A Systematic Review of Traditionally Used Herbs and Animal-Derived Products as Potential Analgesics

Abstract

Pain is a distressing but fundamental manifestation that prepares the body for potentially detrimental stimuli while ensuring its protection. Plant and animal products have traditionally been used to relieve pain for centuries. However, no attempt has been made to compile a single report of plant and animal products possessing analgesic properties. This review enadeavours to recover data from published articles to establish a collective literature review on folk remedies from plant and animal sources used as analgesics and in the treatment of pain-related conditions, identifying gaps in existing knowledge and future works. Relevant information was systematically retrieved using the PRISMA method. In this review, in total, 209 plants were found to be either used raw or prepared by decoctions or maceration. Administration was either oral or topical, and they were predominantly used in Asian countries. In vivo studies of plants with analgesic properties, which were tested using different methods including acetic-induced writhing test, hotplate test, tail-flick test, and formalin-induced pain test, were compiled. Animal products with analgesic properties were obtained mainly from compounds present in venom; their bioactive compounds were also identified. In the literature search, certain gaps were noted, which could be reviewed in future studies. For instance, there was a disparity of information regarding the traditional uses of medicinal plants. In this review, an attempt was made to critically assess and describe the pharmacological properties and bioactive composition of indigenous plants, some animal species, and animal venom by scrutinizing databases and looking for published articles. Therefore, it can be concluded that the compounds obtained from these sources can serve as important ingredients in therapeutic agents to alleviate pain once their limitations are assessed and improved upon. In the literature search, certain gaps were noted, which could be reviewed in future studies.

1. Introduction

The ubiquitous nature of pain is complex. It entails both the peripheral and central nervous systems with multiple neurotransmitters and receptor-mediated events. In addition, emotional and psychological modifiers participate in the experience [1]. Pain is a distressing but fundamental manifestation that prepares the body for a potentially detrimental stimuli, while ensuring its protection. This notion highlights the biological importance of pain, which is relevant when acute pain is experienced. Basically, acute pain occurs for a short duration and can be attributed to diseases or injury. Nonetheless, pain can also last for a longer duration than the predicted prognosis; this pain is termed chronic or persistent pain. In this condition, pain no longer plays a role as a signal for impeding danger [2].

The International Association for the Study of Pain describes the term “pain” as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.” Consequently, pain is a term that has evolved from a mono-dimensional to a multidimensional entity entailing several aspects, such as sensors, cognition, motivation, affection, behavior, and spirituality [3]. Pain is often subjected to each individual’s perception of their experience related to injury or physical damage. Pain can be classified based on pain physiology, intensity, temporal characteristics, type of tissue affected, and syndrome.

Despite the fact that pain is regarded with such significance, chronic pain is considered a plague. It is quite perplexing to evaluate, manage, and treat it as a multifactorial condition [4]. A statistical report stated that more than 1.5 billion of the global population suffers from this agonizing condition [5]. Regardless of the alarming prevalence of chronic pain, the mechanisms underlying the transition from acute to chronic pain are still unclear. The amplification of pain is multifactorial. Risk factors contributing to the severity of the condition include genetic predisposition, age, gender, previous experience, and attitude toward pain [6]. Some of the most commonly experienced pain-related conditions include back pain, headaches, migraines, angina pectoris, arthritis pain, nerve damage pain, and cancer pain. In other conditions, such as fibromyalgia, patients experience pain at a significantly higher level [7]. Therefore, pain relief and management are a matter of great importance and have been regarded as one of the uttermost human equity.

Moreover, pain can also be trivial and transient; thus, the ascendency and favorable outcomes of folk remedies or conventional methods for its treatment cannot be left unnoticed [8]. Nevertheless, at times, pain may be perpetual, and conventional methods, including opioid and non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), and corticosteroids, among others, are less potent [9]. Medications commonly used to alleviate pain include drugs such as ibuprofen, naproxen, aspirin, acetaminophen, anti-depressants, and anti-seizure medications [10]. However, conventional therapies have been linked with multiple challenges including long-term efficiency, dosage, and tolerance issues and other side effects [11]. These limitations have led to an increased prevalence of folk remedies as supported by numerous anecdotal accounts [12, 13]. The use of folk remedies in recent times is correlated with psychosocial factors, ethnic and cultural characteristics, accessibility to healthcare resources, and individual perceptions of physical and medical conditions [14]. The most acknowledged therapies used for pain management are herbal remedies.

Herbal medicine has been a tradition for centuries. Some terrestrial plants are considered medicinal owing to their analgesic properties. Some of the most commonly used analgesics from food plant sources are moringa/drumstick (Moringa oleifera), guava (Psidium guajava), turmeric (Curcuma longa), and ginger (Zingiber officinale) for abdominal pain; potato (Solanum tuberosum) for headache; carrot (Daucus carota) for painful urination; and celery (Apium graveolens) for labor and joint pain [13, 15-18].

Numerous studies have emphasized the application of countless medicinal plants for pain management in different regions. However, an updated compilation of the available literature on plants, animals, and related products that are used as analgesics across the world as well as their pharmacology is lacking. In this context, we aimed to recover data from numerous published articles to establish a collective literature review on folk remedies from plant and animal sources used as analgesics and in the treatment of pain-related conditions.

2. Methodology

2.1. Search Strategy

Relevant information was systematically retrieved using the PRISMA method. Databases such as PubMed/Medline, Science Direct, and Google Scholar were scrutinized. Alternate sources, including books, dissertations, and online published material, were considered as well. Scientifically, a plant was identified according to the International Plant Name Index (www.ipni.org) and The Plant List database (theplantlist.org). The main chemical constituents of each plant were identified using the PubChem database. Similarly, potential pain killers from animal origin were searched and their chemical constituents were identified.

Databases were scrutinized using numerous keywords, such as “medicinal plant,” “traditional,” “medicinal,” “herbal remedies,” “analgesics,” “pain,” “pain management,” and “pain relief;” additionally, at times, a combination of keywords was used. The published literature was mainly taken from primary sources. In vitro, in vivo, and clinical studies were taken into consideration, and the literature search was limited to the English language. The search strategy for Medline (by PubMed) was (“analgesics” [Pharmacological Action] OR “analgesics” [MeSH Terms] OR “analgesics” [All Fields]) AND (“plants” [MeSH Terms] OR “plants” [All Fields] OR “plant” [All Fields]).

2.2. Study selection

Studies were selected according to two inclusion criteria. First, the original research articles must be published in English; second, the articles should date from 2009 to 2019. To ensure consistency, reproducibility of the process, and transparent reporting, the recommendations of the PRISMA statement were followed [19]. The selection process of the articles is represented in a flowchart (Fig. 1).

Fig. (1).

Flowchart of selection process.

2.3. Data Extraction and Description of Sections

In this review, we evaluated the traditional uses, chemical composition, and pharmacological properties of various plants used as analgesics. After screening the articles, the data was extracted and tabulated (Table 1) with regard to the ethno-pharmacological uses of the medical plants used for pain management; the data included the plant family, scientific name, common name, country, method of preparation/dosage, ailments, and references to provide an overview of the various applications of the plants used for pain relief. Section 3 provides a comprehensive and critical analysis of the pharmacological properties of each plant (Table 2), with regard to the chemistry and traditional uses.

Table 1.

Traditional remedies of plant used to relieve pain.

Family	Scientific Name		CEM/VN					Type of Pain				Region			Part of Plant Used			Method of Preparation			Administration	Refs.
Acanthaceae	Justicia adhatoda L.		Malabar nut, adulsa, adhatoda, vasa					Headache				India			Leaves			Fresh leaves are placed on forehead			Topical	[20]
Acoraceae	Acorus calamus L.		Sweet flag					Earache Toothache				Myanmar			Rhizome			Decoction			Rhizome extract as eardrop Oral	[21]
Agavaceae	Sansevieria trifasciata Hort. Ex Prain		Snake plant, mother-in-law's tongue, and viper's bowstring hemp					Earache				India			Stem			Maceration			Ear drops	[15]
Amaranthaceae	Achyranthes aspera L.		Chaff-flower, prickly chaff flower, devil's horsewhip					Toothache Abdominal pain				Pakistan			Leaves			Decoction			Oral	[24]
Amaranthaceae	Aerva lanata (L.) Juss.		Mountain knotgrass					Angina pectoris				India			Whole plant			Powder			Oral	[12]
Amaranthaceae	Alternanthera sessilis (L.) R.Br. ex DC.		Sessile joyweed anddwarf copperleaf					Eye pain				India			Leaf			Juice			Oral	[12]
Amaranthaceae	Achyranthes aspera L.		Chaff-flower, prickly chaff flower, devil's horsewhip					Toothache				India			leaves			Cotton soaked in leaf juice			Topical	[20]
Amaranthaceae	Amaranthus viridis L.		Slender amaranth or green amaranth.					Labor pain				India			Seeds			Seeds fried in clarified butter are given to pregnant ladies to curb			Topical	[20]
Amaricaceae	Tamarix arceuthoides Bunge		Gaz					Myalgia Back pain Hand and foot pain Knee pain				Iran			Stem Leaves			Decoction of mixed herb, Heated on embers			NI	[13]
Amaryllidaceae	Allium oreophilum C.A.Mey.		Pink lily leek					Abdominal pain Labour pain				Iran			Leaves Root			Raw			Oral	[13]
Anacardiacea	*Mangifera indica L.		Mango					Abdominal pain				Nepal			Bark			Crushed			Oral	[17]
Anacardiaceae	Spondias pinnata (L.f.) Kurz		Wild (or forest) mango, Amda					Earache				India			Leaves			NI			NI	[22]
Anacardiaceae	*Mangifera indica L.		Mango					Labor pain				India			Stem bark			Powder and paste			Oral	[12]
Anacardiaceae	Pistacia atlantica Desf.		Mt. Atlas mastic tree, Persian turpentine					Back pain Toothache Abdominal pain Arthralgia				Iran			Leaves, Fruits			Decoction, Pulverized, Burned on embers, Smoke Inhalation, Poultice, Liniment, Condensed			Topical	[13]
Anacardiaceae	Pistacia khinjuk Stocks		Kasour					Back pain Abdominal pain				Iran			Leaves, Fruits			Raw, Decoction, Pulverized, Poultice			Oral	[13]
Apiacea	Prangos latiloba Korovin		Paterk					Abdominal pain				Iran			Leaves, Stem			Raw taken with garlic			Oral	[13]
Apiacea	Achillea eriophora DC.		Anboul					Abdominal pain				Iran			Leaves, Stem			Decoction, Maceration, Pulverized			Oral	[13]
Family	Scientific Name		CEM/VN			Type of Pain					Region		Part of Plant Used				Method of Preparation				Administration	Refs.
Apiaceae	*Foeniculum vulgare Mill.		Fennel			Angina pectoris Renal pain					India		Seeds				Seeds boiled in milk				Oral	[23]
Apiaceae	*Daucus carota L.		Carrot			Dysuria							Root				Extract				NI	[18]
Apiaceae	*Apium graveolens L.		Celery			Arthralgia Myalgia Abdominal pain Labor pain					Iran		Aerial parts, Leaves, Seeds				Decoction, Pulverised, Poultice, Infusion				Topical	[13]
Apiaceae	Bunium persicum (Boiss.) B. Fedtsch.		Great pignut, black zira, earthnut			Toothache Renal pain Abdominal pain					Iran		Flower, Seeds				Decoction, Pulverised, Poultice Bath, Liniment				Topical	[13]
Apiaceae	Dorema ammoniacum D. Don		Poushk Oshterk			Toothache Renal pain					Iran		Aerial parts, Leaves				Decoction, Pulverised, Poultice				Topical	[13]
Apiaceae	Ducrosia anethifolia (DC.) Boiss.		Goatak			Abdominal pain Headache Renal pain Foot pain					Iran		Aerial parts, Leaves, Fruits				Decoction, Infusion, Pulverised,				Topical	[13]
Apiaceae	Achillea wilhelmsii K.Koch		Berenjask			Abdominal pain					Iran		Aerial parts, Leaves, Fruits				Decoction, Maceration, Pulverised				Topical	[13]
Apiaceae	Acroptilon repens (L.) DC.		Russian knapweed			Hands and foot pains					Iran		Aerial parts				Heated on embers				Topical	[13]
Apiaceae	Artemisia deserti Krasch.		Drannag			Abdominal pain					Iran		Aerial parts, Leaves, Flower				Decoction, Maceration, Pulverised				Topical	[13]
Apiaceae	Cousinia pseudomollis C. Winki		Polouah			Headache, Hand and Foot pain					Iran		Aerial parts				Vapour bath				Topical	[13]
Apiaceae	Echinops endotrichus Rech.f.		Chazhou			Abdominal pain					Iran		Rhizome				Decoction				Topical	[13]
Apiaceae	Pulicaria gnaphalodes (Vent.) Boiss.		Boumadran			Abdominal pain					Iran		Aerial parts				Decoction, Infusion, Raw, Maceration, Liniment				Topical	[13]
Apiaceae	Dorema ammoniacum D.Don		Poushk Oshterk			Toothache Renal pain					Iran		Aerial parts, leaves				Decoction, Infusion, Raw,				Oral	[13]
Apiaceae	Ducrosia anethifolia (DC.) Boiss.		Goatak			Abdominal pain Headache Renal pain Foot pain					Iran		Aerial parts, leaves, fruits, seeds				Decoction, Infusion, Pulverised				Topical	[13]
Apiaceae	Scorzonera tortuosissima Boiss.		Marooba			Abdominal pain					Iran		Aerial parts, leaves				Raw				NI	[13]
Apiaceae	Centella asiatica (L.) Urb.		Centella			Myalgia					Nepal		Leaves				Crushed				Oral	[17]
Apocynaceae	Alstonia scholaris (L.) R. Br.		Blackboard tree, devil tree, ditabark, milkwoodpine, saptparni, shaitan tree, white cheesewood			Myalgia Back pain					Nepal		Bark and sap				Bark placed into water and slightly cut stem to get sap				Oral	[17]
Family	Scientific Name		CEM/VN		Type of Pain				Region					Part of Plant Used		Method of Preparation			Administration			Refs.
Apocynaceae	Holarrhena pubescens Wall. ex G.Don		Big tiger milk		Myalgia Abdominal pain				Nepal					Bark		Dry, pulverize and mix with water			Oral			[17]
Apocynaceae	Calotropis gigantean (L.) Dryand		Crown flower		Myalgia				Nepal					Latex, leaves, bark, stem and root		Crushed			Topical			[17]
Apocynaceae	Carissa carandas L.		Kalakkai		Abdominal pain				India					Fruit		Pickle			Oral			[12]
Araceae	Rhaphidophora peepla (Roxb.) Schott		Mini Monstera		Toothache				Myanmar					Leaves		Boil leaves and gargle			Gargle			[21]
Asclepiadaceae	Calotropis procera (Aiton) Dryand		Apple of Sodom, king's crown, rubber tree		Arthralgia				India					Leaves		Leaves soaked in hot mustard oil are fastened on joints			Topical			[20]
Asphodelaceae	*Aloe vera (L.) Brum.		Aloe vera		Myalgia				Nepal					Leaves		Pound and drink juice			Oral			[17]
Asteraceae	Chrysanthemum indicum L.		Indian chrysanthemum		Earache				India					Leaves		Maceration			Ear drops			[15]
Asteraceae	Arctium lappa L.		Greater burdock		Myalgia				India					Leaves, Root		Paste			Topical			[23]
Asteraceae	Taraxacum campylodes G.E.Haglund		Common dandelion		Labor pain				India					Leaves		Cooked as vegetables and given to pregnant ladies			Oral			[23]
Asteraceae	Taraxacum campylodes G.E.Haglund		Common dandelion		Labor pain				India					Leaves		Cooked			Leaves are cooked as vegetable and given to pregnant ladies at the time of delivery for reducing labour pains			[18]
Asteraceae	Achillea nobilis L.		Noble yarrow		Dysmenorrhea				India					Aerial parts		Infusion			Oral			[18]
Asteraceae	Artemisia maritima L.		Sea wormwood, old woman		Arthralgia				DeosaiPlateau					Leaves		Infusion			Oral			[25]
Asteraceae	Erigeron multiradiatus var. multiradiatus		Himalayan fleabane		Abdominal pain				DeosaiPlateau					Leaves		Paste			Oral with water			[25]
Asteraceae	Matricaria chamomilla L.		Chamomille		Myalgia				Deosai Plateau					Leaves Aerial part		Paste Infusion			Oral			[25]
Asteraceae	Achillea millefolium L.		Common yarrow		Toothache				India					Root		Cotton soaked in fine root paste			Topical			[20]
Berberidaceae	Berberis integerrima Bunge		American barberry or Allegheny barberry		Myalgia				Iran					Fruit		Tablets, Mashed, Condensed			Oral			[13]
Bignoniaceae	Millingtonia hortensis L.f.		Indian cork tree		Abdominal pain				India					Root		Maceration			Oral			[15]
Family	Scientific Name		CEM/VN		Type of Pain				Region					Part of Plant Used		Method of Preparation			Administration			Refs.
Bignoniaceae	Oroxylum indicum L. Kurz		Midnight horror, oroxylum, Indian trumpet flower, broken bones		Myalgia				Nepal					Bark		Crushed			Topical			[17]
Bombacaceae	Bombax ceiba L.		Red cotton tree		Abdominal pain				Nepal					Resin, bark and root		Crushed			Oral			[17]
Boraginaceae	Alyssum meniocoides Boiss.		Espantan koohi		Angina pectoris				Iran					Fruits		Decoction, Infusion			NI			[13]
Boraginaceae	Clypeola jonthlaspi L.		Toutary		Abdominal pain, Angina				Iran					Fruits		Decoction, Infusion			NI			[13]
Boraginaceae	Descurainia Sophia (L.) Webb ex Prantl		Flixweed,herb-Sophia and tansy mustard		Abdominal pain				Iran					Seeds		Syrup			Oral			[13]
Brassicaceae	Descurainia Sophia (L.) Webb ex Prantl		Flixweed,herb-Sophia and tansy mustard		Myalgia				India					Whole plant, seeds		Whole plant decoction Seeds powder			Oral			[23]
Brassicaceae	Megacarpaea polyandra Benth.		Barmoola		Abdominal pain				India					Roots		NI			NI			[22]
Brassicaceae	Lepidium sativum L.		Garden Cress		Labor pain				India					Seeds		Seed decoction in milk and clarified butter curbs			Oral			[20]
Bromeliaceae	*Ananas comosus (L.) Merr.		Pineapple		Earache				India					Leaves		Maceration			Ear drops			[15]
Buxaceae	Sarcococca saligna var. chinensis Franch.		Sweet box or Christmas box		Arthralgia				India					Roots		NI			NI			[22]
Caesalpiniaceae	Cassia tora L.		Sickle Senna		Abdominal pain				India					Seeds		Seeds taken with water Relieve side stomach pain			Topical			[20]
Cannabaceae	Cannabis sativa L.		Cannabis		Myalgia				India					Leaves		Juice			Leaf juice obtained after crushing leaves is spread on a cloth which is then tied around limbs to relieve severe pain			[23]
Caricaceae	Carica papaya L.		Papaya, Pawpaw		Abdominal pain				India					Root		Maceration			Topical			[15]
Chenopodiaceae	Chenopodium album L.		Lamb's quarters, melde, goosefoot, manure weed, and fat-hen		Abdominal pain				Pakistan					Whole plant		Cooked juice			Oral			[24]
Chenopodiaceae	Chenopodium album L.		Lamb's quarters, melde, goosefoot, manure weed, and fat-hen		Arthralgia				Nepal					Tender shoots, whole plant		Pound			Oral			[17]
Combretaceae	Terminalia bellirica (Gaertn.) Roxb.		Bahera or beleric or bastard myrobalan, Aksh		Headache				Nepal					Fruit, leaves		Roast (fruit) and pound (leaves and bark)			Oral			[17]
Family	Scientific Name	CEM/VN					Type of Pain			Region				Part of Plant Used		Method of Preparation			Administration			Refs.
Combretaceae	Terminalia chebula Retz.	Black-or chebulic myrobalan					Headache			Nepal				Fruit, leaves and bark		Roast (fruit) and pound (leaves and bark)			Oral			[17]
Compositae	Artemisia indica Willd.	Artemisia indica					Headache			Nepal				Leaves		Pound			Oral			[17]
Compositae	Calendula officinalis L.	Calendula					Myalgia			Italy				Flower		Poultices			NI			[17]
Convolvulaceae	Datura Stramonium L.	Jimsonweed or devil's snare, hell's bells, devil's trumpet, devil's weed, tolguacha, Jamestown weed, stinkweed, locoweed, pricklyburr, devil's cucumber					Knee pain			India				Leaves		Paste			Topical			[26]
Convolvulaceae	Cuscuta capitata Roxb.	Cuscuta capitata					Angina pectoris			India				Whole plant		Juice			Oral			[23]
Convolvulaceae	Ipomoea carnea Jacq.	Pink morning glory					Arthralgia			India				Leaves		Leaves soaked in hot mustard oil are fastened			Topical			[20]
Convolvulaceae	Convolvulus arvensis L.	Lesser bindweed, European bindweed, smallflowered morning glory, creeping jenny, and possession vine					Angina pectoris			Iran				Aerial parts, leaves		Decoction, Infusion			NI			[13]
Costaceae	Costus speciosus (J.Koenig) Sm.	Crêpe ginger					Earache			India				Stem		Maceration			Ear drops			[15]
Crassulaceae	Sedum quadrifidum Pall.	Sooru					Headache Abdominal pain			India				Tender shoots		NI			NI			[22]
Crassulaceae	Rhodiola imbricata Edgew	Rhodiola imbricata					Headache			Deosai Plateau				Root		Powder			Oral with milk			[25]
Crassulaceae	Sempervivum tectorum L.	Sopravvivo					Headache			Italy				Aerial part		Used to be beaten and placed on the brow with a handkerchief			NI			[17]
Cucurbitaceae	*Luffa cylindrical (L.) M.Roem.	Smooth luffa, Egyptian luffa, dishrag gourd, gourd loofa					Arthralgia			India				Leaves		Maceration			Topical			[15]
Cucurbitaceae	*Luffa cylindrical (L.) M.Roem.	Smooth luffa, Egyptian luffa, dishrag gourd, gourd loofa					Abdominal pain			India				Fruit		Boiled with milk			Oral			[18]
Cucurbitaceae	Solena heterophylla Lour.	Creeping Cucumber					Toothache Arthralgia			Nepal				Leaves, fruit and root		Crushed			Oral			[17]
Cucurbitaceae	Bryonia multiflora Boiss.	Bryony					Bladder pain			Iran				Fruits		Poultice			NI			[13]
Cucurbitaceae	Citrullus colocynthis (L.) Schrad.	Colocynth, biter apple, bitter cucumber, desert gourd, wild gourd, vine of Sodom					Hand and foot pain Arthralgia Toothache			Iran				Aerial part, leaves, fruits, seeds		Poultice, Liniment			NI			[13]
Family	Scientific Name	CEM/VN					Type of Pain			Region				Part of Plant Used		Method of Preparation			Administration			Refs.
Cupressaceae	Juniperus communis L.	Common juniper					Causalgia			Pakistan				Fruit		Powder			NI			[27]
Cuscutaceae	Cuscuta europaea L.	Greater dodder					Earache			India				Stem		NI			NI			[22]
Dilleniaceae	Dillenia pentagyna Roxb.	Dillenia pentagyna					Myalgia			Nepal				Bark		Dry and grind			Oral			[17]
Dioscoraceae	Dioscorea alata L.	Purplpe yam, Ube					Abdominal pain			Myanmar				Root		Crushed root			Topical			[21]
Dioscoreaceae	Dioscorea esculenta (Lour.) Burkill	Lesser yam					Causalgia			West Bengal				Tuber roots		Apply grated tuber on swellings			Topical			[27]
Dipsaceae	Scabiosa olivieri Coult.	Brik dal					Foot pain Knee pain			Iran				Aerial parts		Decoction			Topical			[13]
Ebenaceae	Diospyros cordifolia Roxb	Rajaan					Toothache			-				Twig		Brushing teeth with twig			Topical			[20]
Ephedraceae	Ephedra intermedia Schrenk & C.A.Mey.	Houmok Khoumok					Abdominal pain			Iran				Aerial parts		Decoction, Poultice, Pulverised, Condensed			Oral			[13]
Ericaceae	Rhododendron campanulatum D. Don	Shamru					Myalgia Throat pain			India				Flowers and roots		NI			NI			[22]
Euphorbiaceae	Justicia gendarussa Burm.f.	willow-leaved justicia					Renal pain			India				Leaves		Paste			Topical			[26]
Euphorbiaceae	Ricinus communis L.	castor bean or castor oil plant					Arthralgia, Myalgia			India				Seed		Raw			Topical			[12]
Euphorbiaceae	Ricinus communis L.	castor bean or castor oil plant					Arthralgia			India				Leaves		Leaves soaked in hot mustard oil are fastened on joints			Topical			[20]
Euphorbiaceae	Phyllanthus emblica L.	Emblic, India gooseberry, Malacca tree, amla, amalaki					Abdominal pain Headache			Nepal				Fruit, leaves, stem and root		Crushed			Oral			[17]
Euphorbiaceae	Phyllanthus emblica L.	Emblic, India gooseberry, Malacca tree, amla, amalaki					Abdominal pain Headache			Nepal				Fruit, leaves, stem and root		Crushed			Oral			[17]
Fabaceae	Alysicarpus vaginalis (L.) DC.	Alyce clover, buffalo clover, buffalo-bur, one-leaf clover, and white moneywort					Abdominal pain			India				Whole plant		Maceration			Topical			[15]
Fabaceae	Mimosa pudic L.	Sensitive plant, sleepy plant, action plant,Dormilones, touch-me-not, shameplant, zombie plant, or shy plant					Dysuria			Myanmar				Whole plant		Decoction			Oral			[21]
Family	Scientific Name	CEM/VN					Type of Pain			Region				Part of Plant Used		Method of Preparation			Administration			Refs.
Fabaceae	Clitoria ternatea L.	Asian pigeonwings, bluebellvine, blue pea, butterflypea, cordofan pea and Darwin pea					Throat pain			India				Leaf		Paste			Oral			[12]
Fabaceae	Alhagi pseudalhagi (M.Bieb.)	Taranjabi					Bladder pain			Iran				Stem, Seeds		Decoction, Mix with milk, Infusion, Poultice			Oral			[13]
Fabaceae	Astragalus fasciculifolius Boiss	Gonjed					Abdominal pain Toothache			Iran				Stem, Seeds		Decoction, Mix with milk, Infusion, Poultice			NI			[13]
Fabaceae	Astragalus podolobus Boiss	Katek					Abdominal pain			Iran				Aerial parts, Leaves, Flower		Decoction, Raw			Oral			[13]
Fabaceae	Glycyrrhiza glabra L.	Liquorice					Hand and foot pains			Iran				Aerial parts, Flower		Decoction, Pulverised			Topical			[13]
Fabaceae	Sophora alopecuroides L.	Kor, Sophora					Renal pain			Iran				Aerial parts, Leaves		Decoction, Pulverised			Oral			[13]
Fagaceae	Quercus leucotrichophora A. Camus	Banjh oak, Banj					Toothache			India				Bark		Decoction			Topical			[20]
Fumariaceae	Corydalis cornuta Royle	Corydalis cornuta					Abdominal pain			India				Leaves, roots,		NI			NI			[22]
Fumariaceae	Fumaria indica (Haussk.) Pugsley	Fumitory or fumewort					Myalgia			India				Whole plant		Filtrate			The filtrate is used for bathing to cure rheumatic pain			[18]
Fumariaceae	Fumaria asepala Boiss.	Shah tare					Abdominal pain			Iran				Aerial parts, Leaves, Flower		Decoction						[13]
Gentianaceae	Gentiana kurroo Royle	Gentiana kurroo					Abdominal pain			Pakistan				Flower		Infusion			Oral			[25]
Geraniaceae	Geranium wallichianum D.Don ex Sweet	Geranium					Myalgia			India				Root		Herbal tea prepared from roots curbs			Oral			[23]
Labiatae	Colebrookea oppositifolia Sm.	Colebrookea oppositifolia					Myalgia			Nepal				Leaves, tender shoots and root		Pound			Topical			[17]
Labiatae	Ocimum sanctum L.	Holy basil, tulasi					Throat pain			Nepal				Leaves		Crushed			Topical			[17]
Labiatae	Pogostemon benghalensis (Burm.f.) Kuntze	Pogostemon					Headache			Nepal				Leaves		Crushed			Inhale			[17]
Lamiaceae	Clinopodium vulgare L.	Wild basil					Abdominal pain			India				Leaves, Flowers		Powder			Oral			[23]
Lamiaceae	Ocimum tenuiflorum L.	Holy basil, tulasi					Headache			Myanmar				Leaves, Fruits		Boil leaves and fruits			Eat boiled leaves and fruit			[21]
Lamiaceae	Leucas aspera (Willd.)	Thumba					Eye pain			India				Leaf		Paste			Oral Topical			[12]
Family	Scientific Name			CEM/VN			Type of Pain			Region				Part of Plant Used		Method of Preparation			Administration			Refs.
Lamiaceae	Isodon rugosus (Wall. Ex Benth.) Codd			Isodon			Toothache			Pakistan				Dried leaves		Dried			Oral			[25]
Lamiaceae	Ajuga bracteosa Benth.			Bugleweed, ground pine, carpet bugle, bugle			Headache			India				Leaves		Crushed			Topical			[20]
Lamiaceae	Colebrookea oppositifolia Sm.			Colebrookea, Chitti Suaali			Arthralgia Myalgia			India				Leaves		Leaves soaked in hot mustard oil are fastened on the affected part			Topical			[20]
Lamiaceae	Vitex negundo L.			Chinese chaste tree			Toothache			India				Twig		Brushing teeth with twig checks			Topical			[20]
Lamiaceae	Marrubium anisodon K.Koch			Hoarhound, Esped rosh, Kharek barei			Abdomial pain Headache Hand and Foot pain			Iran				Aerial parts, Leaves, Flower		Decoction, Poultice, Heat			Topical			[13]
Lamiaceae	Mentha longifolia (L.) L.			Horse mint			Abdomial pain, Hands and Foot pain Renal pain Labor pain			Iran				Aerial parts, Leaves, Flower		Decoction, Poultice, Heat Raw, Vapour bath			NI			[13]
Lamiaceae	Rydingia persica (Burm.f.) Scheen			Golder			Hand and Foot pain			Iran				Aerial parts, Leaves, Flower		Decoction, Maceration, Pulverised			NI			[13]
Lamiaceae	Perovskia atriplicifolia Benth.			Russian sage			Abdominal pain Hand and Foot pain			Iran				Aerial parts, Leaves, Flower		Decoction, Poultice			NI			[13]
Lamiaceae	Salvia macrosiphon Boiss.			Mor danag			Abdomial pain, Hands and Foot pain Renal pain Labor pain			Iran				Aerial part, Seeds, Leaves		Decoction, Poultice, liniment			NI			[13]
Lamiaceae	Salvia mirzayanii Boiss.			Mor			Abdomial pain			Iran				Leaves		Decoction, Poultice, Maceration			NI			[13]
Lamiaceae	Salvia rhytidea Benth			Mor			Abdomial pain			Iran				Leaves		Decoction			NI			[13]
Lamiaceae	Ziziphora clinopoides Lam.			Gole lala, Chai ka			Abdomial pain, Headache			Iran				Aerial parts, Leaves, Flower		Decoction, Infusion			NI			[13]
Lamiaceae	Ziziphora tenuior L.			Chahi ka			Abdomial pain			Iran				Aerial parts		Infusion			Oral			[13]
Lamiaceae	Salvia macrosiphon Boiss.			Mor danag			Abdomial pain, Angina pectoris			Iran				Aerial part, Seeds		Decoction, Poultice, Liniment			Oral			[13]
Lamiaceae	Salvia mirzayanii Rech.f.			Mor			Abdomial pain, Hands and Foot pain Renal pain Labor pain			Iran				Leaves		Decoction, Poultice, Maceration, Pulverised			Oral			[13]
Lauraceae	Litsea cubeba (Lour.) Pers.			Mountain pepper			Abdomial pain			Myanmar				Fruits, seeds		Powder			Oral			[21]
Family	Scientific Name			CEM/VN			Type of Pain			Region				Part of Plant Used		Method of Preparation			Administration			Refs.
Leguminosae	Mimosa rubicaulis Lam.			Mimosa rubicaulis			Back pain Throat pain			Nepal				Tender and root		Crushed			Topical			[17]
Liliaceae	*Allium sativum L.			Garlic			Arthralgia			India				Bulb, seeds		Cooked			Seeds deep-fried in ghee are eaten to curb arthralgia.			[18]
Liliaceae	Aloe barbadensis L.			Aloe vera			Headache			India				Leaves		NI			Latex is applied on forehead to get relief from headache			[18]
Liliaceae	*Allium sativum L.			Garlic			Arthralgia			India				Bulbs		Curry prepared			Oral			[20]
Lythraceae	Lagerstroemia hypoleuca Kurz			Andaman Crape Myrtle			Abdomial pain			India				Leaves		Paste			Topical			[15]
Lythraceae	Leucas aspera (Wild.) Link			Thumba			Myalgia			India				Leaves		Paste			Topical			[26]
Lythraceae	Woodfordia fruticosa (L.) Kurz			Dhataki			Abdomial pain			Nepal				Flower		Crushed			Oral			[17]
Magnoliaceae	Michelia champaca L.			Champak			Eye pain			India				Leaf		Decoction			Topical			[12]
Meliaceae	Azadirachta indica A.Juss			Neem, nimtree or Indian lilac			Myalgia			India				Seed		Maceration			Topical			[15]
Meliaceae	Melia azedarach L.			Chinaberry tree, cape lilac, Pride of India, bead tree, Persian lilac, Syringa berry tree			Abdominal pain			India				Leaf, stem		Juice Paste			Oral Topical			[12]
Meliaceae	Melia azedarach L.			Chinaberry tree, cape lilac, Pride of India, bead tree, Persian lilac, Syringa berry tree			Headache			India				leave		Leaves are stitched to make a cap and worn on head			Topical			[20]
Moraceae	Ficus religiosa L.			Sacred Fig, Bodhi tree, Bodhi tree, pippala tree, peepul tree, peepal tree, ashwattha tree			Angina pectoris			India				Leaf		Powder			Oral			[12]
Moraceae	Ficus racemosa L.			Cluster fig, Indian fig tree, goolar fig			Abdominal pain			Nepal				Plant sap, resin		Cut stem slightly			Oral			[17]
Moraceae	Morus nigra L.			Shah toot			Abdominal pain			Iran				Leaves, Fruits		Raw, Decoction, Infusion, Pulverised			-			[13]
Moringaceae	*Moringa oleifera L.			Moringa, drumstick tree, horseradish tree, ben oil tree			Abdominal pain			India				Root		Maceration			Oral			[15]
Myrtaceae	Premna barbata Wall.			Premna barbata			Headache			India				Raw fruit		Applied on forehead			Topical			[20]
Myrtaceae	*Psidium guajava L.			Common guava, lemon guava, yellow guava			Abdominal pain,			Nepal				Leaves and bark		Boil			Oral			[17]
Myrtaceae	*Syzygium cumini (L.) Skeels			Jambolan, Java plum, black plum			Abdominal pain			Nepal				Fruit, seed and bark		Dry (fruit) and pound (bark)			Oral			[17]
Family	Scientific Name			CEM/VN			Type of Pain			Region				Part of Plant Used		Method of Preparation				Administration		Refs.
Nitrariaceae	Peganum harmala L.			Espantan, Doudny			Abdominal pain, Toothache Hand and Foot pain			Iran				Aerial part, Leaves, Fruits		Decoction, Maceration, Pou, Raw, Pulverised,				NI		[13]
Nyctaginaceae	Mirabilis jalapa L.			Marvel of Peru, Galwasi			Myalgia			India				Leaves		Boiled leaves are eaten to reduce body pains				Oral		[20]
Orchidaceae	Cymbidium aloifolium (L.) Sw.			Cymbidium aloifolium			Earache			India				Leaves		Maceration				Ear drops		[15]
Oxalidaceae	Oxalis corniculata L.			Creeping woodsorrel, procumbent yellow sorrel, sleeping beauty			Myalgia			Nepal				Whole plant		Crushed				Oral		[17]
Paeonaceae	Paeonia emodi Wallich ex Royle			Dhandra, Chandra			Abdominal pain			India				Leaves, flowers and fruits		NI				NI		[22]
Papaveraceae	Fumaria indica (Hausskn.) Pugsley			Fumitory			Myalgia			India				Whole plant, leaves		Decoction				Decoction of the aerial parts is filtered and the filtrate is used for bathing		[23]
Papilionaceae	Indigofera heterantha Brandis			Himalayan indigo			Angina pectoris			Pakistan				Rhizome		Powder				Oral		[24]
Papilionaceae	Oxytropis lapponica (Wahl.)			Oxytropis lapponica			Arthralgia			Pakistan				Aerial parts		Decoction				Oral		[25]
Phytolaccaceae	Rivina humilis L.			Dogblood			Dysmenorrhea			Jamaica				Whole plant		Decoction				Oral		[16]
Pinaceae	Pinus kesiya Royle ex Gordon			Khasi pine, Benguet pine, three-needle pine			Abdominal pain Toothache			Myanmar				Wood resin		Powder				Topical		[21]
Pinaceae	Cedrus libani A.Rich.			Cedar of Lebanon, Lebanon cedar			Abdominal pain			India				Resin, seeds		Cataplasm Decoction Smear				Topical		[18]
Piperaceae	Piper betle L.			Betel leaves, paan			Myalgia			India				Leaves		Maceration				Oral		[15]
Piperaceae	*Piper clematis Trel.			Pepper			Toothache			Myanmar				Leaves		NI				Chew fresh leaves		[21]
Poaceae	Cynodon dactylon (L.) Pers.			Bermuda grass, Dhoob, dog's tooth grass, scutch grass			Myalgia							Whole plant		Decoction				Oral		[12]
Poaceae	Stipa arabica Trin.			Vasht, Kok Kartek			Hand and Foot pain			Iran				Aerial part		Heat				NI		[13]
Polygonaceae	Persicaria hydropiper (L.) Delarbre			Marshpepper knotwood			Dysmenorrhea			India				Leaves, stem		Leaves extract				Oral		[23]
Polygonaceae	Rheum ribes L.			Pil goshk			Arthralgia, Kidney pain			Iran				Leaves, stem		Raw, Pulverised, Decoction				NI		[13]
Polygonaceae	Persicaria amphibia (L.) Delarbre			Chusmin			Abdominal pain			Pakistan				Leaves		Infusion				Oral		[25]
Pteridaceae	Adiantum capillus-veneris L.			Siah lengok			Hand and Foot pains			Iran				Aerial parts, Leaves		Decoction, Infusion				Topical		[13]
Pteridaceae	Pteropyrum aucheri Jaub.			Karvankosh, Patont			Abdominal pain, Foot pains			Iran				Aerial parts, Leaves, fruits, flower		Decoction, Maceration, Pulverised, Poultice, Condensed				NI		[13]
Family	Scientific Name			CEM/VN			Type of Pain			Region				Part of Plant Used		Method of Preparation				Administration		Refs.
Ranunculaceae	Aquilegia pubiflora Wall. ex Royle			Domba			Toothache			Pakistan				Dried root		Dried				Topical		[25]
Rhamnaceae	Rosa beggeriana Fisch			Khar golok			Abdominal pain			Iran				Stem, Fruits		Tablets, Condensed				Oral		[13]
Rhamnaceae	Amygdalus scoparia Spach			Goatam			Hand and Foot pain			Iran				Leaves, Fruits		Decoction, Infusion, Bath, Poultice				Topical		[13]
Rosaceae	Prunus armeniaca L.			Apricot			Arthralgia			India				Seeds		Seeds along with kernel are burnt to ash				Topical		[23]
Rosaceae	Rubus ellipticus Sm.			Golden Himalayan raspberry, yellow Himalayan raspberry			Abdominal pain			Nepal				Root		Crushed				Oral		[17]
Rubiaceae	Adina cordifolia (Roxb.) Hook. f.			Kadam			Eye pain			Nepal				Tender leaves and bark		Crushed				Oral		[17]
Rubiaceae	Gaillonia macrantha Blatt.			Toso Bodako Khar tos			Abdominal pain, Renal pain			Iran				Aerial part, Leaves, Flower,		Decoction, Pulverised, Infusion				Oral		[13]
Rutaceae	Citrus medica L.			Citron			Arthralgia, Headache			India				Fruit		Paste				Topical		[15]
Rutaceae	Murraya koenigii (L.) Spreng			Curry tree			Eye pain			India				Leaf		Paste				Oral		[12]
Rutaceae	Aegle marmelos (L.) Corrêa			Bael, golden apple, wood apple			Headache			Nepal				Fruit and leaves		Cut and squeeze the fruit and boil the leaves				Oral		[17]
Rutaceae	Aerva javanica (Burm.f.) Juss. Ex Schult			Kapok bush, desert cotton			Arthralgia			India				Leaves		Paste				Topical		[26]
Salicaceae	Salix alba L.			White willow			Leg pain			India				Leaves		Decoction				Oral		[23]
Salicaceae	Salix acmophylla Boiss.			Bid			Myalgia			Iran				Leaves		Heat on embers				Topical		[13]
Sapindaceae	Aesculus hippocastanum L.			Horse chestnut, Buckeye			Back pain			India				Seeds		Oil extract				Topical		[23]
Sapindaceae	Cardiospermum halicacabum L.			Ballon plant, love in a puff			Labor pain			India				Leaves		Juice				Oral		[12]
Sapindaceae	Stocksia brahuica Benth			Kotour			Abdominal pain Myalgia			Iran				Aerial part, leaves		Poultice				Topical		[13]
Saururaceae	Hyptis suaveolens (L.) Poit.			Pignut, chan			Myalgia			India				Leaves		Decoction				Oral		[26]
Saxifragaceae	Bergenia stracheyi (Hook.f.) Engl.			Khichlay			Abdominal pain			Pakistan				Leaves		Infusion				Oral		[25]
Scrophulariaceae	Verbascum carmanicum Bornm.			Mor, Lu leng			Hand and foot pains			Iran				Leaves		Pulverised				Topical		[13]
Solanacea	Lycium ruthenicum Murray			Russian box thorn			Abdominal pain			Iran				Fruits		Decoction, Poultice				Oral		[13]
Solanacea	Solanum nigrum L.			Angour toul			Bladder pain			Iran				Aerial part, fruits, leaves		Decoction				Oral		[13]
Family	Scientific Name			CEM/VN			Type of Pain			Region				Part of Plant Used		Method of Preparation				Administration		Refs.
Solanaceae	Solanum virginianum L.			Surattense nightshade, yellow-fruit nightshade, yellow-berried nightshade, Thai green eggplant, Thai striped eggplant			Toothache			Myanmar				Fruits, seeds		Ashes				Apply ash of burnt fruits and seeds		[21]
Solanaceae	*Capsicum frutescens L.			Chilli pepper			Labor pain			India				Fruit		Paste				Oral		[12]
Solanaceae	Solanum surattense Burm. f.			Neeli Kandiari, Kandiari			Arthralgia			India				Leaves		Leaves soaked in hot mustard oil are fastened on joints				Topical		[20]
Solanaceae	*Solanum tuberosum L.			Potato			Headache			India				Tuber		Paste				Topical		[20]
Solanaceae	Solanum diffusum Roxb			Solanum diffusum			Toothache			Nepal				Fruits		Burn				Inhale		[17]
Solanaceae	Hyoscyamus malekianus Parsa			Kermoshan			Toothache			Iran				Aerial part, seeds		Burn				NI		[13]
Solanaceae	Hyoscyamus pusillus L.			Dantan shan Kermoshan			Toothache			Iran				Seeds		Decoction, Infusion, Mouthwash				NI		[13]
Taxaceae	Taxus wallichiana Zucc.			Himalayan yew			Abdominal pain			Myanmar				Bark		Paste				Add water to powdered bark, apply as paste		[21]
Tiliaceae	Grewia optiva J.R.Drumm. ex Burret			Grewia optiva			Arthralgia			Pakistan				Leaves, bark		Decoction, bark extract				NI		[27]
Urticaceae	Urtica dioica L.			Common nettle, Stinging nettle			Myalgia			India				Whole plant		Whole plant is rubbed on the body				Topical		[23]
Verbenaceae	Vitex negundo L.			Chinese chaste tree, five-leaved chaste tree, or horseshoe vitex			Myalgia			India				Leaf		Decoction				Topical (bath)		[12]
Verbenaceae	Callicarpa macrophylla Vahl			Callicarpa macrophylla			Throat pain			Nepal				Root		Boil decoction				oral		[17]
Verbenaceae	Premna barbata Wall. Ex Schauer			Gineri			Abdominal pain			Nepal				Bark, leaves and flowers		Chew (bark) and dip into water (leaves and flowers)				Oral		[17]
Vitaceae	Vitis parvifolia Roxb.			Creeping grape			Renal pain			Pakistan				Fruit, Leaves		Leaves extract				NI		[27]
Zingiberaceae	*Curcuma longa L.			Turmeric			Abdominal pain Arthralgia Myalgia Headache			India				Rhizome		Paste Maceration				Topical Oral		[15]
Zingiberaceae	*Zingiber officinale Roscoe			Ginger			Abdominal pain			Jamaica				Rhizome		Decoction				Oral		[16]

Keywords: CEN-common English name, VN-vernacular name, NI-not indicated.

Table 2.

Analgesic properties of plants.

Family			Plant					Part of Plant used							Model used In vivo		Test			Extract Type			Positive Control				Main Findings	Refs.
Amaranthaceae			Cyathula prostrate L. Blume					Whole plant							In vivo Wistar rats (100-200g) and Swiss albino mice (20-30g)		AWT HPT			Methanolic			Acetylsalicyclic (10mg/kg) Morphine (10mg/kg)				AWT: It showed maximum inhibitory response (50%) at the dose of 200mg/kg. The inhibition elicited by the extract at 200mg/kg was however lower than that observed for acid at a dose of 10 mg/kg (63%). HPT: It showed a dose dependent effect with maximum inhibition (44%) at the highest dose of 200 mg/kg while Morphine showed a significant protective effect (62% inhibition.	[71]
Amaranthaceae			Celosia argentea L. var. cristata (L.)					Flower							In vivo Albino mice		AWT			Ethanolic			Diclofenac sodium (50 and 100 mg/kg) Tramadol (5 and 10 mg/kg)				AWT: At a dose of 200 mg/kg and 400 mg/kg, the aqueous extract was effective and showed a % percentage protection of 51% and 63% respectively.	[72]
Amarantharceae			Aerva monsoniae					Whole plant							In vivo Wistar albino rats (150-200 g) and Swiss albino mice (25-30 g) of either sex		HPT			Petroleum ether			Diclofenac sodium gel (100 mg/mL)				HPT: The plant extract was an effective analgesic agent at lower dose of 100mg/kg. The animals treated with 250 mg/kg exhibited poor reaction time.	[73]
Anacardiaceae			Antrocaryon klaineanum Pierre					Stem							In vivo Mus musculus white mice (18-25 g) and Wistar albino rats (90- 150 g) aged of 60 days		AWT FT HPT			Methanolic			Paracetamol, 50 mg/kg Morphine, 5 mg/kg				AWT: A decrease in the number of abdominal constrictions induced by acetic acid by 46% at a dose of 600 mg/kg FT: Oral administration of methanol extract of A. klaineanum significantly inhibited the neurogenic phase of formalin-induced nociceptive response by 59% at a dose 600 mg/kg. HPT: At doses of 400 and 600 mg/kg the latency time increased from 3.29 ± 0.26 s to 21.46±0.27 s and from 3.08±0.14 s to 22.90± 1.00 s (n=7) respectively 3 h after treatment. This increasing of the latency times might be due to the central analgesic effect of the extract.	[46]
Anacardiaceae			Lannea coromandelica (Houtt.) Merr.					Leaves							In vivo Swiss albino mice (20-25 g) of both sex		AWT FT			Ethanolic			Diclofenac sodium				AWT: At 50, 100, and 200 mg/kg doses caused a significant reduction in the number of writhing FT: At 50, 100, and 200 mg/kg dose caused a significant dose-dependent inhibition of both neurogenic (0-5 min) and inflammatory (15-30 min) phases	[74]
Family			Plant		Part of Plant used					Model used In vivo								Test			Extract Type			Positive Control			Main Findings	Refs.
Anacardiaceae			Mangifera indica L.		Leaves					In vivo Swiss albino mice of both sexes weighing between 25 g and 30 g and Wistar Albino rats of either sex weighing between 150 g and 200 g								AWT			Methanolic			Diclofenac Sodium (40mg/kg)			Leaves extract reduced the writhing count from 66.75±2.28 to 29.5±2.72/20 minutes.	[75]
Annonaceae			Annona squamosal L.		Bark					In vivo Male Swiss albino mice (20-25 g each) and Wistar rats (150-200 g each)								HPT AWT			Crude petroleum ether			Pentazocin (50mg/kg) Aspirin (100mg/kg)			The maximum activity was observed with caryophyllene oxide (25mg/kg body wt., i.p.) at the 120min time interval, which is comparable to the standard pentazocin. t the dose of 25mg/kg body wt., caryophyllene oxide inhibited the writhing response almost to the same degree as aspirin (74.41%).	[76]
Apiaceae			Heracleum persicum		Fruits					In vivo Male Wistar rats weighing 150-200g and male Swiss mice (25-35 g)								AWT FT			Essential oil Hydroalcoholic			Indomethacin (10 mg/kg) Morphine (10 mg/kg)			AWT: Oral administration of Heracleum persicum essential oil at doses of 50-200 mg/kg and Heracleum persicum hydroalco- holic extract at doses of 250 and 500 mg/kg significantly reduced acetic acid-induced abdominal constrictions FT: Both extracts significantly attenuated the pain response of the second phase of formalin test.	[77]
Apocynaceae			Ichnocarpus frutescens		Roots					In vivo Swiss Albino mice, weighing 20-25 g								AWT			Methanolic			Diclofenac (10 mg/kg)			59%, 51% and 46% inhibition of writhing at 1, 3 and 6 mg/kg dose with much improved level of pain killing effect.	[45]
Aracaceae			Areca catechu Linn.		Seeds					In vivo Male and female Swiss albino mice (25-30 g) and Wistar albino rats (250- 300g)								HPT FT			Hydroalcoholic			Pentazocine (10 mg/kg) Aspirin (300 mg/kg)			HPT: A dose of 1000 mg/kg exhibited highest analgesic (54%) at 60 min and which was gradually decreased at 90min. FT: At a dose of 500 mg/kg, it exhibited 92% of during the second phase (20-25min).	[78]
Araceae			Typhonium trilobatum L. Schott		Leaves					In vivo Swiss-albino mice (both sexes) weighing between (18-25 g) and Wistar rats of the either sex (180-200 g)								AWT			Ethanolic			Diclofenac sodium (10 mg/kg)			50% and 65% writhing inhibition at the doses of 250 and 500 mg/ kg body weight respectively, which was comparable to the standard drug diclofenac sodium that caused 71% inhibition.	[79]
Asclepiadaceae			Pergularia daemia		Roots					In vivo Wister albino rats of either sex weighing about 150- 200 g and adult albino mice of either sex weighing 25 -30 g								HPT AWT			Ethanolic			NI			The highest reaction time was observed for ethanol extract of P. daemia (9.08 sec.) at a dose of 200 mg/kg.	[80]
Family		Plant			Part of Plant used					Model used In vivo								Test			Extract Type			Positive Control			Main Findings	Refs.
Asparagaceae		Sansevieria roxburghiana Schult.			Whole plant					In vivo Young Swiss-albino mice of either sex aged 4-5 weeks, average weight 20-25 g								AWT			Ethyl acetate, Chloroform, Methanolic			Diclofenac sodium			The ethyl acetate, the chloroform and the petroleum-ether soluble fraction of crude methanolic extract of S. roxburghiana demonstrated significant analgesic activity with writhing inhibition of 63%, 60% and 57% respectively	[81]
Asteraceae		Matricaria pubescens (Desf.)			Whole plant					In vivo Swiss albino mice weighing18-25 g								AWT			Crude			Acetyl salicylic acid			Abdominal contortion inhibiting power was observed in mice treated with 200 mg/kg of M. pubescens alkaloids followed by those treated with 100 mg/kg, with percentages of 33.07 and 31% respectively	[82]
Asteraceae		Ageratum conyzoide L.			Leaves					In vivo Swiss-albino mice aged 4e5 weeks (either sex), average weight 20-25 g								AWT			Ethanolic			Diclofenac Sodium (250 and 500 mg/kg-bw)			% of writhing inhibition was highest (45%) at a dose of (500 mg/kg)	[34]
Asteraceae		Mikania cordifolia L.			Leaves					In vivo Swiss-albino mice aged 4-5 weeks (either sex), average weight 20-25 g								AWT			Ethanolic			Diclofenac Sodium (250 and 500 mg/kg-bw)			% of writhing inhibition was highest (42%) at a dose of (500 mg/kg)	[34]
Asteraceae		Inula cuspidata			Stem Root					In vivo Male Swiss Albino mice (Mus musculus) weighing 25-35 g and Wistar albino rats (Rattus norvegicus) weighing 150-200 gm								HPT AWT			Methanolic			Tramadol 10 mg/kg Acetyl salicylic acid 100 mg/kg			HPT: The methanol extracts at both the doses 100, 200 mg/kg exhibited a significant effect at 60 and 90 min readings as compared to control. AWT: All the tested extracts of stem and roots significantly exhibited dose dependent reduction in number of writhes within the 30 min of injection of acetic acid	[83]
Asteraceae		Achillea fragrantissima (Forssk.)			Whole plant					In vivo Mature albino mice and Wistar rats (27-30 g and 150-180 g, respectively) of both sexes								HPT AWT			Ethanolic			Indomethacin (20mg/kg)			HPT: Maximum protection against the thermal stimulus was seen at 90 at a dose of 400 mg/kg of the non-polar extract (81%), which was not statistically different compared to the reference drug (89%) AWT: Maximum protection was observed with a polar extract dose of 400 mg/kg (55%), which was not statistically different than the acetyl salicylic acid reference drug (58%)	[84]
Betulaceae		Alnus nitida (Spach) Endl.			Stem bark					In vivo Six weeks old (180 - 200 g) Sprague Dawley male rats								HPT AWT			Methanolic			Morphine (10 mg/kg)			HPT: Administration of extract at 50 mg/kg, 100 mg/kg and 200 mg/kg has elevated the latency by 56%, 58% and 61% after 120 min of the test sample administration. AWT: At 50 mg/kg (68%), 100 mg/kg (75%) and 200 mg/kg (79%), the extract exhibited the moderate level of analgesic activity.	[85]
Family		Plant			Part of Plant used						Model used In vivo					Test			Extract Type			Positive Control			Main Findings			Refs.
Buxaceae		Sarcococca saligna (D. Don) Mull.			Fruits						In vivo BALB/C mice of both gender, age 4-5 weeks and mean weight of 20- 25 g					AWT			Methanolic			Diclofenac sodium (10 mg/kg)			At a dose of 500 mg/kg, the highest % of writhing inhibition were observed withing 10 min.			[86]
Cactaceae		Opuntia microdasys (Lehm.) Pfeiff			Flower						In vivo Wistar rats and Swiss albinos mice of both sexes weighing 160-180 g and 18-25 g					AWT			Aqueous			ASL at 200 mg/kg			Doses of 50 (58%) and 100 mg/kg (72%) of aqueous extracts significantly decreased the writhing reflex.			[49]
Capparidaceae		Cleome rutidosperma DC.			Whole plant						In vivo Swiss Albino mice (20−25 g)					HPT TFT FT AWT			Methanolic			Morphine (5 mg/kg)			HPT: At the doses of 100 and 200 mg/kg respectively, MECR displayed the significant ability of sustaining the latency of reaction to thermal-induced nociception thoughout the 120 min experiment. TFT: There were no significant difference in the antinoceptive effect of 100 and 200 mg/kg. FT: a dose-dependent antinociceptive effect in both the neurological (0−5 min) and inflammatory (15−30 min) phase at 100 and 200 mg/kg. AWT: A significant inhibition (39% and 47%) of the writhing response at 100 and 200 mg/kg.			[40]
Chenopodiaceae		Bassia eriophora			Whole plant						In vivo Albino Wistar rats and albino Swiss mice					HPT AWT			Alcoholic			Indomethacin (4 mg/kg bw)			HPT: t 90 min, the mean reaction time for indomethacin of analgesia effect showed 9.18 ± 0.22 (n=5), while 250 and 500 mg/kg B. eriophora showed significant analgesic effect (8.10 ± 0.18 and 8.10 ± 0.12, n=5) respectively. AWT: The indomethacin was showed 86% inhibitions of analgesia, while 250 and 500 mg/kg B. eriophora showed 55% and 68% inhibitions of analgesia respectively			[87]
Cistaceae		Cistus salviifolius L. Cistus monspeliensis L.			Whole plant						In vivo Adult Swiss mice and adult Wistar rat					AWT TFT			Aqueous			Aspirin (150 mg/kg) Morphine (0.1 mg/kg)			AWT: Aqueous extracts of both plants (500 mg/kg) caused significant inhibition of writhes 49% compared to the standard drug aspirine hat produced 40% inhibition at 150 mg/kg bw. TFT: Both extracts (500 mg/kg) have maximum effect at 60 min; their effects at 120 min were less than those of the control drug morphine.			[88]
Clusiaceae		Garcinia lanceifolia Roxb.			Whole plant						In vivo 20-25 g Swiss-albino mice (aged 4-5 weeks)					Peripheral: AWT method Central: TFT			Methanolic			Peripheral: Diclofenac (50 mg/kgbw) Central: Morphine			In peripheral antinociceptive activity, 400 and 200 mg/kg of extract exhibited significant inhibition of writhing with 59% and 49% respectively. In central antinociceptive activity, the extract (400 and 200 mg/kg) exhibited significant analgesic activity having 78% and 90% elongation of reaction time respectively in 90 min.			[35]
Family		Plant					Part of Plant used							Model used In vivo			Test		Extract Type			Positive Control			Main Findings			Refs.
Convolvulaceae		Rivea hypocrateriformis					Leaves							In vivo Albino rats of Wistar strain (250 - 300 g)			TFT		Ethanolic			Ibuprofen			Doses of 400 mg/kg increased the pain threshold significantly after 30 min, 1,2 and 4 hours.			[89]
Cucurbitaceae		Citrullus colocynthis Schrad.					Immature seeds Ripe seeds Immature fruits Ripe fruits Stems Roots							In vivo Male adult Wistar rats weighing 160-180 g and Swiss albinos mice (weighing 18-25g)			AWT		Aqueous extract			Acetyl salicylate of lysine 200mg/kg			The immature fruits and seeds possess the highest analgesic properties; the most active of them were immature fruits as well as at 0.1 mg/kg (94%)			[37]
Cuucurbitaceae		Momordica dioica Roxb.					Seed							In vivo Albino mice (Swiss strain) weighing 25-30g either sex			AWT HPT		Methanolic			Paracetamol (50 mg/kg) Pentazocine 10 mg/kg			AWT: At a dose of 50 and 100 mg/kg, the extract showed a reduction in number of writhing, which is 4% and 12% respectively. HPT: A dose of 50 mg/kg was found effective at 60 and 90 minutes.			[90]
Cyperaceae		Cyperus routunds Linn.					Whole plant							In vivo Animals (albino mice of either sex; weight 25-30 gm)			TFT		Ethanolic			Diclofenac sodium (50 m/kg)			The reaction time (1 to 4 hours) to pain stimulus was increased after crude extract administration (300mg/kg)			[86]
Dilleniaceae		Dillenia indica f. elongata (Miq.)					Bark							In vivo Ethyl acetate extracts			HPT TFT FT		Ethyl acetate extracts			Pentazocine 30 mg/kg and 25 mg/kg Indomethacin (10 mg/kg			HPT: Ethyl acetate extract of D. indica f. elongata (300 mg/ kg) showed significant analgesic activity at 60 min respectively. TFT: D. indica f. elongata (100 mg/kg) possessed significant analgesic activity more than that of standard drug pentazocine at 1 h. FT: D. indica f. elongata (100 mg/kg) extracts were potent than indomethacin and decreased the number of paw lickings at the second phase.			[38]
Dipterocarpaceae		Shorea robusta Gaertn.					Bark							In vivo Ethyl acetate extracts			HPT TFT FT		Ethyl acetate extracts			Pentazocine 30 mg/kg and 25 mg/kg Indomethacin (10 mg/kg			HPT: S. robusta was effective at a dose of (300 mg/ kg) at 30 min. TFT: Ethyl acetate extract of S. robusta (100 and 300 mg/kg) showed significant analgesic activity which was more potent than standard pentazocine from 0.5 h to 1 h. FT: S. robusta at 300 mg/kg was more effective than the indomethacin.			[38]
Fabaceae		Cassia siamea Lam.					Stem							In vivo Male and female Wistar rats (200-350 g)			HPT		Ethanolic			Morphine (2mg/kg)			At a dose of 200 and 400 mg/kg, the ethanol extract was more effective.			[91]
Fabaceae		Senna singueana Del. Lock					Leaves							In vivo Swiss albino mice (20-25gm)			AWT HPT FT		Methanolic			Diclofenac sodium (10 mg/kg) Morphine sulfate (5 mg/kg)			Percentage maximum inhibition of writhing response was 80% at a dose of 400 mg/kg. A combination of drug and the plant extract was found more effective in all three methods.			[92]
Family		Plant					Part of Plant used						Model used In vivo				Test		Extract Type			Positive Control			Main Findings			Refs.
Flacourtiaceae		Scolopia crenata (Wight & Arn.) Clos.					Stem bark and leaves						In vivo Swiss albino mice (25-30g)				AWT HPT		Methanolic			Indomethacin (5mg/kg) Morphine (5 mg/kg			The oral administration of methanol extract of leaf and bark at higher dose of 400mg/kg reduced the number of writhings from 65.33 (induced) to 12.83 (80%) and 17.17 (74%), respectively. An increase in the response latency time at 30 min, which persisted in a dose dependent manner of 200 and 400mg/kg.			[93]
Lamiaceae		Hyptis suaveolens L. Poit.					Whole plant						In vivo Male Swiss albino mice (25-30 g)				HPT		Ethanolic			Morphine (5 mg/kg)			AEHS (400 mg/kg) had produced higher latency time at 120 min (after treatment) and mean latency time was 5.30 ± 0.36 s			[36]
Lamiaceae		Mentha rotundifolia L.					Leaves						In vivo Swiss albino mice (25- 30 g)				AWT		Methanolic			Aspirin (150 mg/kg)			Doses of 200, 400, and 600 mg/kg bw had significantly analgesic effects and dose dependent with inhibition percentages from 79% to 85%. The analgesic effect of the extract (at 600 mg/kg bw) was greater than the Aspirin (150 mg/kg bw)			[32]
Lamiaceae		Stachys lavandulifolia Vahl.					Whole plant						In vivo Young-adult male Swiss mice (28-33 g)				FT CNT		Essential oil			Morphine (3mg/kg)			FT: Higher dose (50 mg/kg) produced significant inhibitory (35.50 ± 4.405) effects on nociceptive face-rubbing behavioral response in the first phase. CNT: All doses (78.50 ± 12.68 and 63.00 ± 9.495; or 59.50 ± 13.57 and 48.50 ± 11.48, (n=6)respectively) inhibited nociceptive behavior in mice.			[43]
Lamiaceae		Mentha arvensis L.					Whole plant						In vivo Swiss albino mice of either sex (20-29 g body weight)				AWT		Ethanolic			Diclofenac sodium (25 mg/kg of body weight)			The extract produced 46% and 64% writhing inhibition in mice at oral doses of 250 mg/kg and 500 mg/kg body weights of mice respectively while the standard drug exhibited inhibition of 77% at a dose of 25 mg/kg body weight			[44]
Leguminosae		Dalbegia saxatilis					Leaves						In vivo Wistar rats and mice of both sexes weighing 100-150 g and 20-25 g				AWT HPT		Methanolic			Aspirin (300 mg/kg) Morphine (10 mg/kg)			AWT: The extract significantly decreased the number of writhes caused by acetic acid in a dose independent manner. HPT: The methanol leaf extract significantly increased the reaction. At 30 min, there was significant increase in reaction time in the 500 mg/kg and 1000 mg/kg.			[94]
Leguminosae		Albizia lebbeck Benth.					Bark						In vivo Long-Evans rats (150-200 g) and Swiss albino mice (25- 30 g)				AWT TFT		Petroleum ether, ethyl acetate and methanolic			Aminopyrine (50mg/kg) Morphine (2mg/kg)			AWT: Inhibition of writhing was 52% at 400mg/kg. TFT: % elongation was highest (61.48) using 400 mg/kg at 30 min.			[95]
Leguminosae		Acacia ferruginea DC.					Leaves Bark						In vivo Wistar albino rats (180-220 g, Male) and Swiss albino mice (25- 40 g)				HPT AWT		Hydroalcoholic			Tramadol (10 mg/kg) Aspirin (5 mg/kg)			HPT: Bark extract at the same dose of 100 mg/kg showed higher inhibition (8.85 ± 0.45 min) of thermal stimulation as compared to leaf extract (6.79 ± 0.29 min) at a response time of 90 min. AWT: The maximum protection was observed at a dose of 100 mg/kg in both leaf (91%) and bark extracts (90%) against acetic acid, which was com- parable to standard aspirin (51%).			[96]
Family		Plant				Part of Plant used						Model used In vivo					Test		Extract Type			Positive Control			Main Findings			Refs.
Liliaceae		Polygonatum verticillatum L.				Roots						In vivo Swiss albino mice (20-25g) and Wistar rats (210-270g					AWT FT		Methanolic			Aspirin (300 mg/kg) Morphine (10 mg/kg)			AWT: The analgesic response of PR at 200 mg/kg was quite similar to the positive control (77% at 100 mg/kg) FT: At a dose of 200 mg/kg, the extraxt was effective.			[97]
Malvaceae		Microcos paniculata				Bark Fruits						In vivo Swiss albino mice, 6-7 weeks old, weighting 25-30 g					FT AWT TFT		Methanolic			Aspirin (1.0 ml) Diclofenac sodium (100 mg/kg) Tramadol (10 mg/kg)			FT: Bark extract of 400 mg/kg showed the maximun percentage inhibition (78%) of paw licking in mice in the last phase of formalin injection. AWT: The highest percentage inhibition of writhing resulting from treatment with plant extracts (54%) was obtained by fruit extract at 400 mg/kg. TFT: AT 60 min, the maximum effects of bark extracts at 400 mg/kg, and fruit extract at 200 and 400 mg/kg had significant analgesic activities.			[42]
Moraceae		Ficus racemosa Linn.				Whole plant						In vivo Young Swiss-albino mice of either sex aged 4- 5 weeks, average weight 20-25 g					HPT AWT		Ethanolic			Diclofenac sodium 10 mg/kg			At 90 minutes, the percent inhibition of two different doses (100 and 200 mg/kg body weight) was 50% and 57%.			[98]
Moringaceae		Moringa oleifera Lamarck				Leaves						In vivo Male and female Wistar rats weighing 180-200 g					FT		Hexane			Naproxen (10 mg/kg)			During phase I, significant effect was observed at a dose of 30 mg/kg resembling the effect of the positive control.			[99]
Myrtaceae		Psidium cattleianum Sabine				Leaves						In vivo Male albino mice (20-25 g)					AWT HPT		Hydroalcoholic			Indomethacin (5 mg/kg) morphine (5 mg/kg)			AWT: The inhibition percentage of the number of writhing of acetic acid-induced writhing in mice was 86, 91, 81, 99, and 73% at doses of 60, 80, 100, 200, and 400 mg/kg, respectively. HPT: No analgesic effect on the central nervous system that would contribute to its peripheral analgesic effect.			[39]
Myrtaceae		Syzygium calophyllifolium Walp.				Bark						In vivo Healthy Wistar albino rats (100-150g) and Swiss albino mice (20-25 g), of either sex					AWT HPT FT		Methanolc			Aspirin (150 mg/kg) Pentazocine (5 mg/kg)			AWT: The extract displayed profound analgesic activity (6.75 ± 1.38, n=6) at a higher dose (200 mg/kg). HPT: Oral administration of 200 mg/kg methanol extract showed a sig- nificant capacity to inhibit the pain sense by 81%. FT: A dose of 200 mg/kg increased the latency period (9.00 ± 0.82 s), thereby increasing the heat tolerance of the mice by 54%			[100]
Nymphaeaceae		Nymphaea nouchali Burm.f.				Flower						In vivo Swiss albino mice of either sex, 3-4 weeks of age, weighing between 20-25 g					TFT AWT		Methanolic			Diclofenac sodium (50 mg/kg) Morphine (25 mg/kg)			TFT: The highest dose (400 g/kg) exhibited effective analgesic effect from 60-120 min. AWT: The methanolic extract produced 60% and 65% writhing inhibition at oral doses of 200 mg/kg and 400mg/kg.			[101]
Family	Plant			Part of Plant used					Model used In vivo								Test		Extract Type			Positive Control			Main Findings			Refs.
Oleaceae	Jasminum sambac L.			Roots					In vivo Healthy Charles Foster albino rats (150-200 g) and Swiss albino mice (20-30 g) of either sex								AWT		Ethanolic			Diclofenac (10 mg/kg)			At 400 mg/kg, p.o. reduced writhing counts up to 49%.			[102]
Oleaceae	Jasminum abyssinicum Hochst. ex. DC.			Roots					In vivo Healthy Swiss albino mice, weighing 25-35 g and aged 6-8 weeks								AWT		Methanolic			Aspirin (150 mg/kg, 100 mg/kg)			The percentage inhibition for the extract was 38.7%, 70.6% and 66.8% at 50 mg/kg, 100 mg/kg and 200 mg/kg respectively. The extract at doses of 100 mg/kg and 200 mg/kg showed a better effect than aspirin (which had a percentage inhibition of 56%)			[103]
Oleaceae	Nyctanthes arbortristis Linn.			Leaves					In vivo Male albino mice (Swiss strain) weighing 25-28 g								HPT AWT		Petroleum ether extract			Paracetamol (50mg/kg)			Petroleum ether, chloroform and ethyl acetate extracts (50 mg/kg) produced significant inhibition of writhing reaction induced by acetic acid compared to the control group β-Sitosterol (5, 10 and 20 mg/kg, i.p., each) isolated from petroleum ether extract showed comparable activity with standard drug paracetamol.			[104]
Passifloraceae	Passiflora subpeltata Ortega			Leaves					In vivo Male Swiss albino mice (20-25 g) and Wistar rats (140-170 g)								AWT FT		Acetone			Morphine (10 mg/kg)			AWT: At doses of 200 and 400mg/kg reduced the number of writhes to 8.5 ± 0.29, n=3 (51% inhibition) and 3 ± 0.82 (83% inhibition) respectively. At a dose of 400mg/kg showed higher analgesic activity. FT: The extract possessed only mild inhibitory effect deter- mined from the licking response at the dose of 200 and 400 mg/kg.			[105]
Pinaceae	Pinus roxburghii Sarg.			Stem					In vivo Wistar rats (150-250gm) and Swiss albino mice (20-25 gm) of either sex								AWT TFT		Alcoholic			Diclofenac Sodium (50mg/kg)			AWT: Doses of 100, 300, and 500 mg/kg significantly and dependently reduced the number of abdominal constrictions induced in mice. TFT: The extract showed a significant elongation of reaction time after 30 min to 90 min at 500 mg/kg.			[106]
Piperaceae	Piper nigrum L.			Fruit					In vivo Swiss albino mice of both sex weighing 25-30 g and Swiss albino rats of both sex weighing 150-200 g								TFT Analgesy-meter HPT AWT		Crude Ethanolic Hexane			Diclofenac sodium (5 mg/kg) Acetyl salicylic acid (10 mg/kg)			TFT: Piperine exhibited maximum activity after 120 min at a dose of 5 mg/kg. The hexane extract showed maximum analgesic activity at a dose of 10 mg/kg after 60 min. Ethanol extract was effective at doses of 5, 10 and 15 mg/kg. Analgesy-meter: ethanol extract exhibited maximum analgesic activity at a dose of 10 mg/kg after 60 min. HPT: Maximum analgesic effect was noted at a dose of 10 mg/kg after 120 min for piperine. AWT: Piperine and ethanol extract (10 mg/kg) showed 100% protection. Hexane extract exhibited 99% at 10 mg/kg.			[107]
Family	Plant			Part of Plant used					Model used In vivo								Test		Extract Type			Positive Control				Main Findings		Refs.
Rhamnaceae	Ziziyphus nummularia			Leaves					In vivo Healthy Wistar rats of both sexes weighing 180-200 g and Swiss mice weighing 20-24 g								AWT TFT HPT		Ethanolic			Aspirin 100 mg/kg morphine 5 mg/kg BW				AWT: A reduce number of writhes was observed with an increased dose of plant extract. TFT&HPT: At a dose of 10 mg/kg, the latency time was 09.48 ± 0.34 s, n=6.		[108]
Rhamnaceae	Ziziphus Xylopyrus			Stem					In vivo Swiss albino mice (25-30g) and albino rats of Wistar strain (150-200g) of either sex								HPT TFT		Petroleum ether, choloform and methanolic			Morphine sulphate				HPT: The different dose of methanolic extract of Z. xylopyrus showed highly significant effect at 30, 60,120 and 180 minutes as compared with control group. The chloroform extract 200mg/kg showed a significant activity at 30minute and highly significant activity at 60,120 and 180 minutes. TFT: The methanolic extract of Z. xylopyrus at a dose of 200mg/kg showed peak effect of 13.6±0.173 at 180 minutes		[109]
Rubiaceae	Hedyotis puberula (G. Don) R. Br. ex Arn.			Whole plant					In vivo Male swiss albino mice (20-25 g) and wistar rats (120-150 g)								AWT HPT		Methanolic			Indomethacin (5 mg/kg) Pentazocine (30 mg/kg)				AWT: retreatment with methanol extract of H. puberula at doses of 200 and 400 mg/ kg reduced the number of writhes to 33.83 ± 2.70, n=6 (42% inhibition) and 21.00 ± 0.63 (64% inhibition). The extract dose 400mg/kg registered higher levels of analgesic activity than the positive control. HPT: At 400 mg/kg and 60 min reaction time, the analgesic activity (7.30 ± 0.20 s) of the test extract was higher than the positive control.		[110]
Rubiaceae	Morinda citrifolia L.			Fruits					In vivo Male mice								HPT		Ethanolic			Tramadol (30 mg/kg)				The application of 10% of the noni fruit puree concentrate in the drinking water of the mice for a period of 4 days prior to the experiment resulted in a reaction time of 9.2 s.		[111]
Rutaceae	Clausena anisata (Wild) Hook .F. ex Benth			Leaves					In vivo Swiss albino mice both male and female								AWT FT		Ethanolic			NI				AWT: At a dose of 39 mg/kg, the extract was effective for an interval of 15 min (8.11 ± 0.21, n=6) FT: At a dose of 78 mg/kg, the extract was found more effective (4.82± 0.98) than the standard drug (2.28± 0.22).		[112]
Sapindaceae	Schleichera oleosa (Lour.) Oken.			Stem					In vivo Wistar rats (150-180 g)								FT		Ethanolic			Indomethacin				The extract (400 mg/kg) produced a significant reduction in response time of the animals against pain, from 100 sec in control group to 38 sec		[113]
Scrophulariacae	Scoparia dulcis L.			Whole plant					In vivo Young Swiss-albino mice of either sex aged 4- 5 weeks, average weight								HPT AWT		Ethanolic			Diclofenac sodium 10 mg/kg				At 90 minutes, the percent inhibition of two different doses (100 and 200 mg/kg body weight) was 55% and 62%.		[98]
Solanaceae	Solanum paniculatum L.			Leaves					In vivo Male Swiss Webster mice								AWT		Aqueous ethyl acetate			Acetaminophen (90, 180 or 360 mg/kg bw)				Treatment of mice with ethyl acetate partition (300 mg/kg bw) produced approximately 50% reduction in the writhing nociceptive response		[33]
Family	Plant			Part of Plant used					Model used In vivo								Test		Extract Type			Positive Control				Main Findings		Refs.
Solanaceae	Schwenckia americana L.			Whole plant					In vivo Male albino wistar rats, weighing 200-250g								AWT FT		Methanolic			Piroxicam (10 mg/kg)				AWT: The percentage inhibition (53.3, 58.0 and 86%) of the extract at 25, 50 and 100 mg/kg, respectively were significant. FT: The percentage pain inhibition between 0 and 10min (early phase) were 44.00, 56.04, and 56% for 25, 50 and 100 mg/kg intra-peritoneal doses. The percentage pain inhibition between 15 and 60 min (late phase) were 33.00, 36.63 and 60%, for 25, 50 and 100mg/kg intra-peritoneal doses of the extract		[114]
Vitaceae	Vitis vinifera L.			Leaves					In vivo Swiss albino mice (20-30 g)								FT AWT		Ethanolic			Morphine (10 mg/kg) Indomethacin (10 mg/kg)				FT: In the second phase, the middle, highest dose of the extract (200, 400mg/kg) and morphin all inhibited the licking response significantly the licking times were (33.35 ± 2.29 s), (23.79 ± 1.43 s), (20.32± 0.52 s, n=5) respectively. AWT: A peak inhibitory effect (66%) was observed at a dose of 400 mg/kg.		[41]
Vitaceae	Cissus repanda Vahl			Stem					In vivo Wistar strain albino rats of either sex weighing 200 ± 20g and Swiss albino mice of either sex weighing 30 ± 06g								TFT FT		NI			Pentazocine (20mg/kg) Indomethacin (10 mg/kg)				FT: A significant decrease in % inhibition of paw licking response (17.%) was seen after 24 hours TFT: Not effective		[48]
Zingiberaceae	Alpinia nigra (Gaertn.) B.L. Burtt			Leaves					In vivo 6-week-old Swiss albino mice of both sexes weighing 25-30 g								FT TFT		Methanolic			Diclofenac sodium (5 mg/kg)				FT: The extract at the dose of 200 mg/kg displayed inhibition of the late phase. TFT: It exhibited potent analgesic effect after 30 and 60 minutes of administration at a dose level of 200 mg/kg.		[48]

3. Results and Discussion

3.1. Traditional Remedies Made with Plants Presenting Analgesic Properties

In ancient times, the diverse population of plants represented medicinal wealth for indigenous people. While searching ways to relieve pain and cure diseases, traditional healers discovered new plants that could serve as analgesics. In total, 209 ethnomedicinal studies demonstrated the different uses of combinations of wild and domestic plants for pain relief, which are summarized in Table 1. The study results are presented in alphabetical order of plant families, with their respective scientific name, local name, plant parts used, therapeutic use, mode of preparation, and route of administration for ethnomedicinal application. Most methods of preparation involved decoction or maceration; alternatively, the plants were used in their raw form. The administration was either oral or topical. These medicinal plants were used predominantly in Asian countries, such as India, Nepal, Pakistan, Iran, and Myanmar, and African countries (Table 1).

Accordingly, stomach pain, earache, and joint pain were the most common types of pain that were targeted. As per the study of Bhatia et al. [20], Justicia adhatoda was used to alleviate headaches using fresh leaves that were topically applied on the forehead. In the same study, when mixed with other medicinal plants, Justicia adhatoda was also reported to cure fever, herpes, and pneumonia. Thus, the study showed that plants can have multiple functions by acting at different targets to cure diseases. Recently, Ong et al. [21] have identified wild medicinal plant species and evaluated their properties and uses among the local population. The herb Acorus calamus was reported to relieve earache and toothache when the rhizome extract is applied as a drop and drunk as a decoction, respectively. Other plants, such as Sansevieria trifasciata, Spondias pinnata, Chrysanthemum indicum, Ananas comosus (pineapple), Matricaria chamomilla (Camomile flower), Costus speciosus (Crêpe ginger), Cuscuta europaea, and Cymbidium aloifolium, were found to alleviate ear pain by the application of ear drops prepared by macerating the parts of the plants [15, 22].

Furthermore, Aloe vera (leaves) juice, Matricaria chamomilla (leaves and aerial part), Calendula officinalis (flower), Fumaria indica (whole plant), Geranium wallichianum (root), Alstonia scholaris (bark and sap), Holarrhena pubescens (bark), [17, 18, 23] have been identified as plants with analgesics effects. Ayyanar and Ignacimuthu [12] categorized and grouped various ailments with regard to the human anatomy, and the associated pain was reported in the different sections: stomachache in general health, earache in ear problems, breast pain as genito-urinary ailments, chest pain as respiratory systems disorders, and headaches and body pain as skeleton-muscular system disorder. In this particular survey, commonly used medicinal plants were identified among the Kani tribals (India). Interestingly, pickle was one of the peculiar preparation methods used to cure stomachaches using the fruit Carissa carandas.

In addition, Maleki and Akhani [13] investigated the flora in Iran, where herbs and shrubs are usually used in folk medicine. A remarkable therapy was documented in the same study for the alleviation of muscular, skeletal, and rheumatic pains termed by the local people as “cholzadan.” In this unusual method, the heat arising from burnt plants

and charcoal in a grave-like pit is projected toward the body, which is simply covered with a blanket for approximately 45 minutes. This process is also known as “heated on embers.”

3.2. Analgesic Properties of Plants

In the present review, we evaluated various studies in which pain asessments, such as tail-flick test, hotplate test, acetic-induced writhing test, and formalin test were included. The tail-flick test utilizes a spinal reflex that targets the µ₂- and δ-opioid receptors, whereas the hotplate test demonstrates the supraspinal reflex mediated by the µ₁- and µ₂-opioid receptors [28]. Writhing is induced by the intense intrinsic pain produced by the parenteral administration of acetic acid in mice, which persists for a prolonged period of time. The analgesic effect of a test compound is determined upon a decrease in writhing or inhibition of writhing [29].

Plants contain readily available polyphenols, including flavonoids that possess analgesic and anti-inflammatory properties [30]. Flavonoids cross the brain-blood barrier and manage pain using different mechanisms; they mainly affect the GABA A, opioid, and α-adrenergic receptors and inhibit enzymes that normally participate in inflammatory activities in the brain. They also exert their effects in several areas of the nervous system; inhibition of these receptors results in pain relief. Flavonoids can inhibit the release of cyclooxygenase in tissues and, thus, prevent the generation of prostaglandins. Prostaglandins play a role in stimulating the pain receptors [31].

Boussouf et al. [32] explained that analgesic properties can be assessed using the acetic-induced writhing test, which normally causes sensitization of the nociceptive receptor and the release of prostaglandins, in particular PGE2α and PGF2α, in peritoneal fluids. In their study, the analgesic effect of Mentha rotundifolia leaf extracts (600 mg/kg) was compared with that of aspirin (150 mg/kg). Interestingly, the plant extract was found to be more effective than the drug. In a recent study, de Souza et al. [33] analyzed the analgesic potency of the traditional medicinal plant Solanum paniculatum, which is native to Brazil. The writhing test showed that treatment with the aqueous extract of the plant leaf (partitioned with ethyl acetate) at a dose of 300 mg/kg-body weight (bw) produced an approximately 50% reduction in the writhing nociceptive response.

In addition, Dewan et al. [34] investigated the analgesic potential of the crude ethanolic extract of two plants, Ageratum conyzoides and Mikania cordifolia. Ethanolic extract of both plants leaves were found to exert significant analgesic effects at a dose of 500 mg/kg-bw when the writhing test was performed; moreover, A. conyzoides was fairly stronger in terms of antioxidant potential. However, the positive control, diclofenac sodium (250 and 500 mg/kg-bw), showed a higher inhibition of writhing compared to the two plants extracts.

Ghosh et al. [35] evaluated the antinociceptive (peripheral and central) activity of the methanolic extract of Garcinia lanceifolia (whole plant). At doses of 200 and 400 mg/kg, the plant extract exhibited high antinociceptive activity. Notably, the plant extract demonstrated 50% and 60% of writhing inhibition at doses of 200 and 400 mg/kg, respectively, whereas the standard (diclofenac) showed 60% inhibition. The central antinociceptive activity was evaluated using the tail immersion method. The crude extract at doses of 200 and 400 mg/kg-bw showed significant analgesic activity, with 90% and 78.31% prolongation in the reaction time, respectively, in the 90 min after the sample was administered. This particular study confirmed that the analgesic effect of the plant was attributed to the presence of numerous flavonoids, saponins, terpenoids, diterpenes, and steroids that inhibited the synthesis of prostaglandins.

In the study by Begum et al. [36], the aerial parts of Hyptis suaveolens extracted in 80% aqueous ethanol demonstrated analgesic properties at 400 mg/kg; moreover, the petroleum ether and ethyl acetate extracts exerted remarkable central analgesic effects against heat-induced pain. Naloxone was used to antagonize the action of endogenous opioids; the results demonstrated that the antinociceptive effects of the extracts (400 mg/kg) and morphine (10 mg/kg) were reversed in the hotplate test.

Furthermore, Marzouk et al. [37] evaluated the analgesic properties of an aqueous extract of Citrullus colocynthis fruits and seeds. They found that immature seeds had the highest percentage of writhing inhibition (99%) at a dose of 8 mg/kg. Even at the lowest concentration (0.1 mg/kg), the percentage of writhing inhibition was 94% for the immature fruits. This demonstrates the strong analgesic capacity of these immature fruits and seeds; however, the active compounds (alkaloids, iridoids, flavonoids, steroids, etc.) change according to the maturation process of the fruits.

When evaluating the analgesic effects of the stem bark extracts of Dillenia indica f. elongata and Shorea robusta, Singh et al. [38] performed three tests: the hotplate test, tail-flick test, and formalin-induced pain test, in rats. The hotplate test confirmed the analgesic properties of the ethyl acetate extracts of D. indica f. elongata and S. robusta (300 mg/kg) at 60 and 30 minutes, respectively. Interestingly, the tail-flick test revealed that the analgesic effect of the ethyl acetate extract of S. robusta (100 and 300 mg/kg) was greater than that of the positive control (pentazocine) after 30 minutes. The formalin-induced pain test demonstrated that both plant extracts were more potent than the standard (indomethacin) during the second phase (15-30 min), as the number of paw lickings was significantly reduced. Thus, this study confirmed that ethyl acetate extracts of both plants have central and peripheral analgesic activity that can be attributed to the blockade of opioid receptors (κ, μ, and d), prostaglandins, and histamine.

In the study of Alvarenga et al. [39], the hydroalcoholic extract of the leaves of Psidium cattleianum was screened for in vivo analgesic activity. The results revealed that, in the acetic-induced writhing test, the extract had the highest percentage of inhibition (99%) at a dose of 100 mg/kg compared to the standard drug (indomethacin). Nonetheless, the hotplate test did not show any central analgesic effect. Cleome rutidosperma, which originated in Southeast Asia, is a medicinal plant used in folk medicine. The plant was tested for its analgesic effect, and positive results were obtained in different tests. Specifically, in the hotplate test, at a dose of 200 mg/kg, the methanolic extract of the plant (13.22 ± 0.52, n=5; 53.52%) could sustain the latency time at 30 minutes; this result was comparable to that of the positive control morphine (5 mg/kg; 15.35 ± 0.32, n=5; 67.27%). The results of tail-flick test showed no significant differences in the analgesic effects of the plant extract at the two doses (100 and 200 mg/kg), compared to the standard drugs. In the formalin-induced paw lick test, investigators found that, with the methanolic extract of the plant, the number of paw licks was significantly decreased in both the neurological and inflammatory phases, compared to the positive control. At the same doses, in the acetic-induced writhing test, the extract showed significant inhibition (40% and 47%, respectively) in a dose-dependent manner [40].

Furthermore, the effects of the hydroalcoholic leaf extract of Vitis vinifera (grapevine) were evaluated in the acetic-induced writhing test and formalin-induced paw lick test in mice. The results demonstrated that the extract at dosages of 100, 200, and 400 mg/kg-bw significantly decreased the acetic-induced writhing by 48%, 58%, and 68%, respectively. However, the low percentage of inhibition (50%) suggests that it is not a centrally-acting analgesic. Remarkably, the extract causes a dose-dependent inhibition of formalin-induced pain in the second phase [41].

Aziz [42] evaluated the analgesic properties of the methanolic extracts of the fresh bark and fruits of Microcos paniculata, which has been traditionally used in Bangladesh to treat several diseases such as fever, diarrhea, dyspepsia, heat stroke, colds, hepatitis and wounds. In the formalin-induced paw lick test in mice, it was observed that both extracts (400 mg/kg) showed an increase in the percentage inhibition of paw licking (with the highest inhibition at 78%) from the acute phase to the delayed phase; however, the percentage inhibition of paw licking was lowered in the late phase for the fruit extract. In the writhing test, the extract displayed a significantly higher percentage inhibition of writhing compared to the standard drug (diclofenac sodium, 100 mg/kg). Moreover, the fruit extract showed the highest percentage inhibition of writhing (54%) at 400 mg/kg. However, in the tail immersion test, the tramadol group (positive control group) showed a significant increase in latency after 30 minutes, compared to the plant extract.

Barreto et al. [43] tested the analgesic effect of the extract of Stachys lavandulifolia essential oil, which is commonly used to treat orofacial pain in Turkish traditional medicine. Orofacial pain was induced using formalin in the perinasal area of a rat. The same process was repeated using capsaicin. The essential oil extract caused a decrease in the face-rubbing behavior induced by formalin. At elevated doses of the essential oil extract (50 mg/kg), the inhibitory effect was observed in both phases. Further, it was highlighted that the inhibition in both phases of the formalin test by monoterpenes may be attributed to the blockade of the voltage-dependent sodium ion channels (thus stabilizing the excitable membrane) or the involvement of the descending modulatory pain systems. The capsaicin test demonstrated strong analgesic activity at all doses. This model is relevant to the activation of the capsaicin vanilloid receptors, which elicit axon reflex vasodilation.

Moreover, Mentha arvensis, commonly known as wild mint in India and Bangladesh, was analyzed for its pain-relieving effects. The effects of the ethanolic extract of the plant were evaluated using the acetic-induced writhing test in mice. At oral doses of 250 and 500 mg/kg-bw, the extract displayed 46% and 64% writhing inhibition, respectively, whereas the standard drug, diclofenac sodium, exhibited 77% inhibition at a lower dosage of 25 mg/kg [44].

The root of the climber, Ichnocarpus frutescens, which originated in India, was evaluated for its analgesic efficacy. The methanolic extract of the root demonstrated positive analgesic effects against acetic-induced writhing; furthermore, it exhibited nociceptive peripheral pain effects and the highest percentage of inhibition (59%) at a dose of 1 mg/kg in an in vivo animal model. Therefore, the study confirms the role of the methanolic root extract of Ichnocarpus frutescens in the management of pain in arthritis, comparable to the compound dexamethasone like phytosterol property [45].

The indigenous African plant, Antrocaryon klaineanum, is traditionally used for the treatment of pain. Fongang et al. [46] assessed the analgesic properties of the methanolic extract of the stem bark in a rat model. In the acetic-induced writhing test, at a dose of 600 mg/kg, the extract caused a significant decrease in abdominal constriction at a percentage of 45%. In the formalin test, the plant extract inhibited the nociceptive response by 59% at the highest dose (600 mg/kg). In the hotplate test, at doses of 400 and 600 mg/kg, the extract caused an increase in the latency time, which explains its central analgesic properties. The experiments revealed that the plants could be used to treat acute and neurologic pain.

Sinomenium acutum is used in Chinese herbal medicine to treat rheumatoid arthritis. Sinomenine, a phytochemical compound isolated from the root of Sinomenium acutum, is responsible for its analgesic potential in relieving neuropathic pain. Gao et al. [47] confirmed this by performing the hotplate test and tail-flick test. The results of the hotplate test showed a latency time of 30 min at a dose of 40 mg/kg. In the tail-flick test, a change was observed at 30, 60, and 90 minutes using the same dosage. Harisha et al. [48] evaluated the analgesic effect of the folklore medicinal plant Cissus rependa, which originated in Orissa. The effects of the root and stem extracts were evaluated in the formalin-induced pain test and tail-flick test. The root extract was effective in reducing the paw licking episodes in both phases. Nevertheless, the stem extract of the plant failed to antagonize this effect and no change was seen in the tail-flick test. The aqueous flower extract of Opuntia microdasys (100 mg/kg) reduced pain by inhibiting prostaglandin synthesis. Furthermore, the abundance of polyphenols and, especially, flavonoids, such as kaempferol (159±3 µg/g extract, n=6) and isorhamnetin (14 368±28 µg/g extract, n=6), in the O. microdasys flowers could be correlated with this significant pain-relieving activity [49].

In an experimental randomized study, complex behavior was observed when patients suffering from chronic pain due to fibromyalgia inhaled cannabinoids; only a minimal analgesic response was observed after a single inhalation. However, further detailed studies are necessary to determine if this could be used as a long-term treatment to manage pain [50]. Based on the reviewed literature, leaves (27.5%) (Fig. 1) were the most common plant part studied for their analgesic activity, followed by stem/barks (24.6%) and whole plants (24.6%) (Fig. 2). Other parts, such as seeds and flowers, as well as multiple plants parts, were the least used. This is explained by the fact that leaves are more available, compared to other plant parts, and their plucking would cause no severe harm or impair the survival of the plant or tree, as harvesting the root would [51]. Different types of extraction solvents were used for the different analgesic tests. The most frequently used extraction solvent was methanol (34%), followed by ethanol (29%). Other solvents, such as ethyl acetate (7%), petroleum ether (6%), hydroalcoholic (5%), crude (4%), aqueous (4%), alcoholic (3%), hexane (3%), essential oil (2%), and acetone (1%), were less frequently used (Fig. 3).

Fig. (2).

Plant part used for analgesic activity.

Fig. (3).

Types of extracts used in analgesics tests.

3.3. Bioactive Constituents

Several studies have reported the pharmacological properties, including analgesic and anti-inflammatory effects, of plants utilized for their therapeutic benefits; the effects mentioned in these studies were supported by the presence of phytochemicals. Since ancient times, the most common and natural remedy for the treatment of pain was opium. Greek and Roman medical practitioners used opium as a pain reliever and sleep inducer. From the plant Papaver somniferum, bioactive compounds, such as morphine, codeine, and thebaine, were derived. Researchers have found that opioid analgesics evoke pain relief by the activation of opioid receptors such as the mu opioid peptide receptor. However, several side effects, such as constipation, respiratory problems, depression, and tolerance, were also attributed to opioid use [52]. Mitragynine speciosa, which originated in Thailand, was screened and an alkaloid called mitragynine was found. This compound displayed analgesic, muscle-relaxant, and anti-inflammatory properties. Nevertheless, its administration at high dosages was linked to anorexic effects, tolerance, and unpleasant withdrawal effects. Further, another compound, salvinorin A, derived from the plant Salvia divinorum, was found to be a kappa opioid peptide receptor agonist; this compound was previously used to aid in childbirth [53]. Quintans-Júnior et al. [54] demonstrated the analgesic activity of the monoterpene citronella from the plant Corymbia citriodora; its effect is also mediated via the opioid system.

Opioid peptides, such as beta-endorphin, enkephalin, and diamorphine, are broadly dispersed in the hypothalamus, brain, and spinal cord. Opioid peptides bind to opioid receptors (mu, delta, and kappa receptors) to diminish the release of nociceptive substances and cause a strong analgesic effect. The aromatic monocyclic monoterpene, p-cymene, which is naturally present in the volatile oils of certain plants, was antagonized by naloxone in a tail-flick test [55]. Furthermore, menthol from peppermint is commonly utilized for the relief of pain due to injuries and arthritis. Naloxone and nor-BNI serve as antagonists against the antinociceptive effect of menthol [56]. Quercetin, which is one of the major flavonoids present in allium species, was found to mitigate cancer pain and neuropathic pain in diabetic patients through an opioid-dependent analgesic mechanism [57]. Capsaicin, the dominant ingredient present in hot peppers or capsicum, was suggested to elevate proopiomelanocortin mRNA levels in the arcuate nucleus of rat models, suggesting that the analgesic properties of capsaicin are linked to the cerebral opioid system [58].

Indrayoni et al [59] studied the metabolic profile of Justicia gendarussa. The ethanolic extract of the Justicia gendarussa leaves was tested for its analgesic effect using the acetic-induced writhing and hotplate tests; positive results were obtained. This extract is traditionally used to treat rheumatic pain; the bioactive components present include friedelin, β-sitosterol, lupeol, apigenin conjugates, and justidrusamides A-D. Lupeol, isolated from the stem of Diospyros mespiliformis, displays pain-relieving properties [60]. It mediates the inhibition of interleukin-1 beta and tumor necrosis factor alpha synthesis. Likewise, fridelin, found in Azima tetracantha, and ursolic acid, found in Cissus repens, both displayed analgesic and anti-inflammatory activities [61, 62].

Calotropis gigantea leaves were used by the Bhil tribe in India to treat body pain [23]. Studies have reported that the leaves contain calotropagenin, calactin, calotoxin, calotropin, taraxasteryl acetate, beta-sitosterol, stigmasterol-alpha, and beta-amyrin [63, 64]. Mimosa pudica is an indigenous plant used for the treatment of arthritis in India, headaches in Panama, and stomach pain in Mexico [65]. The aqueous extract of the plant demonstrated antinociceptive activity in the hotplate test, tail-flick test, and acetic-induced writhing test. This extract contained beta-sitosterol, leucoanthocyanidin, dimethyl crocetin, quercetin, luteolin derivatives, mimosainic acid, and mimosinamine [66]. Further, Chan et al. (Chan et al., 2016) reported that the fruits of Vitex trifolia were used to treat headaches, migraines, and rheumatism in Asian regions. They reviewed the compounds that demonstrated analgesic potential and identified the presence of flavones, such as glycosides, luteolin, ursolic acid, and m-hydroxy benzoic acid, and flavonoids, such as casticin, vitexin, artemetin, corniferaldehyde, and vanillin.

In a recent review, [67] gave a detailed account of the pharmacological and remedial activity of several species of mushrooms. They confirmed the effects of the following species together with their respective bioactive compounds: Pleurotus pulmonarius (β-glucans), Pleurotus florida (hydroethanolic extract), Pleurotus eous (methanol and aqueous extract), Agaricus brasiliensis (fucogalactan), Agaricus bisporus var. hortensis (fucogalactan), Agaricus macrospores (agaricoglycerides), Coriolus versicolor (polysaccharopeptides), Cordyceps sinensis (cordymin), Termitomyces albuminosus (crude saponin and polysaccharide extract), Inonotus obliquus (methanol extract), Phellinus linteus (ethanolic extract), Lactarius rufus (soluble β-glucans), and Grifola frondosa (agarucoglycerides).

Wang et al. [68] studied the progress of analgesic components commonly used in traditional Chinese medicine and compiled all the compounds that were shown to produce a positive analgesic effect in vivo. The different compounds obtained from plants were categorized as alkaloids, flavonoids, terpenes, aromatic compounds, coumarins, and lignans. The following 39 alkaloids were reported: trilobine, palmatine, tetrandrine, berberine, rhoifoline A, dicentrine, govaniadine, sinomenine, tetrahydropalmatine, gelsemine, coronaridine, rutaecarpine, mitragynine, harmine, 21-O-syringoylantirhne, alangine, antirhine, harmane, norharmane, mesaconitine, yunaconitine, lappaconitine, bullatine A, aconitine, guiwuline, incarvillateine, 8-O-ethylaconosine, aconicarmisulfonine A, oxymatrine, spectaline, huperzine A, matrine, capsaicin, scotanamine B, skimmianine, veratraline A, veratraline B, veratraline C, and isomurrayafoline B. As for the flavonoids, 16 compounds were screened, including gossypin, hyperin, chrysin, lycopene, eupatilin, acacetin, ellagic acid, quercetin, rutin, kaempferol, hesperidin chalcone, hesperidin, curcumin, kempferol-3, 4′-di-Oα-L-rhamno-pyranoside, and myricitrin. The terpenes consisted of 1,8-cineole, p-cymene, menthol, paeoniflorin, borneol, swertiamarin, geniposide, geraniol, 6-gingerol, and myrtenol. The aromatic compounds were paeonol, divaricatol, cinnamaldehyde, sinapyl alcohol, and caffeic acid. The ten coumarins were as follows notopterol, columbianadin, daphnetin, decursinol, 7-hydroxycoumarin, osthole, albiflorin, scopoletin, fumaric acid, and embelin. Finally, the only lignin was liriodendrin.

In India, spices are one of the pillars of tradition and are widely used in every Indian kitchen. Interestingly, in addition to providing taste and aroma, spices were found to be medically beneficial. Turmeric, which is also known as the golden spice, was found to cure rheumatic pain and gastrointestinal pain and have strong wound healing properties. In vivo, in vitro, and clinical studies have confirmed the efficacy of the different extracts of Curcuma species in osteoarthritic patients. The patients showed significant improvement in terms of pain relief, physical movement, and quality of life after the administration of curcumin. A decrease in the use of concomitant analgesics and side effects was also reported. In vitro research determined that curcumin possibly inhibits the apoptosis of chondrocytes, reduces the release of proteoglycans and metal metalloproteases, and suppresses the expression of COX, prostaglandin E2, and inflammatory cytokines in chondrocytes [69].

Ginger has been traditionally used as a painkiller. This is of interest as it is suggested that ginger can heal multiple types of pain. Ginger ointments are prepared by crushing ginger and then adding water (a little at a time); this preparation is then applied to the forehead to relieve headaches. Applying the same ointment to the gum helps alleviate toothaches. A few drops of ginger juice instilled into the ear can alleviate earaches. New compounds isolated from ginger rhizomes include cassumurins A, B, and C, which are found to have strong antioxidant and anti-inflammatory potential. Numerous spices are prospective sources of compounds useful for the treatment of pain. These include curcuma, black cumin, ginger, garlic, saffron, black pepper, and chilli pepper, which contain many effective bioactive compounds, such as curcumin, thymoquinone, piperine, and capsaicin. These bioactive compounds mainly exert their effects by interfering with various mechanisms such as apoptosis; suppressing proliferation, migration, and invasion of tumors; and sensitizing tumors to radiotherapy and chemotherapy [69, 70].

3.4. Animal-Derived Compounds with Analgesic Properties

Biologically active compounds isolated from animal sources were found to have potent effects. Zadeh-Ardabili and Rad [115] concluded that fish oil and Neptune krill oil could exert a potential analgesic effect by downregulating pro-inflammatory cytokines. Results showed that 500 mg/kg of fish oil and Neptune krill oil reduced the number of writhes by 22.5% and 50%, respectively, in the acetic-induced writhing test in mice. The analgesic effect of the crude petroleum ether and ether extracts of electric rayray fish (Narcine brunnea) was assessed using the hotplate test and tail clip method in rats. In the hotplate test, the petroleum ether extract and ether extract displayed a basal reaction time from 2.150±0.043 and 2.300±0.058 at 0 min to 6.102±0.037 and 8.783±0.070 at 120 min, respectively. In the tail clip method, a significant increase in the basal reaction time of 6.817±0.031 in petroleum ether and 8.852±0.043 in ether extract was observed at 120 min (P<0.05), compared to the control groups (2.233±0.061). The compounds, which are present in the crude extract of the electric ray and are responsible for its analgesic properties, were identified as 3, 5- dihydroxy phenyl acetic acid, N-methyl 2, 3- dihydro 3-but-2-enyl indole 5-sulphonic acid, and 3-but-2 enyl indole-5-sulphonic acid. Interestingly, the same compounds were also identified in other marine sources, such as herring, mackerel, cod liver oil, and shark liver oil [116].

Animal venoms are definite reservoirs for drug discovery and the enhancement of pharmacological tools [117]. Leite dos Santos and colleagues [118] investigated the antinociceptive potential of Micrusrus lemniscatus venom by performing the writhing test, formalin test, and tail-flick test in vivo. Oral administration of a dry crude extract of M. lemniscatus at a dose of 19.7-1600 µg/kg caused a significant inhibition of the abdominal constriction induced by acetic acid. In the formalin test, oral administration of 1600 µg/kg of the extract caused an analgesic effect in both the early and late phases in the central mechanism. An orally administered dose of 177-1600 µg/kg of venom extract enhanced the reaction time in the tail-flick test; this effect lasted for 5.5 hours. The M. lemniscatus venom acts in the opioid system via the µ-opioid receptor.

Saez and Herzig [119] reviewed the versatile repertoires of peptides in spider venom and their therapeutic effects for medicinal application. Some of the pain-relieving peptides are Pn3a (Pamphobeteus nigricolor), Cd1a (Ceratogyrus darlingi), protoxin-III (Thrixopelma pruriens), CcoTx1 (Ceratogyrus marshalli), GpTx1 (Grammostola porteri), and Phα1β (Phoneutria nigriventer) [120-129].

The spider neurotoxin, PhTx3-6, is patented as an antinociceptive agent (Ph α1β). The analgesic effects were assessed using the formalin test in Wistar rats pre-treated with Phα1β (100 pmol/site); the nociceptive behavior was reduced by 72.0±7.8% (n=4-12 per group). Multiple isoforms of Phα1β have demonstrated to have analgesic potency, including PnTx3-3, PnTx3-4 and PnTx3-5 [127]. However, adverse effects, including body shaking and serpentine-like tail movements due to the high dose, have been documented [127]. Similar results demonstrating the synergistic analgesic activity of Phα1 β in combination with the TRPV1 blocker were confirmed in animal studies [130]. Furthermore, Deuis et al. [124] revealed that the original GpTx1 peptide from tarantula exerted analgesic effects when administered locally, but not systemically, as evaluated in an OD1-induced spontaneous pain rat model. Another novel neurotoxin, Huwentoxin-XVI (HWTX- XVI), extracted from the venom of the Chinese tarantula, Ornithoctonus huwena, was tested for its pain relief properties using the formalin test and hotplate test in vivo. A dose of 112.7 nmol/kg was intraperitoneally injected and the effect of the neurotoxin was evaluated in the formalin test; it was observed that pain was reduced only in the second phase. In the hotplate test, an acute thermal pain model was used; a dose of 56.3 nmol/kg of HWTX-XVI showed slight analgesic activity with a maximum effect of 68±7% (n=8) from 0.5 to 1 hour after injection. A plantar incision rat model was used to test the analgesic effect of the venom on mechanical allodynia. Intramuscular infusion of venom at a dose of 56.3 nmol/kg displayed a significant reduction of post-incision allodynia, reaching its maximum effect at 2.5 hours [131].

In a study by Maatooug et al. [132], a new scorpion toxin, Buthus occitanus tunetanus (BotAF), was analyzed for its potent analgesic effect in rodents. The antinociceptive writhing test revealed a positive analgesic effect up to 50%, even after 90 min after the BotAF (5 mg/kg; intraperitoneal) injection. This result also indicated that BotAF is a 2.3-fold stronger analgesic compound than the standard drug beta-endorphin for viscera-somatic pain. BotAF was tested using the hotplate method to evaluate its efficacy in reducing acute somatic nociception. The same dose had a maximum effect at 60 min after intraperitoneal injection. The analgesic activity was further evaluated using the tail-flick test and formalin test. The results of the tail-flick test revealed that a maximal antinociceptive effect was obtained at 60 min and was still significant up to 120 min after injection. The formalin test suggested that BotAF acted on both phases when injected locally; moreover, on average, BotAF was shown to be more efficient (2-fold increase) than morphine sulfate. Furthermore, the venom of scorpion Buthus martensii Karsch is traditionally used to treat several diseases; it has also been used as a painkiller. The peptide BmK AGAP-SYPU2 was assayed using the mouse-twisting model (pain in the internal organs) and the hotplate test (pain in the limbs) in vivo. In the mouse-twisting model, the peptide was intravenously injected at different doses; the maximum dose (0.35 mg/mL) showed an analgesic effect. The hotplate test demonstrated that 0.35 mg/mL of BmK AGAP-SYPU2 had a stronger analgesic effect than the positive control (morphine; 1.5 mg/kg). Therefore, the neuropeptide exhibited a powerful analgesic effect against both visceral and somatic pain [133].

Bee venom has been used in oriental medicine to treat several diseases and relieve pain through a chemical acupuncture point, termed apipuncture [134]. Shin et al. [135] studied the effectiveness of bee venom acupuncture for reducing pain and disability in subjects suffering from chronic lower backpain using a randomized, sham-controlled, triple-blind, two-group parallel clinical trial. Sixty participants were randomly divided into a bee venom acupuncture group and a sham control group. In total, six acupoints (0.1 mL BVA for each acupoint) were injected for an interval of 4 weeks. Both groups responded positively without any adverse reactions and medical interventions showed improvements in pain intensity; thus, it was concluded that this therapy can be considered safe for managing pain. Jeong et al. [136] attempted to enhance the efficiency of bee venom acupuncture by loading the venom into biodegradable poly(d,l-lactide-co-glycolide) nanoparticles (BV-PLGA-NPs) using a water-in-oil-in-water-emulsion/solvent-evaporation technique. A formalin rat test was conducted and bee venom was injected into the Zusanli acupuncture, which significantly reduced pain behavior in the late phase; the effect lasted for approximately 12 hours.

Several bioactive compounds have been identified from amphibian skin secretions. Analgesin-HJ and analgesin-HJ (15T) are two novel analgesic compounds found in the skin of the tree frog Hyla japonica. Multiple tests, including the acetic-induced abdominal writhing test, formalin test, and thermal pain test, confirmed the efficacy of the compounds. In the acetic-induced writhing test, analgesin-HJ (1.25, 2.5, and 5 mg/kg) and analgesin-HJ (15T; 1.25, 2.5, and 5 mg/kg) were found to be more potent than the standard drug (morphine; 2.5 mg/kg). An intraperitoneal injection of analgesin-HJ significantly attenuated neurogenic and inflammatory pain responses. In the formalin-induced test, at doses of 1.25, 2.5, and 5 mg/kg, the licking time was reduced by ~106, 90, and 75 seconds, respectively, in a rat model. Applications of both analgesin-HJ and analgesin-HJ (15T) increased the tail-flick latency. The analgesic effect lasted for a minimum of 360 seconds. In the hotplate test, administration at various doses (1.25, 2.5, and 5 mg/kg) increased the latency time to 15, 17.5, and 19 seconds for analgesin-HJ and 16, 17, and 20 seconds for analgesin-HJ (15T), respectively [137].

Recently, a novel compound, anntoxin, has been identified in skin secretions of the amphibian Hyla annectans (Jerdon). Different pain tests were carried out in both male and female Kunming mice (20-25 g) using recombinant anntoxin at a dose of 2.5 g/kg. The recombinant anntoxin at a dose of 2.5 g/kg delayed the reaction time to 9 seconds after either 30 or 60 minutes of administration. In the hotplate test, the same dose delayed the reaction time to 22.5 seconds after 60 minutes of administration. In the formalin-induced paw licking test, anntoxin significantly inhibited the response time in the late phase. Lastly, in the acetic-induced writhing test, the analgesic effect of anntoxin was demonstrated as the number of writhings decreased from 72 to 39 with increased doses of anntoxin (0.625, 1.25, and 2.5 mg/kg body weight), compared to the control, which was 90 after 30 minutes of administration [138]. Therefore, it was noted that animal sources contain potent analgesic compounds that can be further evaluated for therapeutic consideration.

4. Limitations and Future work

In the literature search, certain gaps were noted, which could be reviewed in future studies. First, there was a disparity of information with regard to the traditional use of medicinal plants. Even though the analgesic effects of many indigenous plants were recorded, there was a paucity of information regarding the mode of administration, variety of plants used, dosage, and method of preparation; these details are essential when carrying out ethnomedicinal studies. It was also found that most studies were conducted in Asian and African regions (Table 1). Furthermore, many studies were rejected as they did not match the inclusion criteria. Correct taxonomic nomenclature, including author citations, allows duplicability and documentation, reducing the risk of misinterpretation [139]. Similar vernacular names are frequently used for numerous species, which are generally not related to each other [140]. Additionally, vernacular names are termed in and within languages, which add further confusion.

Furthermore, it was found that many food plants were traditionally used for their analgesic properties. However, there was no pharmacological validation to critically analyze the data. Therefore, more studies (in vitro, in vivo, and clinical studies) should be carried out using traditional formulations to validate the different pharmacological properties. In the present review, many plants were found to have multiple therapeutic properties along with pain alleviating properties. Other data on the herb-drug interactions can help clarify the pharmacodynamics and pharmacokinetic interactions to limit toxicological issues. Analgesic compounds derived from animal sources remain an issue when it comes to ethics and dietary restrictions.

Maatoug et al. [132] stated that several analgesic compounds were derived from animals; however, to date, ziconotide is the only toxin-derived medicine used in clinics to treat pain. The major challenges posed when translating preclinical trials to therapeutics are: (i) reaching the right potency and selectivity and (ii) providing the correct target accessibility and coverage. Analgesics from venom sources and species require diverse screening strategies that are target-based, toxin-based, and activity-based.

In this review, we found that 24.6% whole plants and 8.7% roots were used to test for analgesics; thus, it should be noted that the extensive use of some plant species may disturb their ecological patterns and populations, leading to extinction. Considerable investigations should be directed to prevent such harm to the ecological patterns of medicinal plants [141]. Eventually, more than half of all hospitalized patients will suffer from pain in the last stages of their lives. Despite the therapies provided to alleviate discomfort and pain, especially for patients with cancer, studies show that 50% to 75% of patients still die in moderate to severe pain.

Preclinical studies aim to discover disease mechanisms and analgesic targets to implement new treatments and provide more sophisticated therapies; however, only a few new such therapies are being practiced in the medical domain. Other challenges include the translation of preclinical research in murine models to clinical studies in patients. Additionally, the complexity of pain makes it difficult to understand the dimensions of pain. Therefore, a better and more detailed comprehension of the role of reward/motivational circuits in pain could promote analgesic drug discovery in a purposeful way [142, 143]. Much work remains to be done to provide effective treatments using natural ingredients in conjunction with advanced technology.

Conclusion

In the present review, the pain was described as sensory occurrence; and was explained as an unpleasant sensory and emotional experience attributed to tissue damage, inflammation and other causative factors. Consequently, this multidimensional entity has been associated with multiple aspects, including sensors, cognition, motivation, affection, behavior, and spirituality. The mechanism of pain is complex, but the condition is still perceived as a plague despite being regarded with such significance. The WHO confirmed that approximately 80% of the global population is deprived of proper access to opioid analgesics for the treatment of pain. Despite the fact that opioids and non-steroidal anti-inflammatory drugs, such as morphine and aspirin, have proven efficacy, they are associated with potentially harmful side effects and societal drawbacks. In this review, an attempt was made to critically assess and describe the pharmacological properties and bioactive composition of indigenous plants, some animal species, and animal venom by scrutinizing databases and looking for published articles. It should be noted that the analgesic activities were highlighted and the in vivo results were also compiled. Therefore, it can be concluded that the compounds obtained from these sources can serve as important ingredients in therapeutic agents to alleviate pain once their limitations are assessed and improved upon.

Authors’ contribution

All authors were involved in conceptualization. F. Mahomoodally and T. Joaheer did the data mining. K. Rangasamy and Yansheng Zhang reviewed and edited the manuscript and language check. All authors were actively involved in the preparation of the first draft and editing.

Consent for Publication

Not applicable.

Funding

None.

Conflict of Interest

The authors declare no conflict of interest, financial or otherwise.