Pain Perception and Management: Where do We Stand?

Abstract

Background:

Pain is often flammable, sharp and sometimes described as an electrical shock. It can be categorized in three different ways as nociceptive, neuropathic and inflammatory. Nociceptive pain always originates in specific situations such as in trauma. Neuropathic pain results in nerve damage. In inflammatory pain, inflammatory mediators are involved in the sensitization of nociceptors. It is important to control the pain as it affects the individual physically, mentally, and socially.

Objective:

Recognizing pain physiopathology and pain pathways, defining the relationship between receptor and transmitter is critical in developing new treatment strategies. In this review, current information on the definitions, classifications, and physiological and chemical mechanisms involved in pain are reviewed.

Methods:

Various search engines were used to gather related articles/information. Only peer-reviewed journals were considered. Additional, books/chapters of standard publishers were also included in the article.

Results:

With a better understanding of the physiological and chemical mechanisms that play a role in pain, significant improvements have been made in pain treatment. Various oral or intravenous drugs, local injection treatments, physical and occupational therapy, electrical stimulation, alternative medicine applications, psychological support, and surgical applications are routinely performed in the treatment, dependent upon the type, severity and cause of the pain.

Conclusion:

Improved understanding of pain physiopathology will serve as the basis for future improvements in the delivery of efficacious and reliable treatments, and is likely to rely on novel technological innovations.

1. INTRODUCTION

According to the International Association for the Study of Pain (IASP), nociception is defined as “the neural mechanisms of encoding and processing harmful stimuli,” while pain is defined as “an undesirable sensory and emotional experience associated with real tissue damage” [1, 2]. Pain is a signal which produces reflex and conscious preventive response to protect the body from actual damage [3]. A plethora of stimuli, such as heat, inflammation, necrosis, spasm, to name a few, are responsible for the initiation of pain [4]. Numerous chemical mediators that express painful conditions have been identified [5, 6].

Pain and inflammation can also occur in the course of various diseases such as rheumatoid arthritis, cancer inflammatory bowel disease and polymyalgia [7]. In majority of cases, pain is always associated with diabetic nephropathy [8, 9]. In the United States of America (USA), over fifty million people are partially or completely disabled due to pain, which severely impacts their lives. Recent research conducted by the US center for Healthcare Statistics has estimated that approximately 32.8% people in the USA suffer from chronic pain [8]. Several synthetic and natural agents possessing strong pain-relieving effects are readily available to treat such pain [10–13].

The purpose of the current review is to address various aspects of pain perception, the status of available therapies for the management of various pain conditions, as well as future directions in the light of present limitations and side effects of clinically used medications.

2. PREVALENCE OF PAIN

Crook et al., performed a prevalence study [14] by selecting a random sample of patients who constantly visited their general practitioners near Toronto, Canada and evaluated the prevalence data. The survey was performed by telephonic calls and received 95% response rate. The survey produced some fascinating results, which demonstrate that as the age increases, the pain increases, and it appears to be a major problem in old age. According to the study by Kending et al., temporary pain has the same prevalence as permanent pain. The latter study was performed in a random sample from community people [15].

It is also noteworthy that older individuals report different pain sites. However, the majority of studies show pain at a specific site in the body. Although prevalence figures are not consistent between surveys, based on the temporary definition of pain, several new trends have appeared. For example, joint pain is reported twice more prevalent in people above 65 years of age as compared to young ones [16–18]. In addition, pain decreases as age increases, above 75 years [19]. According to Grimby et al., in male patients between the 75 to 79 years, joint pain declined almost 20%. While in patients of older than 90 years, it decreased by 8%. Data from female patients are inconsistent, but the trend appears to be the same. In females, joint pain decreased from 35% to 29% [19]. This study also reported that as age increases, foot and leg pain increases [20]. On the other hand, at 45 to 50 years, a high rate of headache has been reported [21–23].

A number of studies show that as age increases, the incidence of headache increases [17, 24–27]. It has been noted that some types of pain decline as the age increases, e.g., visceral pain, dental pain and abdominal pain [26, 28]. Thoracic pain emerges at a high level during late middle age, analogous to cardiovascular diseases [27, 29]. However, data regarding back pain is inconsistent in different ages [18, 30]. Harkins et al. [31] and Von Korff et a1 [18] reported that as age increases, a small increase in back pain has been noted. But there are several studies, which show the opposite results [31–33]. A synopsis of the topic suggests that abdominal, head and thoracic pain prevalence rate is decreased among old age people, whereas musculoskeletal joint pain rises gradually at least until 80 years of age. Although back pain has a different prevalence rate in different studies, it is probably at the highest level in late middle age or early old age, and subsequently decreases with advanced age.

Most epidemiologic studies have demonstrated that females have a higher prevalence rate of pain, as compared to males of the same age [34], although there are several studies that show otherwise [21, 35]. However, in middle-aged females, 15% higher cases of headache are reported. But this possible gender difference disappears in people over the age of 70 [25, 36]. Abdominal and visceral pain cases are most commonly seen in females aged 18 to 40 years, and analogous results are observed between the sexes in older persons [30, 36, 37]. In contrast, in the case of joint pain and back pain, the gender difference is not prevalent, and the pain increases with increased age [23, 30–32].

3. TYPES OF PAIN

Pain can be classified into two types, namely acute pain or chronic pain (Fig.1). Acute pain is always associated with direct damage to the tissue and commonly sharp and fast. It is mostly present along with diseases like MI, trauma, burns and surgery. Acute pain can be further divided into two phases. In the first phase, the brain sends a signal to the body to alert on precarious stimulus. The first phase lasts several seconds. While in the second phase, the body attempts to recover itself from the damaged tissue by a protective mechanism. This phase is also termed as a sub--chronic phase and it can last up to hours or days. (2) In chronic pain, the duration of time is lengthy, which makes the treatment difficult. The pain commonly persists even after recovery from tissue injury; still, the cause cannot be identified [38]. Chronic pain or continuous pain itself appears to be a disease condition which requires treatment [39]. Chronic pain can be classified into neuropathic pain, nociceptive pain and inflammatory pain [40].

Fig. (1).

Three types of Pain. Nociceptive always originates in specific situations like in case of trauma. Neuropathic pain results in case of nerve damage and inflammatory pain. In inflammatory pain, inflammatory mediators are involved in sensitization of nociceptors.

3.1. Nociceptive Pain

Nociceptive pain usually starts due to the activation of primary afferent neurons present in the whole body, even in the absence of sensitization. Nociceptive pain is characterized by normal and acute pain sensation. In case of potential damage to the tissue, this mechanism provides an early alert. Due to the danger of potential harm, this type of pain should be treated by surgical and medical procedures. Nociceptive pain should never be terminated on a permanent basis, as it provides an important physiological sensation [41]. Nociceptive pain can be further divided into two classes’, i.e., somatic nociceptive pain and visceral nociceptive pain. (1) Somatic nociceptive pain originated in bony and muscular tissues and characterized by aching and throbbing sensation. (2) Visceral nociceptive pain commonly appears in basic solid and hollow viscous areas. In that type of painful cramping and squeezing, sensations are felt [42].

3.2. Inflammatory Pain

When inflammation occurs, it leads to the sensitization of peripheral nerve terminals; as a result, pain originates, termed inflammatory pain, e.g., arthritis. Various physiological factors are involved in the origination of inflammatory and non-inflammatory pain. The inflammatory pain can be specifically blocked by non-steroid anti-inflammatory drugs (NSAIDs) and steroids as they can efficaciously decrease the inflammatory effects, and given that no antinociceptive action is involved in it [43–45].

3.3. Neuropathic Pain

When damage occurs to a peripheral nerve or group of nerves, it gives rise to a type of pain known as neuropathic pain. Neuropathic pain is commonly associated with cancer chemotherapy and DM [42, 46].

4. INFLAMMATION AND PAIN

Tissue damage, infection, or irritation can actuate inflammatory mechanisms. The typical symptoms of redness. (Rubor), heat. (Calor) and swelling. (Tumor) are associated with pain. (Dolor). Post-operative pain shows the typical symptoms of inflammatory pain. In some inflammatory diseases, such as arthritis, the inflammation endures and becomes the bases of continuous inflammatory pain. Different substances are involved in the mediation of inflammatory pain and inflammation, such as 5-HT, kinins, histamine, nerve growth factors (NGF), adenosine triphosphate (ATP), PG, glutamate, leukotrienes, nitric oxide (NO), NE and protons [47]. These substances are released when tissue damage occurs, which is then followed by continuous inflammatory processes. Primary afferent nerves are directly actuated and sensitize by inflammatory mediators. Some mediators are also involved in the release of other inflammatory mediators from immune cell. These new mediators are then attracted by some chemicals in the inflammatory soup (all pro-inflammatory mediators). Immune cell bodies gradually accumulate in the tissue-damaged area where these cells serve as a source for growth factors and cytokines. These factors play a major role in the generation and management of hyperalgesia [48–50].

5. PAIN TRANSMISSION

At the synaptic cleft, a presynaptic action potential leads to the opening of calcium channels, with the ensuing release of various neurotransmitters into the synaptic cleft, such as acetylcholine, dopamine and gamma-aminobutyric acid (GABA) [54, 55]. Opioid receptors also involved in pain transmission and glutamate acts as a neurotransmitter in opioid receptors [56]. Acetylcholine, as a neurotransmitter, acts in two modalities. It either propagates the transmission of pain signals or diminishes it. When injected, pain decreases, but in case of injury such as tendinitis, released acetylcholine at the injury site may cause inflammation [57].

Dopamine has a role in pain transmission but in a reverse manner. Dopamine receptors are expressed in primary nociceptors as well as in spinal neurons located in different laminae in the dorsal horn of the spinal cord. It is, therefore, believed that dopamine can modulate pain signals by acting at both presynaptic and postsynaptic targets [58], consistent with observations that in Parkinson’s disease (during which degeneration of nerves occurs), low concentrations of dopamine result in pain propagation.

6. MODULATION OF PAIN

A contrasting mechanism is involved in the modulation of pain, which either increases or decreases pain. Pain is usually modulated at different levels in the body, i.e., at a different peripheral site, in the brain at the cortical area, and in the spinal cord at dorsal level [59]. D2 receptor agonists have no use in thermal nociception; they can only be used in the treatment of mechano-nociception [60]. Catecholamine (nor-adrenaline. and adrenaline) and serotonin affect pain at the spinal and supra-spinal levels [61]. When their absorption is inhibited at the synaptic cleft, it attenuates the pain. Serotonin and dopamine have both nociceptive and anti-nociceptive activity, while noradrenaline shows only anti-nociceptive effects, providing the underpinning as to why SNRI drugs show high anti-nociceptive behavior [62]. In the synaptic cleft, GABA receptors have a vital role in the transmission of pain as do glutamate transporters [63].

7. RECEPTORS INVOLVED IN PAIN PERCEPTION

When an injury occurs, sensory neurons located in the central nervous system (CNS) receive an external stimulus and generate an internal electrical stimulus, referred to as an action potential. Afferent nerves originating from the sensory neuron towards the peripheral nervous system (PNS) carry sensory information towards the CNS [64]. Nociceptors analogous to sensory receptors, transfer the pain signals to the brain through the spinal cord in response to external stimuli. This mechanism of pain transmission is referred to as nociception [65]. Several receptors, which are involved in pain transmission, are discussed below:

7.1. Opioid Receptors

Opioid receptors have a vital role in pain modulation and anti-nociception. Opioid receptors are abundantly distributed in the CNS and gastro-intestinal tract (GIT). Opioid receptors act as inhibitory G-protein coupled receptors. Opioid drugs act on these receptors [66]. Opioid receptors are further classified into three types. (1) Delta receptors are situated in both brain and peripheral sensory neurons and are involved both in pain and depressive illness [67]. (2) Kappa receptors are situated in the peripheral sensory neuron, Substantia gelatinosa of the spinal cord and hypothalamus, and have a vital role in the treatment of pain, stress and depression-like conditions [68]. (3) Mu receptors are situated in the intestine, peripheral sensory neurons and Substantia gelatinosa of the spinal cord and cortex and thalamus of the brain. All Mu receptors have a primary role in analgesia, but Mu1 receptors are particularly involved in the perception of pain. Several other conditions, such as euphoria, respiratory depression, and GIT motility reduction, are also associated with mu receptors [68, 69]. Opioid drugs relieve pain by acting on opioid receptors attenuating pain by a hyperpolarization effect that is mediated by the opening of potassium channels and the closing calcium and sodium channels. Opioid drugs also block the adenylyl cyclase enzyme [70]. Fentanyl, morphine and methadone are important members of opioid drugs, while naltrexone and naloxone are opioid blockers [71].

7.2. Dopaminergic Receptors

Dopaminergic receptors are predominantly located in the CNS. They are G-protein coupled receptors. There are five known types of dopaminergic receptors. Among all types, D1 and D5 receptors (D1 like family) are excitatory in nature. These receptors activate adenylyl cyclase which converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) [72]. D2, D3 and D4 receptors (D2 like family) are all in inhibitory in nature. They block the adenylyl cyclase enzyme, and as a result, cAMP production is decreased [73]. D2, D3 and D4 receptors also have calcium channels opening and potassium channels closing properties [74]. Tergoride, apomorphine, and bromocryptine, to name a few, are activators of D 1 receptors, while ecopipam work as D1 and D5 receptors blocker. Haloperidol, resperidone, domepridone, etc., block D2, D3 and D4 receptors. Apomorphine, pramipenle, bromocryptine, cabergo-line act as agonists of D2 receptors. Among all dopaminergic activating receptors D2, D3 and D4 receptors produce analgesic effect [75].

7.3. Adrenergic Receptors

Adrenergic receptors are also G-protein coupled receptors and are commonly activated by adrenaline and noradrenaline. Adrenergic receptors are further divided into two types, i.e., alpha receptors and beta receptors. (1) Alpha-adrenergic receptors have two important sub-types, namely, alpha-1 and alpha-2 [76]. Peripherally alpha-1 is present post-synoptically and has an excitatory effect, while alpha-2 act as autoreceptors and have a role in the release of norepinephrine. (2) Beta receptors have three important sub--types, including beta-1, beta-2 and beta-3. Alpha-1 and beta-1 receptors are involved in stimulatory responses, while alpha-2, beta-2 and beta-3 have a major role in inhibitory responses. All alpha receptors have a role in the blood vessel constriction and a reduction in gastric emptying [76] [77]. Activation of the alpha-1 receptor is involved in the release of arachidonic acid and alpha-2 receptors are involved in the synthesis of cAMP. cAMP, I turn, acts as a second messenger, opening calcium channels [78]. Tamsulosin, terazosin, and prazosin, to name a few, stimulate the alpha 1 receptors and are characterized as alpha-1 agonists, while methyl-dopa, clonidine, and guanabenz stimulate alpha 2 receptors and are referred to as alpha-2 agonists. Mirtazapine and yohimbine are alpha-receptor blockers. The mechanisms by which alpha receptors act are consistent with antinociceptive properties [79].

7.4.. Lipoxygenase Enzymes

Lipoxygenase (LOX) enzymes are present in basophils, neutrophils, eosinophils and mast cells, which are from the myeloid origin. Lipoxygenase contains iron. In lipids, LOX enzymes cause the deoxygenation of polyunsaturated fatty acids. In phospholipids bilayer, phospholipase enzymes stimulate the production of arachidonic acid. Arachidonic acid is, in turn, converted by LOX enzymes into leukotrienes, which function as pro-inflammatory mediators, and are commonly released from myeloid cells [80]. LOX enzymes are widely abundant in animals and plants. Zileuton and meclofenamate, which inhibit LOX enzymes, are widely used in the treatment of inflammatory conditions [81]. Similarly,a number of plants and plant-derived products have shown efficacy in inhibiting LOX enzymes [82–85].

7.5. Cyclooxygenase Enzymes

Cyclooxygenase enzymes (COX) through the cyclooxygenase pathway cause the synthesis of eicosanoids, e.g., prostacyclins, thromboxane and prostaglandins [86]. Two types of cyclooxygenase enzymes (COX-1 and COX-2) have been identified. Only COX-2 has a role in pain propagation. Prostaglandins are derived from arachidonic acid and catalyzed by these enzymes. The blockade of cyclooxygenase enzymes provides relief from pain [87]. COX-1 enzymes play a key role in the protection of the GIT. They are widely distributed in platelets, kidney and stomach, and are also known as constitutive enzymes [88].

COX-2 enzymes are involved in the synthesis of prostaglandins, which cause inflammation and pain. As COX-2 enzymes are secreted in pain, they are referred to as inducible enzymes. These enzymes are mostly present on leukocytes and macrophages. The blockade of COX-2 enzymes vides relief from pain [89]. The drugs, Meloxicam and Celecoxib, are specific blockers of COX-2 enzymes, naproxen, diclofenac, aspirin are non-specific blockers of COX enzymes [90]. When COX enzymes are inhibited, prostaglandin production decreases, and consequently, pain, inflammatory conditions and fever subside. However, it must be kept in mind that many of the NSAIDs can lead to serious adverse effects, such as GIT bleeding and stomach ulceration [91].

8. RESPONSE AND PERCEPTION OF PAIN

Compared to the elderly, pain measurement in young individuals is different to gauge [92]. The sensation of pain is higher in females as compared to males [93]. Pain perception also appears to be culture-dependent. Some say that the origin of the pain is psychological and some say it is natural [94]. Some individuals are more sensitive to pain, that is why they pay more attention to it, and as a result, feel greater pain [95]. Fatigue, anxiety and pain are interrelated to each other. Increased level of fatigue and anxiety is also responsible for increased perception of pain [96].

9. SELF-REPORTING METHODS FOR ASSESSMENT OF PAIN

In clinical settings, the most common method of assessing pain severity is a numerical rating scale (NRS) of points (i.e., 0 to 10). The beneficial aspects of this technique are the comfort for the assessor, the easiness of applying on the patient and the relative sensitivity to the pain becomes different from the treatment. One point of criticism is that NRS does not really provide pain scales at the level of proportions. Therefore, after the treatment, if the pain feeling by a patient is declined from 8 to 4, it cannot be pretended that the pain has decreased by 50%. On a statistical basis, this can cause trouble; on a clinical point of view, however,a reduction of this magnitude would be desirable (regardless of whether it is an actual 50% reduction or not).

Another common pain assessment method is verbal assessment scales (VRS), where patients choose a word that more accurately reflects their level of pain (e.g., painless, mild, moderate, severe). While the numbers are often assigned to each descriptor, the VRS are actually categorical rather than ordinal or relationship scales (unless the numeric weights for the descriptors have been empirically determined and validated) [97].

For evaluation, the Visual Analog Scales (VAS) are often used, in which patients presenting with a predetermined length line anchored at each end with descriptors (e.g. “painless” and “greater pain than you can imagine”) present the pain to patients a marker dividing the line to get a measure of their pain intensity. The line length reaching to the point is documented. VAS has an outstanding statistical characteristic, including the relationship level scale. On the other hand, they spend large time managing and qualifying, and many people have a problem with understanding this concept. Both electronic and mechanical VAS are available, which can improve ease of use and reduce evaluation errors [97–99]

10. DIFFERENT ROUTES OF ADMINISTRATION FOR PAIN MANAGEMENT

There are several drug delivery routes and several different drug formulations (Table 1). Most pain-relieving drugs are administered parenterally (which is opposite to a local administrating drug), which forces the drug to enter the hypothetical central compartment before entering the action compartment. Parenteral administration has a huge capability for initiating important pharmacokinetic variations in the drug molecule based on its chemical and physical properties. Chemical analgesic becomes the cause of a large number of drug-target interactions in pain modulating tissues.

Table 1.

Different drug formulation for the management of pain [100].

Systemic Administration	Dosage Form	Example	Dose
Oral	Tablets	Paracetamol	0.5 −1 gram every 4–6 hours
	Effervescent tablets	Diclofenac sodium	75–150mg daily in 2–3 divided doses
	Mixture	Ibuprofen	300–400mg 3–4 times a day
	Drops	Aspirin	325–1000mg every 4–6 hours
	Syrup
Transmucosal	Lozenges	Fentanyl	Initially 100mcg repeated if necessary after 15–30min
Transdermal	Spray	Fentanyl
	Patches
	Iontophoresis
Rectal	Suppository	Paracetamol	60–125mg every 4–6 hours as necessary
Intravenous	Infusion (continuos/intermittent)	Paracetamol	10mgkg every 4–6 hours, max 30mg/kg
	PCA
	Bolus injection	Ketorolac	Single-dose: 60mg IM or 30 mg IV or 30mg IV/IM every 6 hours
Intramuscular		Diclofenac Sodium
Subcutanous
Epidural	Intrathecal	Bupivacaine	75–150mg,dose administered using a 5mg/ml(0.5%) solution
Local	Gel	Diclofenac Sodium Aspirin
	Cream
	Ointment

10.1. Solid State Analgesics

Solid-state analgesics, which are available in oral dosage form (e.g., tablets or capsules), have the ability to be easily swallowed by the patient. When patients take tablets in erect standing form and with plenty of water, it prevents tablets from retaining in the esophagus, while lying in a horizontal position can retain tablets in the esophagus regardless of the size and shape of the tablet. The tablets commonly exert an analgesic effect within 0.5 to 1 hour (with a few exceptions) after decomposition and absorption [101].

10.2. Liquid State Analgesics

Patients who have decreased saliva secretion problem and those are having difficulty in swallowing food, show decrease compliance to therapies containing tablets. Similarly, older people and children show the same attitude towards tablet regimens. Liquid formulations of analgesics such as elixirs, suspensions and syrups eradicate the swallowing problems, usually faced during tablet regimens. Chewable tablets or chewing gum also facilitate the drug administration by releasing the drug in saliva before it enters the esophageal cavity [102].

10.3. Parenteral Administration

Postoperative analgesia relies mainly on administrating opioids intramuscularly (i.m); For-example, administering pethidine and morphine i.m, makes it more efficacious analgesics. However, i.m. administration may cause great discomfort due to injection, irregular tissue penetration (from the muscle compartment deposition site to the central area). On the basis of the percentage of the number of patients, poor analgesia has been observed by i.m injection as compared to epidural analgesia and patient-controlled analgesia [103].

Subcutaneous administration (s.c.) may be very effective in relieving pain-specific clinical situations and this route is commonly used in chronic end-stage pain. Pain relief begins almost immediately upon the subcutaneous drug administration. However, injection by the s.c. route may cause low--grade pain and the effects may last for a long time [104].

The best route for the treatment of severe postoperative pain is the intravenous (I.V) route. Permanent venous access is usually present at the end of the surgical procedure when the patient moves to a recovery zone. Continuous i.v infusion provides pain control as long as the steady-state concentration of the selected drug is maintained above the minimum effective analgesic blood levels. NSAIDs given parenterally, including diclofenac sodium, ketorolac, and paracetamol (i.e., the precursor of paracetamol) are popular because of their so-called opioid effect. Parenteral administration of NSAIDs does not eliminate well-known adverse effects observed after oral administration. Conscious and swallowing patients have no advantage over oral versus oral routes [105].

A non-invasive technique that prevents the oral cavity is beneficial for by-passing liver (first-pass metabolism) and also helpful in patients who show no compliance through oral therapy. This pathway is also useful for low molecular weight lipid-soluble drugs because the dermis layer shows resistance to the permeation mechanism. It is, therefore, in chronic pain conditions, those opioids which have high potencies such as buprenorphine and Fentanyl are manufactured in transdermal patches form [106].

Oral transmucosal Fentanyl citrate (OTFC) contains a sugar-filled pill that releases the drug promptly and then oral mucosa absorbed it rapidly. OTFC and injectable form of Fentanyl has the same terminal half-life, but the former provides a rapid analgesic effect. That is why OTFC is mostly used for chronic pain and also preferred over orally used morphine [107].

11. ANTI-NOCICEPTIVE DRUGS AND ITS ADVERSE EFFECTS

Nowadays, various pain-relieving medicines are used, and are obtained from different sources, e.g., animals, plants and some are obtained from synthetic sources [108]. The most commonly used pain-relieving drugs in this modern world include benzodiazepines, steroids, morphine (opioids) and NSAIDs, but different adverse effects associated with these drugs limit their use [109]. Among the above-mentioned classes, NSAIDs are the most frequently used drugs, including indomethacin, diclofenac, ibuprofen, naproxen, aspirin, celecoxib, etc [90]. Although affording a tremendous approach towards pain-relieving, all NSAIDs have some adverse effects. For example, Aspirin is associated with a stomach ulcer, Naproxen causes swelling and itching of tissues and Piroxicam and Ibuprofen are reported with GIT disturbances like diarrhea, Aspirin and indomethacin are associated with tinnitus (ringing in the ears) [110]. Opioids are a class of drugs, which have strong analgesic efficacy. These drugs are further divided into three sub-classes. (1) Natural opioids, which include morphine and codeine. (2) Semi-synthetic opioids, which include nalbuphine and oxymorphone. (3) Synthetic opioids include meperidine and methadone [111]. However, opioids are also associated with several adverse effects such as constipation, difficulty in urination, and sexual dysfunction. Their long term use is also reported with addiction, abuse, and tolerance cases [112]. Steroids are most frequently used in some inflammatory diseases like gout and rheumatoid arthritis [113].

Steroids are also divided into three subclasses, which include (1) Short-acting steroids, e.g., hydrocortisone and cortisone, (2) intermediate-acting steroids, e.g., Prednisolone and Prednisone, (3) long-acting steroids,e.g., Betamethasone and Dexamethasone [114]. Steroids also have some adverse effects like glaucoma, insomnia, blood pressure and osteoporosis. Abrupt discontinuation of steroids can cause some withdrawal effects such diarrhea, fainting, hypoglycemia [115]. Benzodiazepines are used in anxiety and panic conditions, but they have adverse effects too, like sleep disturbances, depression and irritation [116]. Besides these mild adverse effects, benzodiazepines are also associated with some serious adverse effects, e.g., sexual dysfunction, dependence and tolerance [117].

12. COMPUTATIONAL STUDY OF LIPOXYGENASE AND CYCLOOXYGENASE ENZYMES

Lipoxygenase (LOX, EC 1.13.11.12) are key enzymes in the biosynthesis of a variety of bio-regulatory compounds such as hydroxyeicosatetraenoic acids (HETEs), leukotrienes, lipoxins and hepoxylines [118]. It has been found that these LOX products play a role in a variety of disorders, such as bronchial, asthma and inflammation [119]. and tumor .angiogenesis [120]. LOXs are, therefore, a potential target for rational drug design and discovery based on the inhibition mechanism of inhibitors for the treatment of bronchial asthma, inflammation, cancer and autoimmune diseases.

CONCLUSION

Pain-inducing mechanisms need to be well understood in order to develop efficacious drugs to ameliorate it. Molecular mechanisms associated with pain physiopathologically have yet to be fully understood. Pain sensation occurs at different layers of the peripheral nerves, spinal cord and brain. Although great strides have been made in recent years, the unknowns about pain and physiopathology are unknown. Accordingly, studies on pain, its etiology and treatment are timely and meritorious. Understanding pain perception, information on pain and coping mechanisms are also critical for the development of efficacious novel therapies. Furthermore, multidisciplinary research should be carried out to evaluate treatment processes, since the manifestation of pain is an amalgamation of physical, psychological and socioeconomic interactions. Each discipline should be aware of new developments when examining the pain complex.

LIST OF ABBREVIATIONS

IASP

International Association for the Study of Pain

NSAIDs

Non-steroid anti-inflammatory drugs

DM

Diabetes Mellitus

NGF

nerve growth factors

ATP

adenosine triphosphate

PG

prostaglandin

USA

United States of America

NO

Nitric oxide

GABA

Gamma amino. Butyric acid

CNS

Central Nervous System

PNS

Peripheral Nervous System

GIT

Gastro-intestinal tract

ATP

adenosine triphosphate

cAMP

Cyclic adenosine monophosphate

LOX

Lipoxygenase

COX

Cyclooxygenase enzymes

VRS

Verbal Assessment Scales

VAS

Visual Analog Scales

i.m

Intramuscularly

s.c.

Subcutaneous administration

I.V

Intravenous

OTFC

Oral transmucosal Fentanyl citrate

HETEs

Hydroxyeicosatetraenoic. acids