molecules Review The Role of Organic Small Molecules in Pain Management Sebastián A. Cuesta and Lorena Meneses * Laboratorio de Química Computacional, Facultad de Ciencias Exactas y Naturales, Escuela de Ciencias Químicas, Pontificia Universidad Católica del Ecuador, Av. 12 de Octubre 1076 Apartado, Quito 17-01-2184, Ecuador; [email protected] * Correspondence: [email protected]; Tel.: +593-2-2991700 (ext. 1854) Abstract: In this review, a timeline starting at the willow bark and ending in the latest discoveries of analgesic and anti-inflammatory drugs will be discussed. Furthermore, the chemical features of the different small organic molecules that have been used in pain management will be studied. Then, the mechanism of different types of pain will be assessed, including neuropathic pain, inflammatory pain, and the relationship found between oxidative stress and pain. This will include obtaining insights into the cyclooxygenase action mechanism of nonsteroidal anti-inflammatory drugs (NSAID) such as ibuprofen and etoricoxib and the structural difference between the two cyclooxygenase isoforms leading to a selective inhibition, the action mechanism of pregabalin and its use in chronic neuropathic pain, new theories and studies on the analgesic action mechanism of paracetamol and how changes in its structure can lead to better characteristics of this drug, and cannabinoid action mechanism in managing pain through a cannabinoid receptor mechanism. Finally, an overview of the different approaches science is taking to develop more efficient molecules for pain treatment will be presented. Keywords: anti-inflammatory drugs; QSAR; pain management; cyclooxygenase; multitarget drug; Citation: Cuesta, S.A.; Meneses, L. cannabinoid; neuropathic pain The Role of Organic Small Molecules in Pain Management. Molecules 2021, 26, 4029. https://doi.org/10.3390/ molecules26134029 1. Introduction Inflammation is a very complex self-defense biological process to protect the body Academic Editors: Giovanni Ribaudo against harmful stimuli including pathogens, physical injury, or contact with irritant sub- and Laura Orian stances [1]. There are five classical signs of inflammation, i.e., pain, redness, swelling, heat, and loss of function. Although the function of an inflammatory process is to elimi- Received: 31 May 2021 nate the cause of injury and heal damaged tissue by clearing dead cells, sometimes this Accepted: 27 June 2021 response is too aggressive, causing excessive pain and incapacity [2]. In these cases, Published: 1 July 2021 an anti-inflammatory drug is needed to ameliorate symptoms and allow the person to continue a normal life. Inflammation is involved in many disorders and complex diseases, Publisher’s Note: MDPI stays neutral including metabolic syndrome, autoimmune, depression, and neurodegenerative dis- with regard to jurisdictional claims in eases [1,3,4]. In first-world societies, the excessive nutrient storage caused by food security published maps and institutional affil- and lack of physical activity have stressed humans’ metabolic pathways, causing diseases. iations. The metabolic syndrome is composed of a group of conditions including dyslipidemia, hypertension, obesity, and elevated glucose levels, causing diabetes and atherosclerotic cardiovascular disease [5]. It is known that inflammation plays a pivotal role in the patho- genesis of the metabolic syndrome. Although the mechanism is not yet fully understood, Copyright: © 2021 by the authors. it is believed that reactive oxygen species, free fatty acid intermediates, and adipose tissue Licensee MDPI, Basel, Switzerland. dysregulation promote inflammation through high levels of proinflammatory adipokines This article is an open access article and low levels of anti-inflammatory adiponectines [4,6–8]. The inflammatory process is so distributed under the terms and complex that whole animal models are needed. In this sense, the zebrafish has emerged as conditions of the Creative Commons a key tool to study inflammatory diseases. Zebrafish present receptors, mediators, and in- Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ flammatory cells similar to mammals and humans making them suitable animal models to 4.0/). study new anti-inflammatory agents and their mechanisms [9]. There are different types Molecules 2021, 26, 4029. https://doi.org/10.3390/molecules26134029 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 19 Molecules 2021, 26, 4029 2 of 19 anti-inflammatory agents and their mechanisms [9]. There are different types of anti-in- flammatory agents, including small molecules, peptides, and antibodies. In this review, of anti-inflammatory agents, including small molecules, peptides, and antibodies. In this there will be a focus on small molecules for anti-inflammatory treatments as they have review, there will be a focus on small molecules for anti-inflammatory treatments as they been the center of traditional medicine. Small molecule drugs are compounds with low have been the center of traditional medicine. Small molecule drugs are compounds with molecular weight that can easily enter the body and modulate biochemical processes to low molecular weight that can easily enter the body and modulate biochemical processes treat medical conditions [10]. Cyclic small molecules including naturally occurring and to treat medical conditions [10]. Cyclic small molecules including naturally occurring and synthetic heterocyclic and polycyclic compounds are key to produce new drugs to target synthetic heterocyclic and polycyclic compounds are key to produce new drugs to target the inflammation process [11]. the inflammation process [11]. Nature represents one of the greatest sources of anti-inflammatory agents. Recent Nature represents one of the greatest sources of anti-inflammatory agents. Recent in- investigations have found novel anti-inflammatory agents from natural sources, includ- vestigations have found novel anti-inflammatory agents from natural sources, including cyanobacterialing cyanobacterial extract extract [12], a [12], norditerpenoid a norditerpenoid from the from Hainan the softHainan coral softSinularia coral Sinularia siaesensis [siae-13], andsensis peptides [13], and extracted peptides from extracted the adzuki from beanthe adzuki [14]. Traditional bean [14]. Chinese Traditional medicine Chinese has medi- used herbscine has such used as herbsAndrographis such as paniculataAndrographisto treatpaniculata fever, to coughs, treat fever, and coughs, other cold and symptoms. other cold Thesymptoms. active ingredient The active andrographolide ingredient andrographolide extracted from extracted this herb hasfrom been this tested herb as has a multi- been targettested inflammatoryas a multitarget drug, inflammatory showing good drug, results showing against good multiple results sclerosis, against some multiple respiratory sclero- diseases,sis, some andrespiratory osteoarthritis diseases, [15 ].and Complex osteoarthritis ancient [15]. preparations Complex usedancient for preparations centuries, such used as thefor Shiyifangcenturies, Vinumsuch as containing the Shiyifang 13 herbs, Vinum have co beenntaining employed 13 herbs, to treathave pain been and employed inflamma- to tiontreat [ 16pain]. One and ofinflammation the first anti-inflammatory [16]. One of the treatments first anti-inflammatory described by treatments ancient civilizations, described suchby ancient as Egyptians, civilizations, Greeks, such Sumerians as Egyptians, and Chinese, Greeks, was Sumerians the use ofand the Chinese, willow barkwas [the17– 19use]. Preparationsof the willow of bark Salix [17–19]. species havePreparations been used of forSalix centuries species to have alleviate been pain used and for to centuries treat fever to andalleviate rheumatic pain and conditions to treat fever [17–20 and]. Its rheumati principalc conditions active ingredient [17–20]. isIts called principal salicin, active which ingre- is useddient asis called a prodrug salicin, of salicylatewhich is used [21]. as Willow a prodru barkg of is salicylate considered [21]. one Willow of the bark first is examples considered of modernone of the drug first development examples of modern from herbal drug plants. development Salicylic from acid herbal was obtained plants. Salicylic from hydrolysis acid was followedobtained from by oxidation hydrolysis of salicin.followed An by acetylated oxidation derivativeof salicin. An of salicylicacetylated acid derivative became oneof sali- of thecylic most acid important became one drugs of the in most the world, important aspirin drugs (Figure in the1)[ world,17]. The aspirin effectiveness (Figure 1) and [17]. safety The profileeffectiveness of herbal and medicines safety profile such of as herbal willow medi barkcines extract such isas of willow great interest.bark extract In this is of sense, great theinterest. ethanolic In this extract sense, showed the ethanolic to be effective extract andshowed safe toto treatbe effective low back and pain safe [21 to,22 treat], and low it showedback pain a moderate[21,22], and analgesic it showed effect a againstmoderate osteoarthritis analgesic effect [17]. against The action osteoarthritis of willow bark[17]. extractThe action as an of anti-inflammatory willow bark extract agent as was an compared anti-inflammatory to celecoxib agent and acetylsalicylicwas compared acid, to andcelecoxib it was and found acetylsalicylic to be as effective acid, as and these it was drugs found [23]. to The be extract as effective