Introduction

Pain is a symptom of most of chronic clinic pathological processes, being opioids widely used in the last decade for its management (^{Cooper et al., 2017}; ^{Raub & Vettese, 2017}). The term opioid refers to compounds with a structural relation with products found in opium, to date, more than eighty alkaloids of this type have been described, most of them with therapeutic properties. In that regard, morphine is one of the most used opiate alkaloids for pain management, and present in higher proportion (4-21 %) in the juice of the opium poppy in comparison with other alkaloids as noscapine, codeine, thebaine, papaverine and narceine (^{Khademi et al., 2016}; ^{Mesa-Vanegas, 2017}).

The term opiate is used to refer to compounds originating from opium, while an opioid is an endogenous or exogenous substance which has an analogous effect to that of the morphine, because it is possible to obtain totally synthetic substances since 50 years (Figure 1), almost without chemical relation with morphine but with similar effect to it. Opioid drugs constitute a group of drugs characterized by having a selective affinity for central and peripheral opioid receptors inhibiting the transmission of nociceptive input and pain perception (^{Pedrero-Pérez et al., 2020}).

(Modified from ^{Devereaux et al., 2018}).

Figure 1 Principal opioids of clinical interest according to their chemical structure. 

The analgesic effect of opioids is obtained when agonists bind to specific receptors coupled to G protein, located in the brain and the spinal cord. Research on the study of opioid receptors pointed at these ones as a good option for chronic and neuropathic pain management, as well as depression and anxiety (^{Van Rijn et al., 2013}). Other works reported that opioid receptors were related to cancer progression, such as mu receptor (MOR) expression, associated to hepatocellular carcinoma (Chen et al., 2018).

Opioid receptors

There are three main categories of opioid receptors, described in Table 1, which are found in diverse sites of the Central Nervous System (CNS) and other tissues, all are members of the G-protein-coupled receptors family and show a significant homology of amino acids sequences. Of the three categories, opioids are especially headed towards MOR receptors (Galligan & Sternini, 2016). The diverse pharmacological effects of opioids are due to the fact that they can act with different potency as agonist, partial agonist or antagonist in more than one category of receptor subtype (^{Álvarez & Farré, 2005}).

When an opioid receptor results inactive by its ligand, the signaling cascade associated to its G protein begins. Initially, the receptor changes shape and interacts with the G protein in the intracellular side. Then, the “α” subunit of the G protein exchanges a GDP molecule (diphosphate guanosine) for a GTP molecule (triphosphate guanosine), which causes its separation of the “β” and “γ” subunits. Then, the “α” subunit is spread towards the membrane until finding its target. This can lead to the binding with the adenylate-cyclase enzyme, with the resulting inhibition of the production of the cAMP (cyclic adenosine monophosphate) second messenger and the affectation of a series of signaling cascades promoting neuronal excitability that regulate genes expression and phosphatases and kinases activity.

Similarly, the “α” subunit of the G protein can change the function of an ionic channel, for instance, increasing the conductance of the potassium channel (generating hyperpolarization and decrease of the duration of the action potential) or decreasing the entry of calcium through voltage-gated ion channels, thus reducing the release of neurotransmitters. These effects were schematically illustrated in Figure 2. Altogether, these actions drive to a reduction of neuronal excitability, with the resulting diminution of the nociceptive information traffic in the pain pathway and the respective analgesia management. After a while, GTP is converted into GDP, therefore the system turns back to its initial inactivation state, with the re-association of the three G protein subunits.

(Source: Own).

Figure 2 Signaling cascade mediated by G protein-coupled metabiotropic receptors. 

Neuroanatomy of addiction

Opioid receptors are widely distributed through the body and expressed in different cell types, including the peripheral and CNS, immune system cells, adrenal medulla and gonads, explaining the wide range of secondary effects and its capacity of modulating both physiological and psychological processes (^{Kibaly et al., 2019}).

As mentioned in the previous section, the analgesic effect of opioids is mediated by MOR receptors, specifically the mu/delta-opioid receptor, which results relevant from the neuroanatomical perspective, since brain regions regulating pain perception (periaqueductal gray, thalamus, cingulate cortex, insular cortex) and the region of emotional responses induced by pain (amygdala) contain high levels of these receptors. Moreover, another region with a high MORs expression are those associated with the experience of pleasure or reward when consuming opioids as ventral tegmental area and the nucleus accumbens.

Opioids also produce changes at the brain level in regions associated to cognitive functions, such as hippocampus, temporal and parietal cortices, driving to an attention and memory deficit and alterations in behavior, these neuronal disorders can affect the adhesion to pharmacological treatments (^{D’Souza, 2019}). Finally, MORs are also located in the ventrolateral bulb, explaining why opioids are able to cause respiratory depression (^{Volkow et al., 2018}). MOR receptors distribution was illustrated in Figure 3 in different brain regions.

1) Control of food and drug intake is regulated by MOP in the prefrontal cortex (PFC); 2) analgesia, slow breathing and relaxation can be induced by the activation of MOP in the anterior cingulate, thalamus, brainstem nuclei, and spinal cord 3) sensory perception can be influenced by MOP in parietal and temporal cortices; 4) motivation, desire and associative learning involve stimulation of MOP in the nucleus accumbens (NAc), caudate-putamen (CPu) nuclei, ventral tegmental area (VTA) and substantia nigra (SN); 5) MOP is expressed in the amygdala (AMG), which is required for emotional conditioned learning and responses; 6) MOP activation in the hppocampus (HIPP) can alter learning and neurogenesis; 7,8) and MOP is present in both the locus coeruleus, a structure important in stress and drug withdrawal, and the cerebellum. (Modified from ^{Kibaly et al., 2019}).

Figure 3 Distribution of MOR receptors in the cerebral cortex. Opioids activate centrally located receptors, such as the μ-opioid peptide receptor (MOR), that play a variety of roles in brain function. 

Analgesia and secondary effects

Opioid receptors activation produces a deep analgesia mediated by a combined presynaptic and postsynaptic effect. At the presynaptic level, opiate analgesics act on primary nociceptive afferents (inhibition of calcium channels), resulting in a reduced neurotransmitters release, such as P substance and glutamate, involved in nociceptive transmission. At the post-synaptic level, opiate analgesics directly inhibit neuronal activity by hyperpolarizing cell membranes through the opening of potassium channels (Galligan & Sternini, 2016). The type of interaction with these receptors (excitation or inhibition) determines the distinct actions of opioid drugs and their adverse effects.

Considering the aforementioned, each individual probably has different receptor quantities and subtypes. In addition to analgesia, opiates have other therapeutic practical uses, such as antitussive and antidiarrheal ones, due to the reduction of the gastrointestinal tract motility under the action of exogenous opioid agonists in the enteric nervous system (^{Farmer et al., 2019}; ^{Lee & Hasler, 2016}).

Due to the wide distribution of opiate receptors, both inside and outside of the nervous system, opioid analgesics also produce a wide spectrum of adverse effects including euphoria, dysphoria, sedation, respiratory depression, constipation, suppression of endocrine systems, cardiovascular disorders, such as prolongation of the QT interval, convulsions, nauseas, vomits, miosis and dry mouth; though the scope of these adverse effects can differ among individual opiates according to the dose or in combination with benzodiazepines or antidepressants (^{Soleimanpour et al., 2016}). In this regard, the combination with benzodiazepines results especially dangerous, since these last ones have been evidenced to be able to strengthen the effect of respiratory depression caused by opioids. In the United States of America (USA), it has been calculated that there is a comorbidity with the use of benzodiazepines in 30 % of deaths related with an opioid overdose (^{Sun et al., 2017}).

Another secondary effect of the chronic use of opioid analgesics is an imbalance in the physiological hormonal action or endocrinopathy, thus resulting in the development of hypogonadism in both sexes, contributing to sexual impairment, through the diminution of libido and causing infertility (^{Gudin et al., 2015}). In addition to the effect of opioids in their related receptors and in signaling pathways, these compounds also introduce multiple cellular and behavioral adaptations, which were dealt with in the following sections.

Development of tolerance and addiction

The tolerance to a specific drug is a physiological response to the persistence and presence of agonists in various receptors in the CNS, most of the time as a result of the use of opioids, benzodiazepines or alcohol (^{Gil-Martín et al., 2014}). The term tolerance indicates an adaptation to the effects of a medicine, conducting to a diminution of its effects despite the consumption of a constant dose or concentration. The tolerance is a consequence expected by long-term therapies, particularly to high doses, where the MO-DOR heteromer is involved in mediate the tolerance in humans (^{Portoghese et al., 2017}). It is important to distinguish the short-term or “acute” tolerance that develops within minutes or various hours, from a long exposure at high opioids concentrations, which, on the contrary, produces a higher tolerance than the intermittent exposure (^{Morgan & Christie, 2011}). An individual exposed for some time to opioids shows a certain level of tolerance, and if the drug is suddenly moved away, abstinence symptoms appear, whose importance depends on the dose and duration of the exposure to it, such situation does not mean an addiction state by itself. The American Society of Addiction Medicine (ASAM) points out that opioids addiction is characterized by a loss of control on the consumption of drugs, being possibly caused by the environmental social factor (^{Juurlink & Dhalla, 2012}), other factors involved are genetic variations and/ or epigenetic alterations (^{Hancock et al., 2018}). At the genetic scale, addiction risks to opioids are associated to alterations in genes of potassium channels (KCNC1 y KCNG2), to an auxiliary protein of glutamate receptor (CNIH3), as well as a variant of the opioids receptor gene (OPRM1), which is the most studied gene to understand the addiction to opiates codifying for the μ receptor (OPRM1) used for binding to opioids (^{Berrettini, 2017}).

hysiological component

The chronic administration of opioids drives to the development of a dependence state, a condition in which the cessation of the use of opioids or the administration of an antagonist of the opioid receptor (naloxone, naltrexone) results in the incidence of symptoms of withdrawal syndrome. Since opioids represent an inhibitory signal transduction for the cell, they increase signaling to compensate and return to the normal function. Eliminating the inhibitory signal results in an over-activation of the cellular pathways affected, driving to a variety of symptoms caused by the over-activation of the somatomotor cortex and the autonomous nervous system (^{Schaefer et al., 2017}).

At the organic systems scale, withdrawal syndrome appears through an increase in autonomous stimuli, such as nervousness, hyperalgesia, hyperthermia, hypertension, diarrhea and pupil dilatation. As affective symptoms, withdrawal causes dysphoria, anxiety and depression. Such phenomena are considered very aggressive and make the person consuming the drug making a greater effort to avoid the withdrawal.

The repeated supraphysiological stimulation of the dopaminergic system, produced by continuous opioids consumption, can induce changes in brain plasticity, which result in a diminution of the inhibitory control on the seeking behavior and consuming of substances that can become compulsive. In that regard, miRNAs expression in the brain plays an important role in the regulation of the memory and of the aggressive and impulsive behavior, where a diminution of miR-190b, miR-28a, miR-340, miR-219a and miR-491 expression has been demonstrated in the amygdala, which is associated to an impulsive behavior (^{Quinn et al., 2018}).

Social and behavioral component

Reward positive effects of opioids are considered as the essential component for starting to use it for recreational purposes. The stimulus to acquire the drug causes seeking behaviors of the substance, occurring in spite of the physical, emotional and social damages caused to the drug addict, therefore the obsession or addiction to acquire and use the drug is considered as a reflect of an addiction state. About the reasons why some people develop addiction and others do not, some studies indicate that it is a combination of genetic predisposition and environmental and social factors (^{Eitan et al., 2017}). The dilemma of opioids analgesics is that they are indispensable medicines to relieve determined types of chronic pains, but at the same time, they can lead to cause great suffering to people developing addiction and/or overdose.

Addicts to an opioid medicine that quit consuming the drug can experience severe withdrawal symptoms that begin as early as a few hours after the drug was last taken. These symptoms include: pain in muscles and bones, problems to sleep, diarrhea, vomits, shivers, uncontrolled leg movements and intense drug craving (^{Sandí-Brenes & Sandí-Esquivel, 2016}).

Opioid consumption in United States

Presently, USA suffers from an epidemic of opioids overdose, more than 33,000 deaths are attributed to the illicit and licit consumption of these drugs (^{Manchikanti et al., 2018}). In 2015, 40.5 million people were addicted to legally or illegally prescribed opioids, with a daily mortality rate of 91 persons by overdose (^{Degenhardt et al., 2019}). From 1999 to 2015, it has been estimated that 15,000 deaths occurred due to the abuse of these substances and in 2016, more than 64,000 deaths due to overdose have been reported, including 15,000 by heroin and more than 20,000 by synthetic opioids, such as fentanyl. As indicated by the previous numbers, the increase in deaths due to overdose has been accelerated for the last few years and could even cause a reduction of population life expectancy (^{Guardia-Serecigni, 2018}; ^{Volkow et al., 2018}).

The main cause of the epidemic in the use of opioids is due to the fact that more narcotic medicines are consumed in USA than in any other nation in the world. The International Narcotics Control Board (INCB), a division of the United Nations (UN), estimates that pharmaceutical companies in 2011 produced more than 75 tons oxycodone per year, compared to the 11.5 tons produced in 1999, from which more than 80 % is consumed in USA (^{Milani & Scholten, 2011}).

In the specific case of USA, the Center of Disease Control and Prevention (CDC) affirms that 20 % of people receiving an initial prescription for 10 days of opioids analgesics, will keep on using drugs over a year or including in a lifetime. In addition, they recognize that the simultaneous consumption of opioids analgesics and benzodiazepines quadruplicates the risk of death due to overdose, compared to the consumption of opioids only (^{Becker et al., 2008}).

The volume of prescribed opioids reached its maximum point in 2011 with 240 thousand of millions of milligrams of morphine equivalents and decreased of 29 % at 171 thousand of millions in 2017, in response to higher regulations, awareness, education and to responsible opioid prescription. This trend contrasts with the increase corresponding to the treatment strategy adopted through drug-assisted therapies for the dependence on opioids use, in which a duplication of treatments per month from 44,000 to 82,000 was observed from 2015 to 2017 (^{IQVIA, 2018}). Recent data show that 62 % of deaths were related to the consumption of illicit drugs and 38 % of deaths were related to prescribed medicines (^{Jozef Š & Henrieta Š, 2019}).

Due to this problem, for some years, the government and health institutions have looked for strategies to put an end to this epidemic of consumption and abuse of opioids, forcing them to reassess and examine policies that restrict the therapy with opioids to patients depending on arbitrary thresholds; and encourage the commitment of doctors and health personnel to help all patients to gain access to assistance based on evidence for pain and disorders for the use of substances, through drug-assisted therapies. The Federal Drug Administration (FDA) encouraged medical-assisted treatment, which has derived into the first steps towards the action against the inappropriate use of opioids (^{Urman et al, 2019}), it is reported that the therapy with opioids decreases in 2.9 millions of treatments per month at the end of 2017, while medical assisted treatment increased drastically (^{IQVIA, 2018}).

The American Medical Association (AMA) keeps urging doctors to make decisions of sensible and informed prescriptions to reduce the risk of damages related to opioids, but recognizes that, for some patients, opioids therapy can be medically necessary and appropriate, even when doses higher than the recommended by some entities are prescribed (^{AMA, 2019}). Although the opioids crisis is highly related to the use of these substances with therapeutic purposes, from 2013 the use of synthetic opioids was increased through the illegal market, mainly fentanyl and its different types of analogous. The afore-mentioned results are important in the Mexican context, so they will be discussed further.

Use and abuse of opioids in México

Fortunately, the consumption of opium and its derivatives has not been quantitatively important in the Mexican society, despite that the production of opium poppy has never stopped in Mexico. The most affected zone corresponds to the northern border of the country, where the heroin flow never stops and the consumption mainly occurs among marginalized populations of this geographical zone, although it is important to mention that this circumstance could change in the next years, increasing the consumption of these substances among the general population, the modernity of social networks use helps increase drugs consumption among users, a higher behavioral intention to imitate risky health behaviors.

Due to the geographical location of Mexico and being a transit country of population from Central- and SouthAmerica to USA, a similar trend in opioids consumption to the one presented in USA is expected, mainly in the states adjacent to this country. A study performed among the population on both sides of the border showed an increase in the prevalence of drugs use in the migrating population (^{Borges et al., 2016}). However, among the general population of Mexico, contrary to USA and Canada, the medical use of opioids is low and it has been estimated that the coverage only fulfills 36 % of the population requiring this type of analgesics (^{Ling et al., 2011}).

In spite of the low percentage of opioids consumption compared to other illegal drugs (0.1 %) (^{ENCODAT, 2017}), an ascendant trend is observed, which could be increased in the next few years, due to a series of factors, such as a higher demographical movement between USA and Mexico, the increase of diseases requiring a more effective pain management, the inclusion of opioids in health systems and insurances, the change in laws regarding the medical use of opioids and the illegal production of synthetic opioids (^{WHO, 2017}; ^{Armenian et al; 2018}).

With respect to the inclusion of opioids into Mexican health public systems, some modifications in the requirements have been performed from 2014 for its prescription in palliative pain treatment, therefore, in the Secretary of Health, treatments with buprenorphine, morphine, oxycodone and tramadol have been authorized, which are found in the basic table of medicines for analgesia in the 2019 Universal Catalog of Health Services (^{CNPSS, 2019}). In addition, the FDA requested to move oxymorphone hydrochloride away from its medication list, a morphine derivative used as a sedative before surgeries and as an auxiliary in anxiety treatment (^{FDA, 2017}), therefore its introduction in Latin-American countries could be in the spotlight of pharmaceutical companies.

Another important factor to consider is the abuse of synthetic opioids, although up to date, its use is lower compared with other illegal drugs. In that regard, a high quantity of fentanyl is produced illegally in Mexico, which is mainly allocated to USA, in addition to the fact that criminal organizations established in Mexico make the introduction of fentanyl produced in China into USA easier, through the northwestern border of our country (^{Armenian et al., 2018}). For the aforementioned, an upturn in the illegal consumption of fentanyl and others analogous could be expected in the near future in Mexico, which, in addition to the inclusion of opioids in the basic table of the health system, could lead to a similar epidemic to the one presently lived in USA.

Pharmacotherapy in opioid addiction

The prevailing opioid crisis has required understanding the main treatments of opioids addiction and the chemical and neuromolecular detoxification (^{Kaski et al., 2019}). Heroin is metabolized enzimatically and spontaneously by an in vivo hydrolysis/deacetylation of 3- acetylmorphine (3-AM) and 6-acetylmorphine (6-AM), then both compounds to morphine; shown in Figure 4, being these ones the active metabolites, since they present a higher affinity to MOR receptors. This chemical knowledge allows using 6-AM as a biomarker of the identification of heroin in the organism, due to heroin having a very short half-life (2-4 minutes approx.). Codeine is transformed to morphine by the cytochrome P450 enzyme (^{Meyer et al., 2015}; ^{Dinis-Oliveira, 2019}). The effectiveness of pharmacotherapies to control opioids addiction is estimated at 60-70 % (^{Crist et al., 2018}). The most used medicines are methadone, buprenorphine and naloxone or naltrexone, pharmacotherapies targeted to OPRM1 receptor (^{Fonseca & Torrens, 2018}).

(Source: Own).

Figure 4 Metabolic pathway of heroin, codein and morfine. hCE - human carboxylesterase; BChE - butyrylcholinesterase; CYP - cytochrome P450 

The response to the treatment depends on the genes regulating the synthesis, metabolism and transport of neurotransmitters involved in the behaviour of opiates consumption. Pharmacogenetic studies demonstrated that methadone clearance can be regulated by variantes in cytochrome P450 (CYP) 2B (CYP2B6) and CYP3A4*22, enzymes metabolizing methadone (^{Csajka et al., 2016}), this is a tool which would allow dosifying properly the pharmacotherapy, in a personalized, safe, optimized and targeted way, taking into account ethnic and environmental factors and genetic polymorphism (^{Berrettini, 2017}; ^{Eissenberg & Aurora, 2019}). Other studies have demostrated that individuals with OPRM1 A118G polymorphism respond correctly to treatment with naltrexone, these findings can determine that the response to a pharmacotherapy of the patient requires less dose of naltroxone to produce the expected therapeutical effect, avoiding toxicity related to high doses of treatment, including death in the worst cases (^{Taqi et al., 2019}).

Conclusion

In spite of the addictive nature of opioids, they are indispensable in pain management therapies, especially in moderate to severe pain treatment, being the most effective and used analgesics up to date. However, their psychotropic effects make them particularly vulnerable to misuse and abuse. In USA, they became a public health issue, in such an extent that they have been categorized as an epidemic. In Mexico, we are not exempt from this concern, since there is a potential risk of an increase in the use and abuse of opioids, mainly due to: 1) the constant population mobility among Mexico, USA and Canada; 2) the incorporation of these drugs into health systems; 3) the illegal use of synthetic opioids. Therefore, scientific research is essential for the development of new analgesic drugs, without addictive effects and less severe adverse reactions. Nonetheless, new strategies have to be developed as well to allow facing issues that could originate from the increase of the use of prescribed and not prescribed opioids, such as the case of pharmacotherapy, which has shown good results for controlling opioids addiction.