Journal of Pain Management & Medicine

Pharmacodynamics of Opioid Analgesics in Pharmacogenetics

Issam Smith^* Department of Medicine, Icahn School of Medicine, Mount Sinai, New York, United States
^*Correspondence: Issam Smith, Department of Medicine, Icahn School of Medicine, Mount Sinai, New York, United States, Email:

Received: 24-Jun-2022, Manuscript No. JPMME-22-17560; Editor assigned: 28-Jun-2022, Pre QC No. JPMME-22-17560 (PQ); Reviewed: 12-Jul-2022, QC No. JPMME-22-17560; Revised: 19-Jul-2022, Manuscript No. JPMME-22-17560 (R); Published: 28-Jul-2022, DOI: 10.35248/2684-1320.22.8.179

Description

Opioids are frequently used to treat both acute and chronic pain that is moderate to severe. Alternative potent opioids include morphine, oxycodone, hydromorphone, and fentanyl, all of which have comparable efficacy at the population level. The effectiveness and side effects of opioid analgesics vary greatly from person to person at the individual level, for unknown reasons that may in part be genetic. Up to 30% of patients with cancer-related pain do not respond well to morphine, either as a result of insufficient pain relief or intolerable side effects. When given an alternative opioid, the majority of these morphine "non-responders" experience a better clinical outcome. Opioids frequently cause hallucinations, drowsiness, confusion, and nausea and vomiting as side effects.

Opioid analgesics pharmacodynamics

Opioid receptors are members of the G-Protein-Coupled Receptor (GPCRs) family. The three different kinds of classical opioid receptors are mu (μ), kappa (κ), and delta (δ). They have seven transmembrane domains, an intracellular C-terminus, an extracellular N-terminus, and a high degree of structural homology in common. The extracellular loops and N-terminal domain show the most variations. Extracellular loops play a crucial role in ligand binding and are hence crucial. It has been demonstrated that opioid receptor mRNA can create several receptor subtypes, some of which may have functional significance.

Studies using gene knockout mice have shown that the -opioid receptor is the main mediator of the analgesic response to opioids. An opioid response has been linked to genetic variations in the human μ-opioid receptor gene (OPRM1) in a number of distinct clinical contexts, including acute postoperative pain, chronic non-cancer pain, and cancer-related pain.

The most often documented example of a relationship between genetic variation in OPRM1 and opioid responsiveness is the non-synonymous exonic SNP (Single nucleotide polymorphisms) c.118A>G (rs1799971). The functional significance of this SNP, which causes an asparagine-to-aspartic acid change at location, a possible N-glycosylation site in the critical extracellular Nterminal region, is still unknown. c.118A>G variation G alleles have been linked to higher morphine dose requirements in cancer patients and people recovering from surgery. Similar to this, the common ‘A’ allele has been linked to better morphine analgesia in cancer-related pain. However, no correlation with higher pain and only a slight association with increased morphine dose requirements in homozygous carriers of the variation G allele were discovered when these opioid pain studies were combined in a meta-analysis.

Additionally linked to the opioid-related adverse effects is c. 118A>G. Carriers of the variation G allele experienced decreased sedation and nausea in a post-operative trial of morphine-treated patients. Another post-operative research of tramadol and intrathecal morphine for osteoarthritis likewise found a link between the variation G allele and reduced nausea and vomiting. However, in another post-operative pain trial, the c.118A>G genotype was not linked to fentanyl-induced postoperative nausea and vomiting. Lower opioid receptor sensitivity is shown by the pattern of less analgesia and less side effects (upper gastrointestinal and central).

For instance, in the European Pharmacogenetics Opioid Study (EPOS), additional SNPs from the classical opioid receptor genes, such as OPRK1 and OPRD1, as well as OPRM1, have been examined. With 2294 patients using opioids for pain associated with cancer, EPOS is the largest genetic association research of opioid responsiveness to date. The link between oral equivalent morphine dose needs and a total of 112 SNPs in 25 genes, including OPRM1, OPRK1, and OPRD1, was examined. However, none of the SNPs examined in the development and validation analyses showed any connection.

In one cancer-related pain study (n=207), two primary components were found when morphine response phenotypes were mathematically evaluated using principal component analysis: analgesia and central side effects. To predict response, ORPM1, OPRD1, and OPRK1 SNPs were combined with clinical and genetic variables using multivariate regression analysis. A model that took into account the OPRK1 SNP rs7824175, two different classes of concurrent medicine, including betablockers, anti-emetics, and daily morphine dose, predicted a total of 16% of variability in analgesic response.

Two SNPs, OPRM1 rs2075572 and OPRK1 rs10504151, predicted a total of 10% of variability in central side effects of morphine, including concurrent use of steroid medicines and a diagnosis of sarcoma malignancy. This is a novel approach to phenotypic definition that takes into account both clinical and genetic aspects. STAT6 is a crucial transcription factor that controls how TH2 cytokines like interleukin 4 regulate the production of OPRM1 (IL-4). STAT6 polymorphisms have been linked to both opioid switching and the overall response to morphine in cancer-related pain.

An intracellular protein known as β-arrestin 2 is crucial for the internalization and deactivation of μ-opioid receptors. Opioid receptor agonists variably cause receptor phosphorylation and β - arrestin 2 recruitment upon binding. Mice lacking the β-arrestin 2 (ARRB2) gene display sustained analgesia after morphine administration at lower doses, according to knockout experiments. It is important to keep in mind, nevertheless, that in the knockout animal model, prolonged analgesia in mice lacking β-arrestin 2 may possibly result from a mixture of more complex effects transmitted by several GPCRs. The overall response to morphine and opioid switching has been linked to polymorphisms in the ARRB2 gene.