to treat oral pain owing to its analgesic, anti-inflammatory, and anesthetic properties attributed to its bioactive compounds, especially phytosterols, phenolic compounds, and N-alkylamides 48,50,51 . Spilanthol, which is mainly present in the flowers and shoots of S. acmella, is the most representative compound found in this genus. This plant species and other species such as H. longipes are used worldwide as traditional remedies for their analgesic, antinociceptive, antioxidant, and anti-inflammatory effects. The analgesic effect of this compound is attributed to GABA release in the temporal cerebral cortex, whereas the antinociceptive effect is caused by the activation of the opioid-adrenergic, serotonergic, and GABAergic systems 52 .
The flavonoid baicalein, which can be extracted from S. lateriflora, exerts sedative and anxiolytic effects by binding to GABAA receptors and, hence, could be used to manage orofacial pain. This flavonoid is also believed to modulate both intra-and extracellular calcium levels, which play key roles in pain signaling and transmission 44 .
GABA receptor systems are found in peripheral pathways and the spinal cord, which are both important sites for pain impulse formation and transmission; they are located in the marginal zone and substantia gelatinosa of the dorsal horn, which are essential for interpreting and responding to pain signals. These findings indicate that GABA plays a key role in nociceptive processing. Consequently, agents that modify the function of this inhibitory neurotransmitter are used as analgesics 46 .

Anti-inflammatory mechanism (COX and LOX pathways)
Inflammation is mediated by several families of mediators such as eicosanoids, which are lipid mediators produced through arachidonic acid metabolism, primarily in the COX and LOX pathways 53 . The COX pathway leads to the formation of prostanoids (prostaglandins (PG), prostacyclin, and thromboxane), whereas the LOX pathway leads to the production of leukotrienes (LTs) 54 .
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the COX pathway, whereas other drugs such as licofelone are dual inhibitors that block both COX and LOX 54,55 . However, the selective inhibition of the two COX isoforms by NSAIDs has several reported side effects. This has encouraged the search for a dual inhibitor of both COX-2 and 5-LOX that possesses improved antiinflammatory potency and fewer side effects 53,56 .
This anti-inflammatory effect leads to the elimination of harmful stimuli and the restoration of normal physiology through the complex molecular cascade mentioned above 3,21 . This is thought to be the mechanism by which herbal extracts act in the treatment of toothache 21 . Accordingly, medicinal plants, particularly herbs whose main component is curcumin, such as C. longa, seem to provide several advantages through their mediating action on the COX and LOX pathways. As a dual inhibitor, curcumin exhibits synergistic effects and optimal anti-inflammatory activity 57 . Allium cepa (onion), which also contains polyphenols and flavonoids, inhibits the COX and LOX pathways and prevents the formation of LTs, thromboxane B2 (TXB2), and prostaglandin E2 (PGE2) 58,59 .
Additionally, various ginger compounds, such as gingerols, shogaols, zingerones, gingerdiols, and paradols, exhibit antioxidant, analgesic, and anti-inflammatory activities. More specifically, they act through the inhibition of COX and LOX in addition to their antioxidant activity resulting in an analgesic effect 60 . Allium sativum also has antioxidant and anti-inflammatory properties, and its efficacy in reducing pro-inflammatory responses is based on its nature as a COX and LOX inhibitor 59 .

Bioavailability of medicinal plants
In humans, most phytochemicals exhibit low bioavailability after ingestion 9 . Hence, polyphenols have a rather low bioavailability because they exert most of their antioxidant activity in the gastrointestinal tract 61 . Additionally, a challenge with flavonoids is their low water solubility, which leads to decreased absorption and consequently decreased bioavailability following oral administration 62 .
Interindividual variability, which depends on several factors such as diet, genetic background, composition, and activity of the intestinal microbiota, must also be considered. For example, polyphenols are relatively poorly absorbed (0.3-43%), resulting in low circulating plasma concentrations of their metabolites 63 . Additionally, the quantity and composition of phytochemicals in plants are influenced by species, age, plant part, cultivation method, harvesting season, conservation method, and geographic distribution 9,64 .
To improve bioavailability, proper decoction practices and various plants combinations have been suggested 65 . due to their different phytochemical components and because they may provide different health benefits without requiring an increase in the dose 9 . For example, Piper sarmentosum combined with ginger is used to soothe toothache 66 . Medicinal plants containing hundreds of phytochemicals can produce many metabolites in the body, exerting more efficient beneficial effects than individual phytochemicals 9 . However, their combination can also directly affect their bioavailability in the body via mechanisms such as the first-pass effect 18,67 .

Medicinal plants vs pharmaceutical drugs
Comparisons between the analgesic effects of medicinal plants and pharmaceutical drugs have shown that the rhizome of Zingiber officinale (ginger) has long been used in traditional Chinese and Indian medicine to treat a wide range of ailments, including toothache 68 . Fresh ginger extracts have been subjected to chromatographic purification, and the resulting fractions were analyzed to assess their effect on PG synthesis. Through this method, plant extracts belonging to the Zingiberaceae family were found to inhibit PG synthesis in vitro 69 .
The rhizome of Z. officinale has pharmacological properties similar to those of dual-action NSAIDs [55.. It inhibits both COX and LOX and has significantly fewer side effects than conventional NSAIDs 69,70 . Licofelone is an example of a dual-action NSAID (5-LOX/COX) that is currently in phase III clinical development 55 . Studies have shown that orally administered dry ginger or ginger extract can reduce acute inflammation 68,71 , and in vitro and in vivo comparisons have confirmed the anti-inflammatory and analgesic actions of ginger extract 69,70 .
However, most in vitro studies analyzed phytochemical profiles using indices such as the half-maximal inhibitory concentration (IC 50 ), and the medicinal plant extracts have been tested for only a single biological target, COX or LOX. This is insufficient to validate their anti-inflammatory and analgesic properties and hinders direct comparisons between plants and dual-action NSAIDs 72 .
The anti-inflammatory properties of ginger extracts come from a mixture of biologically active components such as gingerols, shogaols, and paradols, which are phenolic compounds 73 . The inhibitory effects of ginger on PG synthesis can be attributed to the presence of hydroxymethoxyphenyl compounds in gingerols and shogaols, which in turn inhibit arachidonic acid metabolism via the COX pathway 69,74 . Moreover, ginger components inhibit several genes encoding cytokines and chemokines involved in inflammatory responses 69,75 .
Essential oil from the fruit of the plant Dennettia tripetala (DT), commonly known as pepper fruit, has analgesic effects like those induced by opioids morphine, aspirin, and indomethacin. The analgesic mechanism of DT has been inferred from studies showing that naloxone, which inhibits the analgesic effect of morphine, could also inhibit DT. These findings suggest that DT can also be used for toothache relief 22 .

Plant combinations
Mixtures of medicinal plants are a key field of research which accounts for a large volume of information because their polyvalent effects can be used to cure multicausal diseases 76 . In different regions and cultures, plants are used as the entire plant, a combination of plants, or a combination of a plant and a drug. When medicinal plants are mixed, side effects are more likely to happen because interactions can occur between individual components. The most desirable interactions provide additional therapeutic benefits. However, natural extracts also contain multiple components. Therefore, the effects of interactions between two plants are often unpredictable and complex 77 .
Additionally, a combination of two or more phytochemicals does not always enhance a specific effect. Combining two or more active chemical substances can produce additive, synergistic, or antagonistic effects 9,78 . An example of synergism in the use of medicinal plants is Iberogast®, a phyto-preparation used in European countries consisting of nine plant extracts. It is considered to have a multi-target effect (at the gastrointestinal level). Such a multi-target effect has advantages over that of synthetic single-target drugs 79,80 .
Another example is the phytotherapeutic drug Lenidase®, which, when compared to ibuprofen, more efficiently and safely controls postoperative pain and discomfort following third molar extraction. Lenidase® contains a blend of herbal extracts, such as baicalin (190 mg), bromelain (50 mg), and escin (30 mg) 81 , which exhibit anti-inflammatory activities. Bromelain inhibits pain mediators such as PGE2 and substance P and exhibits anti-edematous activity. Baicalin regulates several genes associated with inflammation, such as COX, LOX, and the inducible nitric oxide synthase gene. Escin exerts antiinflammatory and anti-edematous effects through antihistaminic and antiserotonergic activities 81 .

ResuLts And disCussiOn
As discussed above, medicinal plants, their phytochemicals, and their mechanisms of action are key subjects of scientific research because they are used to treat and prevent various diseases. Further, plants are the basis of many drugs. Although they are highly complex compounds and are not always suitable substitutes for synthetic agents 82 , phytochemicals have been used to provide relief from toothache in various regions of the world, as outlined in the five tables included in this review.
The components of the medicinal plants used and their preparations vary by location and between species. For example, a study conducted  in America revealed that leaves were the most commonly used plant parts and that the most common preparations were pastes, extracts, and rinses 83 . Another study conducted in Africa found that Datura stramonium L. roots, leaves, stems, and seeds were often used to provide relief from toothache 3 . These findings demonstrate the need for further phytochemical and pharmacological studies to identify the plant part that is most effective for toothache treatment and the optimal application  [3,191] alkaloids, stereol and polyterpene.

Roots
Chewed Alkaloids, saponin glycosides, x x Antioxidant activity [3,193] [90,374] flavonoids, and phenolic compounds GABA mechanism method to increase its action. The parts used may vary with the medicinal plant; however, we found that the most commonly used plant parts were leaves and roots, followed by the bark, stem, and seeds (Fig. 1). Preferentially using the leaves instead of roots can also prevent detrimental effects on the plants.
The most common phytochemicals involved in the mechanism of action of medicinal plants for toothache treatment are polyphenols, more specifically, flavonoids and terpenes, which are the most abundant secondary metabolites and antioxidants in the human diet 3, 5-7 . Flavonoids are the most ubiquitous group of all plant phenolics, which could explain the implicit antioxidant capacity of all medicinal plants 84 . Furthermore, flavonoids can modulate the function of ionotropic GABA receptors, suggesting that these phytochemicals can exert different mechanisms of action to relieve pain 20 .
Polyphenols are strong antioxidants that neutralize free radicals by donating an electron or a hydrogen atom 61 , thus exerting antioxidant effects in plants and organisms that consume them. However, polyphenols decrease the concentrations of ROS and RNS far from the site of the primary response because the local concentrations of these radicals around the inflammatory site are substantially high (> 1 mM). Therefore, polyphenols are highly unlikely to be effective where these free radicals are produced but could be quantitatively more effective as antioxidants in the surrounding unaffected tissues 85 .
Substances such as capsaicin, allicin, camphor, and menthol cause a state of activation and desensitization in the TRP receptor pathway through which pain may be reduced 18,43 . Of these phytochemicals, only allicin was analyzed in the studies included in this review. Moreover, allicin and spilanthol, compounds present in A. caulirhiza, have various biological and pharmacological effects, which may cause analgesia 3,52 . Further studies should be performed to better understand the roles of these phytochemicals.
T h e m e c h a n i s m s o f a c t i o n o f phytochemicals in toothache relief are only partly understood. This review shows that these mechanisms involve antioxidant activity, action on TRP receptors, GABA mechanism, and COX/LOX inhibitory activity. The tables in this review outline 163 medicinal plants with antioxidant mechanisms of action, 20 with an anti-inflammatory mechanism (COX/LOX), four with GABA mechanism, and two with TRP mechanism. Some plants have two reported mechanisms of action. However, in general, there is insufficient literature addressing each mechanism responsible for toothache relief.
Several reports cite the use of various plants for toothache treatment; however, in many of these reports, the mechanism of action underlying pain relief is not specified, as indicated in the tables in this review. Moreover, in several studies, the phytochemicals potentially responsible for the analgesic effect were not reported. Accordingly, future studies should focus on identifying the exact mechanisms that contribute to dental analgesia and the phytochemicals involved. Additionally, the "common names" of medicinal plants were not included in this research, considering the extensive information involved in the preparation of this manuscript.
As mentioned above, we found only one study comparing the pharmacological properties of medicinal plants with those of conventional pharmaceutical drugs 81 . However, 30 plants with dual anti-inflammatory mechanisms (COX/LOX) were identified, as outlined in the tables for each continent. This information could be useful in future comparative studies of conventional or dual NSAIDs.
Although dual inhibition of microsomal PGE2 synthetase (mPGES-1) and 5-LOX has not been described as a mechanism of action in the reports included in this review, several plants (some of which are indicated in our tables) contain acylphloroglucinols, phenolic compounds, and non-phenolic acidic structures that exhibit such dual action 86 . mPGES-1 is an inducible enzyme at inflammatory sites that preferentially receives its substrate from co-induced COX-2 and is responsible for the excessive formation of PGE2 during acute and chronic inflammation [87, 88.; thus, its inhibition could be a promising strategy for toothache treatment with medicinal plants. Furthermore, natural mPGES-1 inhibitors have advantages over NSAIDs since they are nonsynthetic and safer because they do not inhibit COX-derived homeostatic eicosanoids 86 .
However, in several in vitro and in vivo studies (utilizing indices such as IC 50 ), the vast majority of medicinal plant extracts have been tested only against one biological target (COX or LOX), which is insufficient to validate their anti-inflammatory and analgesic properties and hinders direct comparisons between plants and conventional or dual-action NSAIDs 72 . Therefore, further studies should be conducted to address this gap in research and gather more relevant information.
Multiple experimental studies of COX-1/ COX-2 inhibition have used IC 50 (the concentration at which an NSAID produces 50% inhibition of both COX enzymes) to rank the relative inhibitory activity of NSAIDs on these enzymes, and consequently, establish their selectivity over COX, correlating this in vitro inhibition with clinical efficacy and toxicity levels 89 . However, IC 50 values do not indicate the mechanism of enzyme inhibition and vary with substrate concentration. Furthermore, these values are not directly comparable unless identical experimental conditions are used, and they must be analyzed carefully when inhibition is time-dependent 89 . These drawbacks also (91) hinder direct comparison between medicinal plants and NSAIDs.
Only two studies on plant combinations were found for this review. The study on phytotherapeutic Lenidase® 81 . was already described above. The other reported on the use of seven popular medicinal plant mixtures for toothache in Europe (Catalonia), including several species 76 . whose use was not found in other continents.
Although medicinal plants are distributed throughout the world 90 , biodiversity could affect how intensely such plants are used for toothache, and thus the discovery of new drugs 91 . The 17 most megadiverse countries in the world are Brazil, Colombia, Mexico, Peru, Ecuador, Venezuela, the United States of America, Indonesia, Australia, Madagascar, China, the Philippines, India, New Guinea, Malaysia, South Africa, and the Democratic Republic of Congo; most of these are in the American continent 49 . However, in this present review, most of the information on medicinal plants was gathered from Asia (Table 4) and Africa (Table  5), possibly because herbal medicines remain a key component of healthcare systems in the developing cultures of these continents 90 . Oceania has only two of the 17 megadiverse countries, which may explain the scarcity of plants in this continent (Table 5). Nevertheless, in some regions, much of the traditional knowledge about medicinal plants is only spread verbally and, thus, remains unexplored and unreported 93 .
In terms of plants used in different continents, A. sativum was found in America (Table  1), Europe (Table 2), and Africa (Table 3); A. cepa and Syzygium aromaticum were found in Europe, Africa, and Asia; and Acmella oleracea, Jatropha curcas, and Jatropha gossypiifolia were all found in America (Table 1), Africa (Table 3), and Asia (Table 4). Conversely, some species are found only in one continent, such as Thymus schimperi Ronniger in Africa, perhaps because this species is a rare plant highly localized in and endemic to Ethiopia 94 .
Among the families of medicinal plants used worldwide, Asteraceae was the most common, followed by Solanaceae, Fabaceae, Lamiaceae, Euphorbiaceae, Rutaceae, and Myrtaceae (Fig. 2). The first three of these families have been widely reported as those most commonly used to treat inflammation and various types of pain 44,44,76 .
Notably, the present review discusses several medicinal plants for toothache treatment, which have been globally classified by continents, unlike all the referenced studies, which were approached separately. Moreover, the five tables provide details about the parts used, preparation, phytochemicals, analgesic/anti-inflammatory effect, and mechanisms of action, contrary to most studies that do not include such details. Additionally, this review analyzes all the mechanisms of action of the medicinal plants that have been ascribed until now for toothache treatment, unlike many studies that only cite these mechanisms. Furthermore, we have included a section comparing medicinal plants and pharmaceutical drugs, unlike all the referenced studies that do not provide such a comparison. Finally, this review discusses the use of medicinal plants for the treatment of dental pain, while most articles deal with this topic on a general basis.

Future perspectives
Although phytotherapy has a long history, natural medicines are considered a hidden source of drugs because many medicinal plants have not been studied in depth 79 . Accordingly, further studies should be conducted to better understand the role and benefits of phytotherapeutic drugs 81 . for toothache treatment, particularly when combined based on the multi-objective therapeutic principle of phytotherapy 79,95 . This principle would be analogous to the multimodal analgesic approach used for NSAIDs [96][97][98] .
A r o m a t h e r a p y a l s o h a s n o npharmacological therapeutic potential for reducing toothache by combining highly complex mixtures of essential oils to produce a therapeutic effect 95 . Therefore, further research should be conducted in this field of alternative medicine.
Although polyphenols in organic food extracts (extractable polyphenols) have already been analyzed, significant amounts of potentially bioactive polyphenols that remain in the residues (non-extractable polyphenols) have been overlooked. Additionally, significant amounts of non-extractable polyphenols are found in foods and vegetables 61,99 . Therefore, these compounds should be considered for future studies.
A promising therapeutic option for the administration of flavonoids that may increase their bioavailability is to develop protective systems, such as microcapsules, nanoparticles, and nanoformulations, which improve water solubility, dissolution, absorption, and thermal stability. Accordingly, in the near future, such systems should be developed and administered for pain management 62 .
Finally, human clinical trials are essential to confirm the effectiveness of traditional phytotherapy for toothache and to investigate the pharmacodynamic and pharmacokinetic interactions between medicinal plants and other synthetic drugs. Similarly, predictive (in silico) models, phytochemical analyses, and ethnopharmacological studies could be milestones for drug discovery in traditional medicinal plants for toothache treatment, because many of them lack information or have not been studied.

COnCLusiOn
This is the first review to compile a large volume of data on the global use of medicinal plants for the treatment of toothache. A total of 21 species of medicinal plants were found in America (Table 1), 29 in Europe (Table 2), 192 in Africa (Table 3), 112 in Asia (Table 4), and 10 in Oceania (Table 5). Asia and Africa are the continents where the most research has been done on this topic. Asteraceae was the most commonly found plant family in this review, followed by Solanaceae, Fabaceae, Lamiaceae, Euphorbiaceae, Rutaceae, and Myrtaceae.
In total, 364 medicinal plants used for toothache treatment were identified, of which 139 have not yet been scientifically studied, highlighting opportunities for ethnopharmacological research on toothache treatments. The most common species were A. sativum, A. cepa, A. oleracea, J. curcas, J. gossypiifolia, and S. aromaticum. These families and species were more commonly found in Africa and Asia, corroborating our previously reported findings. As determined in this review, the most commonly used plant parts were the leaves and roots, followed by the bark, stems, and seeds.
We identified four mechanisms of action of medicinal plants implied in toothache treatment, namely, the antioxidant effect, effects mediated through TRP receptors, GABA mechanism, and the anti-inflammatory mechanism (COX/LOX). Flavonoids, terpenes, polyphenols, and alkaloids are the phytochemicals most commonly associated with toothache treatment. Many of the plants analyzed in this review have the potential to be used as agents for toothache treatment. Therefore, future studies must prioritize the analysis of their pharmacodynamic and pharmacokinetic interactions.
Finally, to more precisely clarify the usefulness of medicinal plants as a valid option for toothache treatment, comparative studies between medicinal plants and commonly used pharmaceutical drugs should be conducted. In addition, studies published in Spanish should be included in future reviews since we only analyzed studies published in English, and this may have limited our ability to gather additional information.

None. ethical statement
Ethical approval was not required for this review article.

Conflicts of interest
The authors declare no conflicts of interest.