Search Results (61)

Background: Osteoarthritis (OA) of the hip and knee is a common age-related degenerative disease characterized by joint pain, stiffness, and gait disturbances. This study investigated the influence of genetic polymorphisms in the OPRM1 (rs1799971) and COMT (rs4633, rs4680, rs4818, and rs6269) genes on the postoperative analgesic requirements in 195 diabetic and non-diabetic patients undergoing total hip or knee arthroplasty. Methods: The prospective study included all patients who were admitted between January and September 2020 and agreed to participate. Postoperative pain management was assessed based on acetaminophen, ketoprofen, and morphine consumption on the first and second postoperative day. Results: Multilevel regression analyses revealed a significant three-way interaction between diabetes, type of analgesic, and OPRM1rs1799971 polymorphism, indicating different analgesic dosing patterns in diabetic and non-diabetic patients. Two-way interactions between diabetes and COMT polymorphisms rs4633, rs4680, and rs6269 further influenced the analgesic requirements. No significant associations were found for COMT rs4818. The results show that diabetes and genetic factors significantly influence opioid requirements and pain perception. Conclusions: Given the complexity of pain management in diabetic patients, personalized analgesic strategies tailored to genetic and metabolic profiles could be useful in postoperative pain management and reducing opioid consumption. Full article

Background/Objectives: Genetic variants, such as the µ-opioid receptor 1 (OPRM1) rs1799971 and the catechol-O-methyltransferase (COMT) rs4680, have been considered among the potential causes in the development of some chronic pain conditions. In this regard, there are controversial results regarding their roles in fibromyalgia (FM). We aimed to investigate whether the OPRM1 rs1799971 and COMT rs4680 polymorphisms are associated with the development of or susceptibility to FM, as well as their potential association with syndrome characteristic variables, in a sample of the Spanish population with and without FM. Methods: The present study analysed COMT Val158Met and OPRM1 Asn40Asp genetic variants in 311 FM patients (301 women and 10 men) and 135 non-FM participants (120 women and 15 men). In addition to clinical variables, widespread pain index (WPI), symptom severity scale (SSS) (fatigue, rest quality, and cognitive symptoms), pain, stress episodes, and Borg scale were collected. Results: The main results indicate that women carrying the Val/Val genotype (i.e., high COMT activity) exhibited significantly lower levels of fatigue, cognitive impairment, and total SSS than heterozygote carriers. In addition, Met allele carriers (i.e., lower COMT activity) showed higher probabilities of suffering a stress episode and higher levels of exertion during daily activities. Conclusions: The present research suggests a link between dopaminergic dysfunction and exacerbated, frequently described symptoms in female FM patients. Although further research with wider genetic variants and recruited patients is needed, these results point out the necessity of considering gender as a separate category in chronic pain studies. Full article

Pain management in children remains a challenge. Postoperative pain assessment, which currently relies on behavioral and subjective scales, could be enhanced by the identification of single nucleotide polymorphisms effect on pain thresholds and opioid metabolism. This study explores the impact of nine SNPs—rs1799971, rs4680, rs4633, rs6269, rs4818 (with catechol-o-methyltransferase haplotypes), rs7832704, rs1801253, and rs1045642—on postoperative pain intensity, opioid requirements, coanalgesic use, C-reactive protein levels, and post-anesthesia care unit length of stay. This study involved 42 pediatric patients undergoing scoliosis correction surgery with postoperative sufentanil infusion. The genotyping was performed using real-time PCR with peripheral blood samples. Patients with the rs1801253 ADRB1 GG genotype showed significantly lower 24 h NRS pain ratings (p = 0.032) and lower sufentanil infusion rates at the level of statistical tendency (p = 0.093). Patients with the rs1205 CRP CT genotype had a shorter PACU length of stay (p = 0.012). In contrast, those with the rs1045642 ABCB1 GG genotype had a longer PACU stay by 0.72 h (p = 0.046). No significant associations were found for OPRM1 rs1799971, COMT, or ENPP2 SNPs. ADRB1 rs1801253may be a novel SNP indicating higher postoperative pain risk, while rs1205 CRP and rs1045642 ABCB1 could predict increased care requirements in PACUs. The ADRB1 rs1801253 SNP may also predict opioid demand. These results suggest SNPs should be considered in acute pain assessment. Full article

Background/Objectives: Pain management in colorectal cancer is influenced by genetic variability in opioid receptor genes (OPRM1 and OPRD1), potentially affecting opioid efficacy and adverse drug reactions (ADRs). This study evaluated the association of OPRM1 (rs1799971 and rs510769) and OPRD1 (rs2236861) polymorphisms with pain severity, opioid efficacy, and ADRs in Chilean colorectal cancer patients. Methods: The genotypes of OPRM1 and OPRD1 polymorphisms and clinical data from 69 colorectal cancer patients were analyzed. Associations between genotypes, ADRs, and pain severity (maximum Visual Analog Scale, VAS) were evaluated under inheritance models. Results: The OPRM1 rs1799971 G allele was significantly associated with pain presence (p = 0.008), while OPRD1 rs2236861 was linked to ADR risk (p = 0.042). Allelic distribution analysis revealed higher frequencies of the OPRD1 G allele and OPRM1 rs510769 T allele in patients with ADRs and pain, respectively. For OPRM1 rs510769, the dominant model showed a significant association with pain severity (p = 0.033), while the overdominant model revealed a trend toward significance (p = 0.0504). Logistic regression model tests showed no significant predictive associations for the maximum VAS or ADRs under inheritance models. Conclusions: Genetic variations in OPRM1 and OPRD1 may play a role in pain perception and ADRs in colorectal cancer patients. These findings contribute to the understanding of pharmacogenomic factors in opioid therapy, emphasizing the need for further research to validate the clinical utility of these genetic markers. Full article

Fentanyl is a synthetic opioid widely used for its potent analgesic effects in chronic pain management and intraoperative anesthesia. However, its high potency, low cost, and accessibility have also made it a significant drug of abuse, contributing to the global opioid epidemic. This review aims to provide an in-depth analysis of fentanyl’s medical applications, pharmacokinetics, metabolism, and pharmacogenetics while examining its adverse effects and forensic implications. Special attention is given to its misuse, polydrug interactions, and the challenges in determining the cause of death in fentanyl-related fatalities. Fentanyl misuse has escalated dramatically, driven by its substitution for heroin and its availability through online platforms, including the dark web. Polydrug use, where fentanyl is combined with substances like xylazine, alcohol, benzodiazepines, or cocaine, exacerbates its toxicity and increases the risk of fatal outcomes. Fentanyl undergoes rapid distribution, metabolism by CYP3A4 into inactive metabolites, and renal excretion. Genetic polymorphisms in CYP3A4, OPRM1, and ABCB1 significantly influence individual responses to fentanyl, affecting its efficacy and potential for toxicity. Fentanyl’s side effects include respiratory depression, cardiac arrhythmias, gastrointestinal dysfunction, and neurocognitive impairments. Chronic misuse disrupts brain function, contributes to mental health disorders, and poses risks for younger and older populations alike. Fentanyl-related deaths require comprehensive forensic investigations, including judicial inspections, autopsies, and toxicological analyses. Additionally, the co-administration of xylazine presents distinct challenges for the scientific community. Histological and immunohistochemical studies are essential for understanding organ-specific damage, while pharmacogenetic testing can identify individual susceptibilities. The growing prevalence of fentanyl abuse highlights the need for robust forensic protocols, advanced research into its pharmacogenetic variability, and strategies to mitigate its misuse. International collaboration, public education, and harm reduction measures are critical for addressing the fentanyl crisis effectively. Full article

Opioid use disorder (OUD) affects millions of people worldwide. While it is known that OUD originates from many factors, including social and environmental factors, the role of genetic variants in developing the disease has also been reported. This study aims to investigate the genetic variants associated with the risk of developing OUD upon exposure. Twenty-three subjects who had previously been given opioid-based painkillers to undergo minor surgical treatment were recruited at Prisma Health Upstate clinic and elsewhere. Eleven were considered nonpersistent opioid users (controls), and 12 were persistent opioid users (cases) at the time of sample collection after an initial surgery. The subjects were asked to provide saliva samples, which were subjected to DNA sequencing at Clemson University Center for Human Genetics, and variant calling was performed. The genome-wide association studies (GWASs) for genes known to be associated with OUD resulted in 13 variants (intronic or SNV) with genome-wide significance (raw p-value < 0.01) and two missense variants, rs6265 (p.Val66Met in BNDF isoform a) and rs1799971 (p.Asn40Asp) in OPRM1, previously reported in the literature. Furthermore, extending the GWASs to find all genomic variants and filtering the variants to include only variants found in cases (persistent opioid users) but not in controls (nonpersistent opioid users) resulted in 11 new variants (p-value < 0.005). Considering that OUD is a complex disease and the effect might come from different variants in the same genes, we performed a co-occurrence analysis of variants on the genes. We identified eight additional genes that harbor multiple variants, including four genes: LRFN3, ZMIZ1, RYR3, and OR1L6, with three or more variants in the case subjects but not in the control individuals. The performed PPI network construction, along with functional enrichment, indicated that the variants occur in calcium signaling, circadian entrainment, morphine addiction, alcoholism, and opioid signaling pathways, which are closely related to OUD or addiction in general. Full article

Knowledge about determinants of addiction in people taking addictive substances is poor and needs to be supplemented. The novelty of this paper consists in the analysis of innovative aspects of current research about relationships between determinants of addiction in Polish patients taking addictive substances and rare available data regarding the relationships between these factors from studies from recent years from other environments, mainly in Europe, and on the development of genetic determinants of physiological responses. We try to explain the role of the microelements Mn, Fe, Cu, Co, Zn, Cr, Ni, Tl, Se, Al, B, Mo, V, Sn, Sb, Ag, Sr, and Ba, the toxic metals Cd, Hg, As, and Pb, and the rare earth elements Sc, La, Ce, Pr, Eu, Gd, and Nd as factors that may shape the development of addiction to addictive substances or drugs. The interactions between factors (gene polymorphism, especially ANKK1 (TaqI A), ANKK1 (Taq1 A-CT), DRD2 (TaqI B, DRD2 Taq1 B-GA, DRD2 Taq1 B-AA, DRD2-141C Ins/Del), and OPRM1 (A118G)) in patients addicted to addictive substances and consumption of vegetables, consumption of dairy products, exposure to harmful factors, and their relationships with physiological responses, which confirm the importance of internal factors as determinants of addiction, are analyzed, taking into account gender and region. The innovation of this review is to show that the homozygous TT mutant of the ANKK1 TaqI A polymorphism rs 1800497 may be a factor in increased risk of opioid dependence. We identify a variation in the functioning of the immune system in addicted patients from different environments as a result of the interaction of polymorphisms. Full article

Background/Objective: There are several questionnaires for the challenge of anticipating opioid use disorder (OUD). However, many are not specific for chronic non-cancer pain (CNCP) or have been developed in the American population, whose sociodemographic factors are very different from the Spanish population, leading to scarce translation into clinical practice. Thus, the aim of this study is to prospectively validate a predictive model for OUD in Spanish patients under long-term opioids. Methods: An innovative two-stage predictive model was developed from retrospective (n = 129) and non-overlapping prospective (n = 100) cohorts of real-world CNCP outpatients. All subjects used prescribed opioids for 6 or more months. Sociodemographic, clinical and pharmacological covariates were registered. Mu-opioid receptor 1 (OPRM1, A118G, rs1799971) and catechol-O-methyltransferase (COMT, G472A, rs4680) genetic variants plus cytochrome P450 2D6 (CYP2D6) liver enzyme phenotypes were also analyzed. The model performance and diagnostic accuracy were calculated. Results: The two-stage model comprised risk factors related to OUD (younger age, work disability and high daily opioid dose) and provided new useful information about other risk factors (low quality of life, OPRM-G allele and CYP2D6 extreme phenotypes). The validation showed a satisfactory accuracy (70% specificity and 75% sensitivity) for our predictive model with acceptable discrimination and goodness of fit. Conclusions: Our study presents the results of an innovative model for predicting OUD in our setting. After external validation, it could represent a change in the paradigm of opioid treatment, helping clinicians to better identify and manage the risks and reduce the side effects and complications. Full article

Pain is an unpleasant sensory and emotional experience. Adequate pain control is often challenging, particularly in patients with chronic pain. Despite advances in pain management, drug addiction, overtreatment, or substance use disorders are not rare. Hence the need for further studies in the field. The substantial progress made over the last decade has revealed genes, signalling pathways, molecules, and neuronal networks in pain control thus opening new clinical perspectives in pain management. In this respect, data on the epigenetic modulation of opioid and cannabinoid receptors, key actors in the modulation of pain, offered new perspectives to preserve the activity of opioid and endocannabinoid systems to increase the analgesic efficacy of opioid- and cannabinoid-based drugs. Similarly, upcoming data on cannabidiol (CBD), a non-psychoactive cannabinoid in the marijuana plant Cannabis sativa, suggests analgesic, anti-inflammatory, antioxidant, anticonvulsivant and ansiolitic effects and supports its potential application in clinical contexts such as cancer, neurodegeneration, and autoimmune diseases but also in health and fitness with potential use in athletes. Hence, in this review article, we summarize the emerging epigenetic modifications of opioid and cannabinoid receptors and focus on CBD as an emerging non-psychoactive cannabinoid in pain management in clinical practice, health, and fitness. Full article

Oleoylethanolamide (OEA) is a lipid with anti-inflammatory activity that modulates multiple reward-related behaviors. Previous studies have shown that OEA treatment reduces alcohol self-administration (SA) while inhibiting alcohol-induced inflammatory signaling. Nevertheless, the specific mechanisms that OEA targets to achieve these effects have not been widely explored. Here, we tested the effects of OEA treatment during alcohol SA, extinction or previous to cue-induced reinstatement of alcohol seeking. In addition, we measured gene expression changes in the striatum and hippocampus of relevant receptors for alcohol consumption (Drd1, Drd2, Cnr1, Oprm) as well as immune-related proteins (Il-6, Il-1β, Tlr4) and the brain-derived neurotrophic factor (Bdnf). Our results confirmed that when administered contingently, systemic OEA administration reduced alcohol SA and attenuated cue-induced reinstatement. Interestingly, we also observed that OEA treatment reduced the number of sessions needed for the extinction of alcohol seeking. Biochemical analyses showed that OEA induced gene expression changes in dopamine and cannabinoid receptors in the striatum and hippocampus. In addition, OEA treatment modulated the long-term immune response and increased Bdnf expression. These results suggest that boosting OEA levels may be an effective strategy for reducing alcohol SA and preventing relapse. Full article

Tramdol is one of most popular opioids used for postoperative analgesia worldwide. Among Arabic countries, there are reports that its dosage is not appropriate due to cultural background. To provide theoretical background of the proper usage of tramadol, this study analyzed the association between several genetic polymorphisms (CYP2D6/OPRM1) and the effect of tramadol. A total of 39 patients who took tramadol for postoperative analgesia were recruited, samples were obtained, and their DNA was extracted for polymerase chain reaction products analysis followed by allelic variations of CYP2D6 and OPRM A118G determination. Numerical pain scales were measured before and 1 h after taking tramadol. The effect of tramadol was defined by the difference between these scales. We concluded that CYP2D6 and OPRM1 A118G single nucleotide polymorphisms may serve as crucial determinants in predicting tramadol efficacy and susceptibility to post-surgical pain. Further validation of personalized prescription practices based on these genetic polymorphisms could provide valuable insights for the development of clinical guidelines tailored to post-surgical tramadol use in the Arabic population. Full article

Humans are the result of an evolutionary process, and because of this, many biological processes are interconnected with each other. The intestine–brain axis consists of an intricately connected neuronal–neuroendocrine circuit that regulates the sensation of hunger and satiety. Genetic variations and the consumption of unnatural diets (ultra-processed foods, high contents of sugars, etc.) can override this circuit and cause addiction to certain foods and/or the inability to feel satiety in certain situations. The patients who come to consultations (mainly psychology or nutrition) in an attempt to resolve this problem sometimes fail, which leads to them looking for new strategies based on biological predisposition. This investigation aims to evaluate the genetic studies regarding the microbiota carried out in the last 12 years in humans to try to determine which genes and microbes that have been recently studied are related to patients diagnosed with binge eating disorder or compulsive eating (presenting obesity or not). The protocol followed the PRISMA statement, and the following databases were searched from 2012 until the present day: PubMed, PsycINFO, SCOPUS, and Web of Science. Twenty-four international articles were analyzed, including cross-sectional or exploratory studies; five of them referred to the microbial composition, and in nineteen, the existence of genetic polymorphisms present in binge eating disorder or in compulsive eating could be observed: DRD2, OPRM1, COMT, MC4R, BNDF, FTO, SLC6A3, GHRL, CARTPT, MCHR2, and LRP11. Even though there is still much to investigate on the subject, it must be highlighted that, in the last 4 years, a two-fold increase has been observed in potential markers and in studies related to the matter, also highlighting the importance of different analyses in relation to psychosocial factors and their interaction with the genetic and microbial factors, for which research on the matter must be continued. Full article

Declining estrogen (E2) leads to physical inactivity and adipose tissue (AT) dysfunction. Mechanisms are not fully understood, but E2’s effects on dopamine (DA) activity in the nucleus accumbens (NAc) brain region may mediate changes in mood and voluntary physical activity (PA). Our prior work revealed that loss of E2 robustly affected NAc DA-related gene expression, and the pattern correlated with sedentary behavior and visceral fat. The current study used a new transgenic mouse model (D1ERKO) to determine whether the abolishment of E2 receptor alpha (ERα) signaling within DA-rich brain regions affects PA and AT metabolism. Adult male and female wild-type (WT) and D1ERKO (KD) mice were assessed for body composition, energy intake (EE), spontaneous PA (SPA), and energy expenditure (EE); underwent glucose tolerance testing; and were assessed for blood biochemistry. Perigonadal white AT (PGAT), brown AT (BAT), and NAc brain regions were assessed for genes and proteins associated with DA, E2 signaling, and metabolism; AT sections were also assessed for uncoupling protein (UCP1). KD mice had greater lean mass and EE (genotype effects) and a visible change in BAT phenotype characterized by increased UCP1 staining and lipid depletion, an effect seen only among females. Female KD had higher NAc Oprm1 transcript levels and greater PGAT UCP1. This group tended to have improved glucose tolerance (p = 0.07). NAc suppression of Esr1 does not appear to affect PA, yet it may directly affect metabolism. This work may lead to novel targets to improve metabolic dysfunction following E2 loss, possibly by targeting the NAc. Full article

Despite technical and pharmacological advancements in recent years, including optimized therapies and personalized medicine, postoperative pain management remains challenging and sometimes undertreated. This review aims to summarize and update how genotype-guided therapeutics within personalized medicine can enhance postoperative pain management. Several studies in the area have demonstrated that genotype-guided therapy has the ability to lower opioid consumption and improve postoperative pain. Gene mutations, primarily OPRM1, CYP2D6, CYP2C9, COMT and ABCB1, have been shown to exert nuanced influences on analgesic response and related pharmacological outcomes. This review underscores the integration of pharmacogenetic-guided personalized medicine into perioperative care, particularly when there is uncertainty regarding opioid prescriptions. This approach leads to superior outcomes in terms of postoperative pain relief and reduced morbidity for numerous patients. Full article

The main aims of the present study were to explore the relationship of the OPRM1 gene rs1074287 polymorphism in alcohol-dependent women with their personality traits and to try to find out whether any specific features may influence alcohol cravings and be a prognostic for alcohol dependency and treatment in AUD women. Our study found a notable correlation between openness and the interaction of the ORIM1 gene and AUD. The alcohol use disorder subjects with genotype AG showed a higher level of openness compared to the control group with genotypes AG (p = 0.0001) and AA (p = 0.0125). The alcohol use disorder subjects with the AA genotype displayed higher levels of openness than the control group with genotype AG (p = 0.0271). However, the alcohol use disorder subjects with the AA genotype displayed lower levels of openness than the control group with genotype GG (p = 0.0212). Our study indicates that openness as a personality trait is correlated with the OPRM1 gene rs1074287 polymorphism in alcohol-dependent women. These are the first data and results exploring such a relationship between opioid and alcohol pathways and the mental construction of AUD women. Personality traits such as openness to experience and neuroticism might play major roles in the addiction mechanism, especially in genetically predisposed females, independent of the reward system involved in the emotional disturbances that coexist with anxiety and depression. Full article