Abstract

The biological systems are exposed to a complex environment in which the contaminants can interact in a synergistic/antagonistic fashion and for this reason, the study of "chemical cocktails" is of great interest to fully understand the final biological effect. To evaluate the final biological response of a pollutant, it is essential to have an adequate analytical methodology that allows the correct monitoring of environmental systems in order to establish their quality, and, when appropriate, the application of corrective measures. Undoubtedly, massive methods "the omics" are among the most efficient current tools. To this end, transcriptomics, proteomics, metabolomics and chemical speciation can provide very useful information, mainly when they are combined. However, the combination of proteomics with metabolomics has some drawbacks as the temporal space is different (i.e. metabolomics gives information about what happens right now, but it can be related with numerous post-translational modifications happened previously). In this sense, it seems that the combination of genomics with metabolomics is easier. Thus, when metabolomics data are interpreted in combination with genomic, transcriptomic and proteomic results, in the so-called systems biology approach, a holistic knowledge of the organism/process under investigation can be achieved.

Keywords: pesticides, mammals, metabolomics, metals, speciation, omics

## 1. Introduction

The evaluation of the biological response in living organisms against environmental pollution requires the use of environmental bioindicators or laboratory models of increasing complexity (mollusks, crustaceans and rodents) [1, 2]. A mammal should be always included to integrate the diverse biological filters present in humans, like the digestive tract, which regulates the passage of contaminants to be later distributed through the bloodstream to other parts of the body [3]. In

addition, cell cultures are also important in these types of studies, especially to translate the effects of pollutants to humans. The use of cell cultures also allows performing many experiments without the difficulties of the experimentation with animals [4].

Until now, there has been a great concern, mainly relying on individual environmental pollutants, to study their potential risks. However, the evaluation of health effects of chemicals by considering data obtained just from a single chemical, leads to over or underestimates the joint toxicity. In this sense, studies concerning the combined effects of pollutants better than the toxicity assessment of single chemicals, reflect the realistic impact of environmental exposures [5]. Thus, the experimentation with animal models to evaluate the biological response against environmental pollutants, and their possible translation to the effects in humans, should be carried out designing experiments that mimic as much as possible the environment. To this end, controlled exposure experiments to "chemical cocktails" that integrate several environmental pollutants of different chemical groups can be a good approximation. Although the design of experiments is significantly more complex, the obtained information is of great interest to evaluate the real effects of contaminants in the environment [6].

On the other hand, the joint toxicity of chemical mixtures can be independent one from each other (additive), stronger (synergistic) or weaker (antagonistic), depending of on the sum of effects from individual exposures or not [7].

The biological response can be evaluated using model organisms, but also with free-living species that can also serve as biomarkers of environmental pollution. Although the use of free-living organisms allows evaluating the biological response taking into account all the existing environmental factors and their interactions, and for this reason is closer to the reality, the main pitfalls are related with the difficulty to isolate the metabolic responses connected with a particular pollutant [8]. Otherwise, the study with model organisms is easier and cheaper, but requires a qualified technician to administrate single xenobiotics or their cocktails and the results can be biased by the selected administration route (e.g., subcutaneous injection), model organism used, etc., [10]. Nevertheless, the study of the biological response in freeliving animals is of great interest to validate the results obtained in the exposure experiments with model organisms [11, 13].

### 2. Interactions of metals and chemical species through antagonistic and synergistic mechanisms

As previously commented, biological systems are exposed to a complex environment in which contaminants can interact by means of antagonistic or synergistic mechanisms making mandatory global studies (i.e.,‐omics) to evaluate the biological response with an holistic view [14]. In connection to that, selenium has been claimed as the most important element regarding its antagonistic protective action against numerous contaminants (i.e., pesticides and metals). Likewise, it has been stated that cardiovascular damages caused by mercury can be antagonized by selenium [15], but also the neurotoxicity [16] and renal toxicity [17] caused by this element. Moreover, selenium present also protective character against skin cancer induced by arsenic exposure [18], chromosomal aberrations induced by cadmium [19], oxidative stress and lipid peroxidation caused by organophosphorus pesticides [20]. Moreover, the chemical form or specie of selenium is very important since the essentiality or toxicity is directly related to that. Likewise, some of them, especially selenoproteins are peroxidases or oxidoreductases, which protect against oxidative stress [21–24, 26], while inorganic selenium is toxic at high levels [14]. Our research Metabolic Impairments Caused by Pesticides in Mammals and Their Interactions with Other… DOI: http://dx.doi.org/10.5772/intechopen.84966

#### Table 1.

Main interaction of selenium species with other elements.

group has been working with Mus musculus mice exposed to the pesticide dichlorodiphenyldichloroethylene (DDE) and selenium [27] to study the join effect in the metabolome, as well as several exposure experiments to one or two metals (metalloids) in Mus musculus like Se-Cd [2], Hg-Se [28] and others.

Perhaps, the most studied interaction of selenium is with mercury, which was first investigated in 1967 in rats exposed to mercury chloride and selenite [29]. One of the proposed mechanism for this interaction is the formation of Hg-Se complexes, which can result in an increased whole-body retention of Hg after the coexposure to both elements [29, 30]. However, although this interaction is well known, the mechanisms related to that remain unsolved. It has been stated that inorganic mercury can be incorporated to selenoproteins, peptides and prosthetic groups of selenoenzymes, by reaction of mercury with the selenol group of selenocysteine (SeCys) [31]. The lower pKa of SeCys makes it more reactive that Cys and for this reason, the former reacts by means of -she with Hg with stronger affinity than -SH groups. Mercury can be also incorporated into selenoproteins which play important roles in the maintenance of cellular homeostasis [26, 32]. To this end, Hg2˜ can react with Se2˜ (selenides), selenols or hydrogen selenide to form ternary complexes Hg▬Se▬S together with glutathione that finally bond to

#### Metabolic Impairments Caused by Pesticides in Mammals and Their Interactions with Other… DOI: http://dx.doi.org/10.5772/intechopen.84966

selenoprotein P (SelP) [32–34]. The dysfunction of several proteins, like selenoproteins is in the basis of several diseases like carcinogenesis. In this sense, selenoprotein P accounts for the highest content of selenium in serum and can be also present in other selenoenzymes such as thioredoxin reductase (ThxR), glutathione peroxidase (GPx) and selenoprotein P [35, 36].

Previous studies carried out in our research group using Mus musculus mice as a model organism exposed to mercury and selenium demonstrate that the levels of selenoprotein P increase in the liver (extracts from hepatic cytosolic extracts) and serum after Hg exposure, and that selenite supplementation increase the effect [28]. In this context, the synthesis of SelP from selenite increases after mercury exposure since this protein serves as a vehicle for Hg detoxification [37]. This fact is also in good agreement with the decrease observed in the selenometabolites found in serum and the correlative increase in liver, where SelP synthesis takes places from selenite to be later transferred to bloodstream [38]. Moreover, our studies demonstrated that the accumulation of SelP in the liver is higher when the diet is supplemented with selenium. On the other hand, the concentration of selenoalbumin increase in liver and decrease in serum after Hg exposure to transport selenium for the synthesis of SelP [38]. Thus, these results demonstrate the interaction of mercury and selenium in the detoxification process induced by the later, the accumulation of selenoproteins in liver and bloodstream and the homeostasis of elements.

Table 1 shows the main selenium interactions with other metals in mammals.

### 3. Pesticides, metals and their impairments at molecular level

The joint effect induced by pesticides and metal ions increase, in general, the toxicity (synergism) like DNA damage, mortality rate and reduction in the reproduction rate, as well as changes in enzyme activities [86]. The exposure to environmental pollutants such as polychlorinated biphenyls (PCBs), organochlorine pesticides and heavy metals, has been associated to immunotoxic effects in mammals such as alterations of both the innate and adaptive arms of immune systems, which include aspects of cellular and humoral immunity [87].

Metabolic impairments caused by the join exposure of the pesticide DDE and selenium have been studied using a metabolomics approach [27]. In this study, we conclude that about 70 metabolites are altered in the most metabolically active organs, like liver and kidney, but also in brain, and that they are related with the pathways of oxidative stress, degradation of phospholipidic membrane, β-oxidation and energy metabolism, which confirm the potential of combined metabolomic platforms in environmental studies. Moreover, several metabolites present different response (increase or decrease against the control group) in the organs studied indicating a possible traffic between them. This is the case of liver and kidney, which are the most metabolically active organs and present five metabolites altered with the opposite tendency between them, namely: diacylglycerol (DAG) (18:2/ 18:1) and ornithine and triacylglycerols (TAG) (18:4/18:4/20:4), TAG (16:0/18:1/ 22:0) and TAG (18:4/18:4/22:6).

To deep insight into the protective effect of selenium against the toxic effect of DDE, we can compare mice supplemented with DDE, DDE + selenium and selenium against the control group. Selenium counteracts the effect of DDE on seven metabolites because they show a different response among the studied groups when they are compared against the control, which is illustrated in Figure 1. These metabolites can be used a biomarkers of the antagonistic interaction between selenium and DDE.

#### Pesticides - Use and Misuse and Their Impact in the Environment

Figure 1.

Different response of metabolites in Mus musculus mice exposed to: (A) selenium, (B) DDE, (C) selenium and DDE. Red word: Increased; Green word: Decreased.

It is also remarkable that these antagonistic interactions between DDE and Se usually take place in kidney, since the majority of metabolites that present different response between the mice supplemented with DDE and DDE with Se occur in this organ.

### 4. Pharmaceutical active compounds, metals and pesticides and their impairments at molecular level

The high consumption of medicines, cosmetic products, as well as pesticides in modern agriculture or plastics in the handling and conservation of food, among others, has led to the appearance in the environment, mainly in soils and aquatic environment, of a series of compounds harmful to the living organisms that inhabit it. These are the well-known "organic micropollutants" (MCOs), a large group of substances that are continuously incorporated into the environment and that, in general, are difficult to eliminate. These substances are classified into two main groups: priority pollutants, and the so-called emerging pollutants (CE). Its detection in the environment has been possible, in many cases, thanks to the development of new and more sensitive analytical technologies that have allowed the detection of these compounds in all types of environmental samples, even in zones, apparently, not subjected to this "contaminant pressure". The analysis of "effluents of wastewater treatment plants" (WWTPs), urban and industrial, has shown, unequivocally, in general, very poor elimination of most of these substances, which is why an incorporation occurs continuously through this way to aquatic and terrestrial ecosystems [88].

Thus, besides metals and pesticides, pharmacologically active compounds (PAC), is a group of emerging contaminants, which are receiving increasing

Metabolic Impairments Caused by Pesticides in Mammals and Their Interactions with Other… DOI: http://dx.doi.org/10.5772/intechopen.84966

attention because of their potential harmful effects for the environment and human health. The prevention of the emission of priority and emerging pollutants through wastewater treatment plants effluents into the aqueous environment requires the development of new treatment technologies that ensure the quality of receiving water bodies since the actual treatments are deficient and these substances are continuously incorporated into the environment [89]. Actually, analytical methodologies allow determining these substances in almost all samples and at very low levels [88, 90]. All the pollutants present in the aquatic and therefore terrestrial systems, as well as the products that are originated from them by degradation or metabolization, have an inevitable effect on the organisms that inhabit them, it can be highlighted, for example, their presence in coastal sediments or American red crab [90].

The studies related to the effect on biological responses by the presence of chemical cocktails concerning mixtures of pesticides, PACs and metals are scarce [91]. In this context, the effect that the presence of the antibiotic, ciprofloxacin has on the toxicity, distribution and accumulation of copper has been studied in earthworm (Eisenia fetida) [92]. However, the study of the biological response of mammals against "chemical cocktails" including metals, pesticides, and PACs has not been performed until now.

#### 5. Omic methodologies to assess health effects of pesticides and other organic micropollutants

It is essential to have an adequate analytical methodology that allows the correct monitoring of environmental systems in order to establish their quality, and, when appropriate, the application of corrective measures. Undoubtedly, massive methods "the omics" are among the most efficient current tools. In this sense, it has been demonstrated that alterations of the homeostatic cycles are shown at the transcriptional level (transcriptomics) [93], by overexpression or inhibition of proteins (proteomics) [94] and by modifications of the metabolic cycles (metabolomics) [1, 95]. On the other hand, it has been stated that approximately 1/3 of proteins need the presence of metals as cofactors to develop their function (metalloproteins) and that metals influence on more than 50% of the proteins [96]. These metals play essential roles due to their catalytic properties or influence the structure of proteins and generally, the genome determines their presence in molecules [97]. Thus, metallomics allows understanding the distribution of elements, concentration at equilibrium of free metallic ions or free elements in a cellular compartment, cell or organism [98] and refers to the identity and/or quantity of metals/metalloids and their species [99]. Likewise, it has been proposed the integration of a global (holistic) view, much more realistic of the processes that takes place in the environment [95].

To this end, genomics decipher the information that determines cell function which is contained in the cellular core, transcriptomics reveals gene expression and proteomics make possible the examination of protein synthesis and cell signaling. On the other hand, in the establishment of transcriptional expression profiles that explain the gene function is critical in environmental transcriptomics, and the quantification of gene expression changes at the level of mRNA has proved to be an interesting tool in environmental approaches [100]. The transcriptomes of M. spretus mice captured in areas of high industrial and agricultural pollution such as the Domingo Rubio estuary or the industrial pole of Punta del Sebo (Huelva) have been determined, identifying a set of potential biomarkers of environmental contamination [93]. Likewise, the transcriptional profile of contaminants such as the DDE has been determined in controlled exposure studies in the laboratory [101].

On the other hand, proteomics is of great importance to understand cell homeostasis, to perform quantitative analysis and for the identification of potential biomarkers of in vivo toxicity. However, the massive number of proteins and posttranslational modifications difficult the analysis. Proteomics can also assist genomic and transcriptomic studies in the efficient sequencing of complete genomes and to explain differences in susceptibility induced by polymorphisms. Nowadays is accepted that alterations in gene expression do not always induce adverse health effects due to post-translational modifications, as phosphorylation and glycosylation of proteins that determine their function, environmental factors or multigenic processes (e.g., aging and disease). For this reason, environmental proteomics allows understanding the mode of action of pollutants. Likewise, the use of 1st, 2nd and 3rd generation proteomic methods have been used to compare M. spretus mice from different areas within the Doñana National Park (PND) and surroundings, the Estero de Domingo Rubio (EDR) and the Estuary of the Guadalquivir, in order to evaluate the effects of the Aznalcóllar accident and the pesticides used around the PND [102, 103]. The information obtained by this omic can be complemented by oxidative stress and redox proteomics. The study of reactive oxygen species (ROS) related to oxidative damage caused by contaminants is a valuable tool in environmental studies [94]. Although most amino acids are sensitive to oxidation, the thiol group of Cys affects them especially [95] so its analysis allows determining the redox state of the thiol groups of proteins [104, 105], so its analysis allows determining the redox state of the thiol groups of proteins.

Environmental metallomics and chemical speciation requires its own methodology, generally based in the combined use of inorganic mass spectrometry (inductively coupled plasma mass spectrometry, ICP-MS) and organic MS, using a previous chromatographic separation step in order to preserve the integrity of the metal in terms of its union and location in the molecule [106]. Our research group have extensive experience in this field, especially in its projection to the environmental studies [2], and the biological response, at the metallomic and metabolomic levels of the Mus musculus mice exposed to As [99], Cd [2] and Hg [103]. In addition, studies with free living animals in Doñana National Park and surroundings based on these methodologies have also been performed using the Mus spretus mice [11] and the crab Procambarus clarkii.

In addition, in 1999, J. Nicholson defines metabonomics as "the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification" [104], and metabolomics as the measurement of all the metabolites in a specified biological sample [104]. Likewise, metabonomics allows understanding the variation in low molecular mass molecules, namely metabolites, which are the last action mechanism of the organisms, but the additional mentioned "-omics" sciences are related to cellular macromolecules. Then, the last step in the omics, directly in connection with the phenotype, environmental metabolomics allows obtaining a global view of the metabolic fingerprint of the biological systems exposed to contaminants, providing information at the same time that the interactions between the contaminants with the living organisms [105]. Numerous studies have been carried out on different rodents, and several exposure experiments on the Mus musculus laboratory mice can be highlighted. As an example, several studies carried to study of the metabolomic response of the mouse.

M. musculus exposed to inorganic As [99], Cd [95], Se-Cd [2], Hg [99], Hg-Se [28], DDE-Se [27], As, Cd, Se, Hg, deltamethrin + acrolein.

One of the most critical aspects in metabolomics is sample treatment, to extract as many metabolites as possible [10]. The analysis of biofluids for metabolomics in simpler than the extraction of metabolites from tissues and allows obtaining global

#### Metabolic Impairments Caused by Pesticides in Mammals and Their Interactions with Other… DOI: http://dx.doi.org/10.5772/intechopen.84966

information about the state of the organism, but to obtain specific information on a specific organ the direct analysis is mandatory [106].

Finally, metabolomics allows the simultaneous measurement of hundreds of metabolites in vitro cell cultures, in vivo tissues and even in non-invasive blood and urine biofluids. However, the current drawback of this omic is the standardization of quenching, metabolite extraction procedures as well as the complexity of data analysis and interpretation. Moreover, the influence of factors in the results is important (e.g., age, gender, diet, stress, housing conditions, health status). To overcome these limitations, combination of omics seems to be the best option. However, the temporal space is different in metabolomics and proteomics (i.e., metabolomics gives information about what happens right now, but it can be related with numerous post-translational modifications happened previously). In this sense, it seems that the combination of genomics with metabolomics is easier. Thus, when metabolomics data are interpreted in combination with genomic, transcriptomic and proteomic results, in the so-called systems biology approach, a holistic view of the organism or biological process under investigation can be attained.

#### 6. Concluding remarks

The evaluation of the real impact of a pollutant, and in particular of pesticides can be performed in the different environmental compartments or preferably in mammals to decipher the biological response. In this case, the study can be carried out in free-living animals or in laboratory mice exposed to different pollutants that should be combined to evaluate the biological response of the "chemical cocktail" since they can interact in a synergistic or antagonistic fashion. On the other hand, it is essential to have an adequate analytical methodology that allows the correct monitoring of environmental systems in order to establish their quality, and, when appropriate, the application of corrective measures. Undoubtedly, massive methods "the omics" are among the most efficient current tools.

#### Acknowledgements

This work has been supported by the projects CTM2015-67902-C2-1-P from the Spanish Ministry of Economy and Competitiveness and P12-FQM-0442 from the Regional Ministry of Economy, Innovation, Science and Employment (Andalusian Government, Spain). Sara Ramírez-Acosta thanks to Spanish Ministry of Economy and Competitiveness for a PhD scholarship (BES-2016-076364). Finally, authors are grateful to FEDER (European Community) for financial support, grants number UNHU13-1E-1611 and UNHU15-CE- 3140.

#### Conflict of interest

The authors do not have conflict of interest.


*4.2. DNA Isolation and Genotyping PCR*

Embryos and placentas were lysed in tissue lysis buffer (50 mM Tris-HCl (Roth, Karlsruhe, Baden-Wuerttemberg, Germany; #9090.1), 100 mM ethylenediaminetetraacetic acid (EDTA) (AppliChem, Darmstadt, Hessen, Germany; #A4975), 100 mM NaCl (AppliChem, Darmstadt, Hessen, Germany; #A1149), 1% (*w*/*v*) SDS (Merck, Darmstadt, Hessen, Germany; #817039), and 10 mg/mL proteinase K (Merck, Darmstadt, Hessen, Germany; #1245680500)), while DNA from adherent cells was obtained using cell lysis buffer (10 mM NaCl (AppliChem, Darmstadt, Hessen, Germany; #A1149), 10 mM Tris, 10 mM EDTA, 0.5% sarcosyl, and 1 mg/mL proteinase K (Merck, Darmstadt, Hessen, Germany)). DNA was precipitated using isopropanol, pelleted by centrifugation, and washed twice with ethanol (80%). The pellet was then resuspended in H2O (dd) at 37 ◦C. Using NanoDrop 1000 (Thermo Fisher Scientific, Waltham, MA, USA), concentration and purity of obtained DNA was measured. Genotyping was performed by polymerase chain reaction (PCR) using PCR primers. Primer sequences are listed in Supplementary Materials Table S1.


**5. Conclusions**

A 2 h biomedical cyclotron irradiation and 5 h radiochemical separation can produce GBq-scale 165Er suitable for high-yield radiolabelings of DOTA-based radiopharmaceuticals at molar activities befitting investigations of targeted radionuclide therapeutics. The separation utilizes column chromatography with commercially available resins and is well suited for automation. This significant step forward in the production and high holmium/erbium SF radiochemical isolation of 165Er will enable fundamental radiation biology experiments of pure AE-emitting therapeutic radiopharmaceuticals. Proof-ofconcept radiolabeling studies were successfully performed synthesizing [165Er]PSMA-617, which will be utilized in vitro and in vivo to understand the role of AEs in PSMA-targeted radionuclide therapy of prostate cancer.

**Supplementary Materials:** Supplementary Figures S1–S8, Supplementary Material Sections S1–S3, and Supplementary Equation (S1),

**Author Contributions:** Conceptualization, I.D.S., J.C.M., J.W.E. and P.A.E.; methodology, I.D.S., T.R.J., J.C.M., E.A.-S., T.E.B., R.J.N., J.W.E. and P.A.E.; validation, I.D.S., T.R.J., J.C.M. and P.A.E.; formal analysis, I.D.S., T.R.J., J.C.M. and P.A.E.; investigation, I.D.S., T.R.J. and J.C.M.; resources, R.J.N., T.E.B., J.W.E. and P.A.E.; data curation, I.D.S., T.R.J., J.C.M. and P.A.E.; writing—original draft preparation, I.D.S., T.R.J., J.C.M. and P.A.E.; writing—review and editing, I.D.S., T.R.J., J.C.M., E.A.-S., T.E.B., R.J.N., J.W.E. and P.A.E.; supervision, J.W.E. and P.A.E.; project administration, P.A.E.; funding acquisition, J.W.E. and P.A.E.; All authors have read and agreed to the published version of the manuscript.

**Funding:** Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number T32 CA009206 (J.C.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This research is supported in part by the U.S. Department of Energy Isotope Program, managed by the Office of Science for Isotope R&D and Production, grant DE-SC0020955.

**Acknowledgments:** A portion of the LN2 resin used in this work was graciously provided by Triskem Int.

**Conflicts of Interest:** The authors declare no conflict of interest.


**6. Carbonic anhydrase-based biosensing of metal ions**

In the last years the affinity of carbonic anhydrase for metal ions has been applied for the development of fluorescence based biosensors for determination of free metal ions in solution using variants of human carbonic anhydrase (apoCA). In particular, Cu2+, Co2+, Zn2+, Cd2+, and Ni2+ have been determined at concentration down the picomolar range (Fierke and Thompson, 2001; Thompson and Jones, 1993; Mey et al., 2011) by changes in fluorescence emission (Thompson et al., 2000) and excitation wavelength ratios (Thompson et al., 2002), lifetimes (Thompson and Patchan, 1995), and anisotropy (polarization) (Elbaum et al., 1996; Thompson et al., 2000). The sensitivity, selectivity, analyte binding, kinetics and stability of the biosensors have been improved by subtle modification of the protein structure by directed mutagenesis (Kiefer et al., 1995; Hunt et al., 1999; DiTusa et al., 2001; McCall et al., 2004; Burton et al, 2000). These studies have hallowed the development of highly selective and sensitive fluorescence-based biosensors for Zn2+ e Cu2+, which have been shown to be viable approach in some important applications. In fact, the CA-based Cu2+ biosensor has been used to obtain real-time measurement of free Cu(II) at picomolar concentrations in seawater (Zeng et al., 2003), while the CA-base Zn2+ biosensor has been used for measurement of free Zn ion at picomolar levels in cultured cells (Bozym et al, 2004).


**2.2. Chronic pain**

the term narcotic as first analgesics as they were narcotics, and their derivatives and analogs were chemically based on the morphine molecule [1]. Additionally, analgesics may include nonsteroidal anti‐inflammatory drugs (NSAIDs) and paracetamol (acetamin‐ ophen). Practically, the term may also include others like tricyclic antidepressants and substances such as gabapentin, although they are not commonly classified as analgesics [1]. It should be well differentiated that usually analgesics give symptomatic relief, but have no effect on the body condition, although NSAIDs are beneficial in both reducing

Why god created pain? To the author, the answer to this question explains the term "productive pain" which has been described in literatures as a warning on the occurring of injury in the body. This pain will guide the person to seek treatment, and this pain will also facilitate diagnosis. "Nonproductive" pain by definition serves no purpose either as a warning or diagnostic tool. It is important for us to understand pain pathophysiology for

Pain syndromes may be different, but their sensory pathways are the same. It starts from the affected organ and the message flow to the brain for interpretation. The pharmacological path of analgesics' action is by working at the level of the nerves, they work by either blocking the signal originating from the peripheral nervous system, or can work centrally by distorting the

Practitioners' selection of an appropriate analgesic is first based on the type of pain and severity and then the knowledge of risk and extra benefit and indirectly considering existing risk‐benefit of a particular drug. The decision will also depend on the knowledge on the classes of drugs, and their adverse effect. Text books have divided pain into two classes, acute and chronic. In selecting the analgesic to be used, severity and predicted survival of patient

Acute pain duration is self‐limiting and this includes postoperative pain, pain of injury, and childbirth. This type of pain is foreseen to be short in duration so the treatment using narcotic pain killer is considered to be safe as there will not be long‐term addiction prob‐ lem on using narcotics. Using NSAIDs will also be beneficial as it allows fluctuation of dose but with limiting concern on the risk of ulcers. For both categories of painkillers, their doses may be adjusted based on observation of healing rate, changing doses from high to low doses, and from narcotic analgesics to nonnarcotics as required. In severe pain, it is the rule of thumb that patients should not be subject to the return of pain so painkiller needs to be dosed adequately to ensure that pain is at least tolerable to avoid the occurrence of anxiety, usually after the return of pain [3]. Generally, in pain management, painkiller

pain and inflammation.

12 Pain Relief - From Analgesics to Alternative Therapies

management purpose.

**2.1. Acute pain**

interpretation by the central nervous system.

must also be considered as a selection criteria [2].

**2. Pain**

Chronic pain is defined as pain lasting over 3 months and severe enough to have effect on body function. This condition is more difficult to treat, as the expected side effects of the drug are more difficult to manage because of the long‐term exposure to the drug. There will be addiction potential for those who are on narcotic analgesics which can exacerbate to respiratory depression and constipation. For those using NSAIDs, the risk of gastric ulcers is evident. Drugs with narcotic agonist‐antagonist properties such as buprenorphine, nalbuphine, pentazocine, or the COX‐2 inhibitors, such as celecoxib and rofecoxib, which reduces the common side effect, are still not recommended for long‐term management of severe pain. Usually, practitioners following the guidelines for chronic pain management will recommend a combination of drug therapy to suite the lifestyle and other treatment modalities [2]. Modification of the delivery system of the drug for the purpose of long‐term treatment is also beneficial [4].