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Indian Journal of Pain | January-April 2014 | Vol 28 | Issue 1 5

Pain and inflammation: Management by conventional and herbal therapy

IntroductionThe sensation of pain is an indication that something is wrong somewhere in the body. Pain in its real sense has no precise defi nition, but in general term, occurs whenever the body tissue is damaged.[1] The damage may be superfi cial or deep right in the tissue of the body. The function of pain is to draw attention to injury and through the refl exes elicited to protect the injured part. Whenever pain sets in, the individual reacts to remove the pain. Pain receptors and a erent pain fi bers are distributed all round the body. The pain sensation is initiated by peripheral receptors by stimuli: Such as mechanical, thermal, electrical, chemical, etc., at a threshold su cient to cause tissue damage.[2] The pain stimulus is processed in the brain which then sends impulses down the spinal cord and through appropriate nerve which commands the

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ABSTRACTThe sensation of pain is an indication that something is wrong somewhere in the body. Pain and infl ammation may be linked by cyclooxygenase (COX) enzymes most especially COX2, which help in the synthesis of prostaglandins (PGs) precisely PGE2 and PGF2a, found in high concentration at the infl ammatory site. The released PGs either stimulate pain receptor or sensitized pain receptors to the action of other pain producing substances such as histamine, 5-hydroxytryptamine (5HT), bradykinin which initiate and cause the nerve cells to send electrical pain impulse to the brain. In the present review, an attempt is made to unveil the treatment approach adopted in the management of pain and infl ammation as well as animal models used in evaluating herbal plants with analgesic and anti-infl ammatory properties. The choice of the use of herbal medicine have been encouraged due to it availability, affordability, accessibility, and little or no side effect associated with it. However, the question remains can herbal therapy serves as an alternative to available conventional drugs. Different treatment options in the management of pain and infl ammation have been highlighted.

Key words: Conventional drugs, herbal medicine, infl ammation, pain

David Arome, Akpabio Inimfon Sunday, Edith Ijeoma Onalike, Agbafor Amarachi1

Department of Science Laboratory Technology (Physiology and Pharmacology Technology), University of Jos, Plateau State, 1Biochemistry, Covanent University, Ota, Ogun State, Nigeria

body to react, for instance by withdrawing the hand from a very hot object.[3]

Inflammation is a natural response of the body to a variety of hostile agents; invading microbes, physical injury, and toxic substances which lead to the accumulation of blood and plasmatic body f luids.[4] Inf lammation is a normal protective mechanism adopted by the body to get rid of offending stimuli, but if not properly treated may result to a more damage with exuberance to create chronic inf lammation,[5] and other diseases.[6] Inf lammation is characterized by five cardinal clinical signs, namely redness, swelling, pain, heat, and loss of function.[7] Inf lammation can be acute and chronic. Inf lammation is the most frequent triggered of pain. Pain is basically triggered in an inf lamed tissue by arachidonic acid metabolism as well as other pain-producing substances released from the damaged

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Address for correspondence: Mr. David Arome,

Department of Science Laboratory Technology, (Physiology and Pharmacology Tech),

University of Jos - 23473, Nigeria. E-mail: [email protected]

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Arome, et al.: Conventional and herbal therapy for pain and inflammation

6 Indian Journal of Pain | January-April 2014 | Vol 28 | Issue 1

tissue.[8] Inf lammation and pain may be linked by cyclooxygenase (COX) enzymes most especially COX2 which help in the synthesis of prostaglandins (PGs) precisely PGE2 and PGF2a, found in high concentration at the inf lammatory site.[9] The released PGs either stimulate pain receptor or sensitized pain receptors to the action of other pain producing substances such as histamine, 5-hydroxytryptamine (5HT), and bradykinin which initiate and cause the nerve cells to send electrical pain impulse to the brain.

Previous reports have implicated herbal medicine as an alternative therapy to conventional drugs. Herbal preparations are used for wide range of diseases such as pain and infl ammation with little or no side e ect associated with their use. The uses of conventional drugs in the treatment of pain and infl ammation have largely been greeted with side e ects. These presenting challenges have triggered scientifi c researchers all over the world in search of alternative therapy. The present work seek to review the treatment approach adopted in the management of pain and infl ammation as well as animal models used in evaluating herbal plants with analgesic and anti-infl ammatory properties.

Types of PainFast PainThis is a localized pricking type of pain felt less than a second after application of pain stimulus: Electrical, thermal, and stimuli. This type of pain is superfi cial and is not felt in most deep part of the body tissue. Fast pain is transmitted in the peripheral nerves to the spinal cord through a nerve called A delta fi bers (Ad fi bers) at a speed of 5-30 m/s. The high conductive velocity of pain stimulus allows the body to withdraw immediately from the painful and harmful stimuli in order to avoid further damage. For example, touching hot plate and pin pricking.[2]

Slow PainSlow pain is a throbbing, di used, slow burning pain felt few seconds after pain stimulus is applied and may last for minutes, weeks, and even resulting to chronic pain if not properly processed by the body. Slow pain starts immediately after fast pain subsides. It is felt mostly in deep tissue of the body. Slow pain is transmitted by C-fi bers (with diameter 0.2 and one thousand of a millimeter) to the brain at a velocity of 0.5-2 m/s. The response of the body is to hold the a ected body part immobile so that healing can take place. Other types of pain are: Referred pain, viscera pain, etc.[2]

Differences between of fast pain and slow pain

Slow pain Fast pain

Transmitted by very thin nerve fi bers

Transmitted by relatively thicker faster conducting nerve fi bers

Poorly localized Well localized

All internal organs (except the brain)

Mainly skin, mouth, and anus

Body wants to be immobile to allow healing (guarding, spam, and rigidity)

Immediate withdrawal of stimulation to avoid further damage

Effective relief from opioid Little relief from opioid

Pain often radiates or is referred Pain does not radiate

For example, labor pain. For example, pain from a surgical incision[10]

Pain transmission in the spinal cord and brainPain stimulus is transmitted through peripheral nerves to the spinal cord and from there to the brain. This happens via two di erent types of nerve fi bers: Fast pain fi bers and slow pain fi bers.

Fast pain is transmitted by A fi bers to the spinal cord. Fast pain fi ber terminates at luminal one of the dorsal horns of the spinal cord and excite the 2nd order neuron of the neospinothalamic pathway which terminates at the reticular area of the brainstem (ventrobasal complex). Fast pain impulses are transmitted to specifi c and limited area of the brain surface of cortex by neurotransmitter called glutamate secreted by the fast pain nerve ending of the spinal cord allowing for a relative precise localization of the pain.[3]

Slow Pain impulses are distributed di usely to di erent parts of the brain. Each area of the brain elicit di erent responds which explain the whole range of the symptoms that pain can cause such as su ering, sleeping di culties.[3]

Opioid analgesic system of the brainThe components of the opioid analgesic system of the brain are:1. The periaqueductal grey and periventricular area of the

mesencephalon in the upper pons2. The raphe magnus nucleus located in the lower

pons and upper medulla and nucleus reticularis paragigantocellaris.

3. Pain inhibitory complex located in the dorsal horn of the spinal cord.

The nerve endings of the periaqueductal and periventricular grey secrete mostly enkephalin, serotonin, when stimulated. The endogenous mediator blocks signal at both presynaptic and postsynaptic fi bers of the Ad and C-fi bers.

Met, leu enkephalin, dynorphin, and endorphin are the major endogenous opioid substances found in the brain. The




arrival of pain impulses to the brain stimulate the release of stored opioids causing them to bind to the receptors of the terminal end of the ascending pain stimulating fi bers (APSF) to block the transmission and perception of pain.[2]

Infl ammationPrevious reports have shown that inf lammation manipulates two proteins namely: Calcium-activated chloride channel and M-type potassium channel found at the damage tissue of the pain sensing terminals of the nerve cells. These proteins when targeted by bradykinin cause the nerve cells to send electrical pain impulse to the brain. The underlying mechanism to which this electrical signal is generated still remains unclear.[10]

Walling o e ect of infl ammationThe very fi rst e ect of infl ammation is to wall o the injured area from other part of the tissue. This is made possible by the fi brinogen clots which prevent fl uid from reaching the injured area. The important of walling o process is to delay or slow down the spread of bacterial and other toxic products.[2]

Types of infl ammation1. Acute infl ammation: This is the initial response of the body

to harmful stimuli. The stimuli increased the movement of plasma and white blood cells to the injured area.

2. Chronic inf lammation: This occurs as a result of infl ammation being prolonged for a period of time. Some time it may result to autoimmune disease. Other less common types are subacute infl ammation and granulomatous chronic infl ammation.

Subacute infl ammation has a chronic sign similar to acute and chronic infl ammation. It is an intermediate stage between the two major types of infl ammation.

Granulomatous chronic infl ammation is a special type of chronic infl ammation associated with tuberculosis.[3]

Characteristics of Infl ammationInfl ammation is characterized bya. Vasodilation of the blood vessel and increase in blood

fl ow due to release of vasodilators.b. Increase in permeability of capillaries leading to leakage

of fl uid into the interstitial spaces.c. Fluid clotting in the interstitial space due to the

leakage of excess fi brinogen and other proteins from the capillaries.

d. Movement of large granulocyte monocyte to the injured tissue.

e. Swelling of the tissue cells.[2]

Infl ammatory reactionsInfl ammatory reaction has two components1. Innate responseThe innate response is activated immediately after infection or microbes invade the body. Innate responses also prevent the adaptive response from targeting and destroying the host cell. Innate response consists of vascular and cellular element. Innate response is mediated by antigen presenting cells (APC) which is made up of dendritic cells and microphages. APC ingest and process the antigen and present it on the surface of the lymph nodes

2. Adaptive immune responseThis is a complementary response that follows after pathogen has been recognized by the innate system. It is mediated by T and B lymphocyte.

Infl ammatory reactions is controlled by the following system: Cytokines complement, kinin, and fi brinolytic pathways by lipid mediators (PG and leukotrienes) released from a di erent cells and vasoactive mediator release from mast cells, basophils, and platelet.[3]

Models of pain and infl ammation1. Animal models for pain

Models for Peripherally Acting Drugsa. Acetic acid reduced abdominal writhing in miceThis is a widely used experimental model for screening peripherally acting analgesic agents. Mice of either sex of weight 20-25 g are used. The animals are pretreated with the test sample. Thirty minutes after pretreatment, 0.2 ml of 1% of the prepared acetic acid is injected into the animals through intraperitoneal (IP) route, after which the mice are transferred into a plastic bucket and observed. The number of full abdominal writhes is counted for a total duration of 5 min for each mouse.[11]

b. Pain in infl amed tissue (Randall-Selitto test)The principle of this method is based on the fact that infl ammation increases the peripheral analgesic sensitivity to pain. Animal with weight range of 130-175 g fasted for 18-24 h is used. 0.1 ml of 20% suspension of Brewers yeast is injected subcutaneously into the left hind planter side of the paw. Three hours after pretreatment with the test agent, pressure is applied through tip of the plantar surface of the rat foot as a constant rate using analgesiometer. Animal with a control pain threshold greater than 80 g is eliminated and replaced.[12]




Models for centrally acting drugsa. Tail immersion testAnimals used for the test are placed in an individual cage or restrainer, allowing for 30 min of acclimatization leaving the tail hanging out freely. Five centimeter from its tips of the animal tail is marked. The marked part is immersed in cup of freshly fi lled water of temperature of 55C. Stopwatch is used in recording the reaction time, both before and after administration of the test compound. Withdrawal time more of than 6 s is regarded as a positive response.[13]

b. Hot plate testHot plate test is used to assay narcotic drugs or agents. In this method, hot plate surface is maintained at a constant temperature of 55-56C. Animals are placed in a glass bucket of 55 cm diameter or heated surface, and the time between placement and shaking or leaking of the paw or jumping is recorded as index of response latency. Animals receive the test compound orally 1 h before they are placed on the hot plates. Centrally acting analgesic drug prolonged the response time.[14]

Other models for centrally analgesic drugs are:1. Pleurisy test2. Ultraviolent erythema test in guinea pigs3. Oxazolone-induced ear edema in mice4. Granuloma pouch techniques

Animal models for infl ammationExperimental models for acute and subacute infl ammation studya. Carrageenan-induced paw edema in ratThis model is used to assay acute anti-infl ammatory activity of a test agent. One hour after pretreatment of animals with test sample, 0.1 ml of 1% prepared carrageenan is injected subcutaneously into plantar side of the left hind paw of the animal. Paw volume is measured at 30 min interval after the injection of 0.1 ml prepared carrageenan for the total duration of 2-3 h, paw volume of the animal is measured at 0 min with digital plethysmometer before the administration of the test sample. The di erence between the initial and subsequent paw volume values gives the actual paw edema and which compared with the control. Paw volume can also be measured with vernier caliper, pair of divider, and cotton thread.[15]

b. Egg albumin induce paw edema in ratEgg albumin is used to screen agent with acute anti-infl ammatory e ects, especially if infl ammation is not intended to be sustained for long. The procedure used is the same as that of the carrageenan, but with slight

modifi cation in some cases. Here paw volume is measured as 20 min interval after the injection of 0.1 ml of the egg albumin for the total duration of 2 h. Paw volume is measured at 0 min before the administration of the test compound.[16]

Treatment of Pain and Infl ammation1. Nonsteroidal anti-infl ammatory drugs (NSAIDs)2. Narcotic drugs3. Corticosteroids drugs4. Immune selective anti-inf lammatory derivatives

(mSAIDs)5. Herbal therapy

NSAIDsNSAIDs are used for the treatment of mild to moderate type of pain and infl ammation. For example, ibuprofen, indomethacin, and diclofenac. NSAIDs act through inhibition of enzyme COX, most precisely COX2 responsible for the biosynthesis of PGs which triggered infl ammation thereby preventing the amplifi cation of the pain stimuli.[17,18]

Side effects: Nausea, indigestion, bleeding from the stomach, peptic ulcer, and bronchopasm.[19]

Narcotics DrugsBasically used in the treatment of severe type of pain. These are classifi ed into three groups:i. Natural opium alkaloid divided into a. Phenanthrene group: For example, morphine b. Benzylisoquinoline group: For example, papaverineii. Semisynthetic opioid: For example, oxycodoneiii. Synthetic derivatives with structures unrelated to

morphine

Mechanism of actionThe pharmacological action of narcotic is mediated by specific and multiple receptors. mainly: d, m, and k receptors. Stimulation cause the release of the endogenous opioids like enkaphalin, dynorphin from the terminal ending of the descending pain inhibitory fi bers making to attached to receptors of the terminal of the ascending pain carry fi bers, and prevent the release of substance P. All opioid analgesic receptors bind to selective endogenous opioid receptors to elicit their pharmacological action.[3]

Side effect of narcotics analgesic drugs: Euphoria, tolerance, nausea, vomiting, and sedation.




Corticosteroid DrugsThese are anti-inf lammatory agents that prevent phospholipid release and undermines eosinophil action and number of other mechanism involved in infl ammation.[10]

Sets of corticosteroids drugsa. Glucocorticoids are normally prescribed in the

treatment of infl ammatory bowel diseases, hepatitis, and allergic reactions.

b. Mineralocorticoid: Used with other medications in the treatment of cerebral salt wasting.

mSAIDsThis new class of anti-infl ammatory agent is found to alter the activation and migration of immune cells involved in amplification of inf lammatory response. mSAIDs have been implicated as potential veterinary drugs for controlling and reducing infl ammation.[10]

Table 1: Herbal plants with analgesic and anti-infl ammatory propertyPlant (family) Part used Chemical constituents Uses Animal models References

Ficus ingens (Moraceae)

Leaves Alkaloids, glycosides, saponins, fl avonoids, carbohydrates, tannins

Fever, pain, infl ammation, pile, diarrhea, diuretics

Hot plate test, acetic acid-induced writhing test, carrageenan-induced paw edema

[11,14,23]

Zea may Husk (Poacea)

Tannins, steroids, polyphenols Pain, arthritis Hot plate test, formalin-induced paw licking test, carrageenan-induced paw edema

[24-28]

Carica papaya Seeds Alkaloids, resins, carbohydrates, fats, glycosides

Antibacterial, malaria, infl ammation, deworming

Fresh egg albumin [29-31]

Typhonium trilobatum (Araceae)

Leaves Reducing sugar, alkaloids, fl avonoids, steroids tannins, fl avonoids gums, glycosides

Piles, rheumatism, asthma, head ache, gastric ulcer

Acetic acid-induced writhing, xylene-induced ear edema

[32-35]

Dracaena cinnabari Balf

Resin Flavonoids, trepenoids, sterol Gastric sores, diarrhea, dysentery, analgesic, skin and mucosal diseases

Acetic acid test, tail fl ick, carrageenan-induced paw edema, trauma-induced paw edema

[15,36-43]

Kaempferia galanga Rhizomes Volatile oils: Eucalyptol, carvone

Abdominal pain, embrocation applied on muscular swelling, rheumatism

Hot plate test, radiant heat tail fl ick, carrageenan-induced paw edema, cotton pellet-induced granuloma model

[1,6,44-47]

Stachys lavandulifolia

Aerial parts

Flavonoids, saponins, and bitter compounds

Pain, infl ammatory disorders Acetic acid-induced writhing, formalin test, light tail fl ick, carrageenan-induced paw edema

[11,14,15,48]

Jatropha curcas Leaves Alkaloids, saponins, trepenoids, tannins, and steroids

Jaundice, pain, skin diseases, cancer, snake bites

Acetic acid writhing test, egg albumin-induced edema

[49,50]

Tabernaemontana divaricata (Apocynaceae)

Flower Alkaloids, glycosides, steroids, saponins, fl avonoids, terpenes, glycosides, proteins, amino acids, fi xed oil, tannins, and volatile oil

Rejuvenation therapy, pain and infl ammation, improved memory

Acetic acid-induced writhing, hot plate reaction test, carrageenan-induced paw edema

[15,51,52]

Tectona grandis (Verbenaceae)

Leaves Flavonoids, phenolic acids, quinines, terpenes

Analgesic, infl ammation, wound healing

Eddys hot plate, carrageenan-induced paw edema model

[53-60]

Guiera senegalensis Gmel (Combretaceae)

Leaves Alkaloids, glycosides, tannins, and fl avonoids

Diarrhea, rheumatism, syphilis, leprosy, impotence, dieresis, expurgation, fever, malaria

Acetic acid-induced writhing test, egg albumin induced edema,

[61-63]

Litsea sebifera (Lauraceae)

Different part

Alkaloids, fl avonoids, glycosides, and saponins

Antiseptic, expectorant, tonics, fever, pain, infl ammation

Acetic acid-induced writhing in mice, formalin induced hind paw licking test, carrageenan-induced paw edema, egg albumin infl ammation

[64-67]

Markhamia tomentosa (Bignoniaceae)

Leaves Tannins, alkaloids, cardiac glycosides, fl avonoids, phenol, an saponins

Rheumatoid arthritis, edema, gout, headache, snake venom, scrotal elephantiasis

Writhing test, hot plate test, formalin test, immersion test, carrageenan

[14,15,68-71]

Rosa damascene (Rosaceae)

Flavonoids, glycosides, tannins, quercetin, caempterol, terpene, myrcene, vitamin C, carboxylic, essential oil: Geraniol, docosane, beta-citronellol, and nonadacene

Infl ammatory diseases, cough remedy, digestive problems, laxative, antibacterial activity

Writhing test, formalin test, tail fl ick test, formalin-induced paw licking test, carrageenan-induced paw edema

[14,15,72-76]




Herbal TherapyHerbal medicine is the oldest form of healthcare known to mankind. Herbs have been used virtually by all culture throughout history. People around the world in di erent civilization have used plants to treat di erent diseases for several years.[20] Herbal medicine is an alternate treatment of disease which constitutes the use of di erent plants and their extracts. Herbal medicine comes in di erent forms that include extract, tablet, essential oil, or ointment. Herbs are used to treat various disease conditions such as asthma, eczema, premenstrual syndrome, etc., and some cases may have fewer side e ects than conventional drugs.[21] About 28% of all modern drugs in use today are derived directly from naturally occurring substances in plants.[22] Substances derived from plants remain the basis for large proportion of commercial medication Table 1.

ConclusionInfl ammation is a normal defensive mechanism adopted by the body to get rid of invading microbes. However, if left untreated may result to other chronic diseases. Hence, there is need to arrest it before it gets out of control. Di erent treatment options are available in the treatment of pain and infl ammation. Conventional and herbal therapies are the widely used options employed. The use of the former is greeted with numerous unwanted side e ects, which limit their application. The choice of the use of herbal medicine have been encouraged due to it availability, a ordability, accessibility, and little or no side e ect associated with it.

The use of herbal medicine can serve as treatment options or alternative therapy in the treatment of pain and infl ammation.

AcknowledgmentThe authors would sincerely like to appreciate Mr Imadi David for his encouragement and support toward the success of this paper.

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How to cite this article: Arome D, Sunday AI, Onalike EI, Amarachi A. Pain and infl ammation: Management by conventional and herbal therapy. Indian J Pain 2014;28:5-12.

Source of Support: Nil. Confl ict of Interest: None declared.


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