118G Allele Research Articles

The Effect of Genetic Variation on the Sensitivity to Opioid Analgesics in Patients With Postoperative Pain: An Updated Meta-analysis

BACKGROUND: Responsiveness to opioid analgesics differs among patients with acute postoperative pain. OBJECTIVE: Our study presents the most recent evidence on the effect of genetic variations on postoperative pain, opioid consumption, nausea, and vomiting in patients treated with opioids. STUDY DESIGN: An updated systematic review and meta-analysis on the association between single-nucleotide polymorphisms and opioids administered to patients with acute postoperative pain. METHODS: PubMed, Embase, ISI Web of Science, and the Cochrane Library databases were searched for articles published from February 1, 2014, through December 31, 2021. RESULTS: Added to the previous meta-analysis, 39 studies (a total of 7,455 patients) were included in the final meta-analysis. Highlights of the findings include: 1) human mu-opioid receptor gene 118G allele carriers required more opioids during the first postoperative 24 hours (standard mean difference [SMD] = -0.27; 95% CI,-0.40 to -0.14; P < 0.0001) and 48 hours (SMD = -0.52; 95% CI, -0.83 to -0.20; P = 0.001), and reported higher pain scores during the first 24 hours but not at the 48-hour postoperative period (SMD = -0.09, 95% CI, -0.15 to -0.03; P = 0.002) compared to homozygous 118AA patients. 2) patients with the CYP3A4 *1G allele required fewer opioids during the first 24-hour postoperative period (SMD = 0.59; 95% CI, 0.05 to 1.14; P = 0.03) compared to patients with the homozygous CYP3A4*1/*1 allele. 3) Adenosine triphosphate-binding cassette subfamily B member-1 (ABCB1) 3435T allele carriers required more opioids during the 48-hour postoperative period (SMD = -0.21; 95% CI, -0.38 to -0.04; P = 0.02) compared to homozygous CC carriers. 4) Catechol-O-methyl transferase 158A allele carriers required fewer opioids during the first 24-hour postoperative period (SMD = 0.33; 95% CI, 0.15 to 0.51; P = 0.0004) compared to homozygous GG carriers. No significant differences were observed in patients with CYP2D6*10 and ABCB1 G2677A/T genetic polymorphisms. LIMITATIONS: Several loci were not analyzed in detail due to insufficient clinical data. Furthermore, nongenetic factors that affected analgesic efficacy and the clinical outcome of postoperative pain were not discussed and were not the aim of this meta-analysis. CONCLUSIONS: In combination with previous systematic reviews and meta-analyses, our results indicate that the A118G allele variant of OPRM1 and the *1*1G allele variant of CYP3A4 have a profound influence on individual differences in opioid reactivity in patients with postoperative pain. Our results, together with the identification of additional single nucleotide polymorphisms in future studies, may provide a theoretical basis for precise clinical analgesia. KEY WORDS: Single nucleotide polymorphism, postoperative pain, opioid, meta-analysis

Allele frequency and genotype distribution of the opioid receptor μ-1 (OPRM1) A118G polymorphism in the Western Saudi population.

The single nucleotide polymorphism (SNP) A118G (rs1799971) in the Mu Opioid Receptor 1 (OPRM1) gene is associated with significant variations in analgesic doses and adverse effects of opioids. The A118G OPRM1 allele distributions vary significantly between different populations worldwide. The study aimed to assess the allele frequency and genotype distribution of OPRM1 A118G SNP in Saudis. This cross-sectional study included 124 healthy Saudis (62 males and 62 females) visiting the King Abdulaziz University Hospital in Jeddah, Saudi Arabia. The Oragene®-DISCOVER (OGR-600) kits were used to collect saliva samples from the participants. Polymerase chain reaction-restriction fragment length polymorphism was utilized to assess the SNP. Among the tested population, 79.03% (95% C.I. 70.81-85.82) were homozygous wild-type A118A, 16.13% (95% C.I. 10.14-23.80) were heterozygous A118G, and 4.84% (95% C.I. 1.80-10.23) were homozygous mutant G118G. OPRM1 A118G polymorphism allele frequencies were 87% (95% C.I. 79.89-92.44) and 13% (95% C.I. 7.56-20.11) for the 118A and 118G alleles, respectively. A higher frequency of the OPRM1 118G allele was present in females, 21% (95% C.I. 11.66-33.17) compared to males, 5% (95% C.I. 1.01-13.50). Relative to other Asian countries, the Saudi population showed a low prevalence of the OPRM1 A118G polymorphism, with a higher frequency of the 118G allele in females. Our research will contribute to the existing knowledge on the prevalence of OPRM1 A118G polymorphism, which could be considered for the personalized prescribing of opioid analgesics.

Genetics of adult attachment and the endogenous opioid system

Since the pioneering work by Panksepp et al, the neurobiological bases of attachment behavior have been closely linked with opioid neurotransmission. Candidate gene studies of adult individuals have shown that variation in the mu-opioid receptor gene (OPRM1) influences attachment behavior. Early maternal care and the A/A genotype of the A118G polymorphism interact in modulating levels of fearful attachment. Compared to their counterparts carrying the A/A genotype, individuals expressing the minor 118G allele show lower levels of avoidant attachment and experience more pleasure in social situations. Brain imaging research has strengthened the biological plausibility of candidate gene studies. The avoidance dimension of attachment correlates negatively with mu-opioid receptor availability in the thalamus and anterior cingulate cortex, as well as the frontal cortex, amygdala, and insula. Overall, findings from human studies combined with those from animal models suggest that research on the genetic bases of attachment should include the endogenous opioid system among the investigated variables.

Analgesic effects of piritramide in acute postoperative pain - comparison of intramuscular administration with patient-controlled intravenous analgesia and impact of OPRM1 and ABCB1 polymorphisms.

The aim of this study was to compare the efficacy, consumption and safety after piritramide administered either intramuscularly (IM) on demand or via patient-controlled intravenous analgesia (PCA) and to examine the impact of OPRM1 and ABCB1 gene polymorphisms on the drug efficacy/safety in both regimens. One hundred and four patients scheduled for elective inguinal hernioplasty received piritramide with PCA or IM for postoperative pain management. We evaluated piritramide consumption, pain intensity using visual analogue scale (VAS) and adverse effects. Median (IQR) piritramide consumption was 18.5 (13.5-31.2) and 15.0 (15.0-15.0) mg in the PCA and IM groups, respectively (P=0.0092). The respective values of area under the VAS2-16-time curve were 40 and 280 mm.h (P=0.0027). Opioid-induced adverse effects were more frequent in the PCA than in the IM group. Variant OPRM1 allele was associated with decreased pain relief, increased opioid consumption and increased incidence of adverse effects, while ABCB1 polymorphisms showed no impact on the observed parameters. We observed higher piritramide consumption, better pain relief and slightly worse safety profile in the PCA group compared with IM administration. Variant OPRM1 118G allele carriers required higher opioid dosing and suffered from more adverse effects, however, the differences between genotypes have been less pronounced in the PCA patients likely due to improved pain management via PCA.

Increased risk of intracranial hemorrhage in preterm infants with OPRM1 gene A118G polymorphism.

To investigate the relationship between the OPRM1 gene A118G polymorphism and intracranial hemorrhage (ICH) in premature infants and identify the relevant genes in disease occurrence. In the present case study analysis, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect the genotype and allele frequencies of the OPRM1 gene All8G single nucleotide polymorphism (SNP) in a case group of premature infants with ICH (n=167) and a control group of premature infants (n=163) without ICH. In the case group, 73 (43.7%) wild type A118 homozygous (A/A), 82 (49.1%) mutant heterozygous (A/G), and 12 (7.2%) mutant G118 homozygous (G/G) individuals were observed. The frequencies of A and G alleles were 68.3% and 31.7% respectively. In the control group, 89 (54.6%) wild type A118 homozygous (A/A), 68 (41.7%) mutant heterozygous (A/G), and 6 (3.7%) mutant G118 homozygous (G/G) individuals were observed. The frequencies of A and G alleles were 75.5% and 24.5% respectively. There was no significant difference in the frequency distribution of the OPRM1 gene A118G polymorphism between the two groups (χ2=4.839, P=0.089). There was a significant difference in the positive rate of wild-type AA and mutant-type (A/G + G/G) between the two groups (χ2=3.913, P=0.048). Carrying the G allele of the individual was 1.5 times more frequent suffering from the risk of ICH than carrying the A allele [odds ratio (OR): 1.549; 95% confidence interval (CI): 1.003-2.391], indicating that the OPRM1 118G allele was positively correlated with ICH and can increase the risk of ICH occurrence. The OPRM1 gene A118G polymorphism is associated with ICH in premature infants. The OPRM1 gene A118G may play a critical role in the occurrence of ICH.

Evidence of a genomic insertion in intron 2 of SOD1 causing allelic drop-out during routine diagnostic testing for canine degenerative myelopathy.

Degenerative myelopathy is a severe and progressive neurodegenerative disease and, in the majority of breeds, is associated with the c.118G>A substitution in exon 2 of the canine superoxide dismutase 1 (SOD1) gene. Our laboratories have been engaged in determining the cause of many discordant findings between the parental and the offspring genotypes found by different laboratories. In both cases, the discordant findings refer to actual heterozygous dogs that had been typed as homozygous for the variant allele. To that aim, the genomic context of the causative variant was investigated in two Hovawart dogs. An insertion of 54 nucleotides composed of a poly-T stretch and 15 nucleotides containing the duplication of the exon 2-intron 2 junction was found. The insertion was responsible for the partial mismatch of the reverse primer used for a direct sequencing assay. The mismatch hampered the amplification of the corresponding allele and caused an evident drop-out effect. The insertion is in complete linkage disequilibrium with the c.118G allele. The allele containing the insertion was highly prevalent in Hovawart dogs, accounting for the 26.6% of allele frequency. The insertion was also found in other unrelated breeds such as Rough Collies and Standard Poodles. In conclusion, the study illustrates the importance of correctly designing the primers to avoid inaccurate genotyping of the degenerative myelopathy causative variant in exon 2 of the SOD1 gene.

Genetic variants associated with thermal pain sensitivity in a paediatric population.

Pain sensitivity is an inherited factor that varies strongly between individuals. We investigated whether genetic polymorphisms in the candidate genes COMT, OPRM1, OPRD1, TAOK3, TRPA1, TRPV1, and SCN9A are contributing to experimental pain variability between children. Our study included 136 children and adolescents (8-18 years). Cold and heat pain thresholds were determined with a Thermal Sensory Analyzer. Women and young children were significantly more sensitive to pain (P < 0.05). After correction for age, gender, reaction time, and correction for multiple testing, OPRM1 118A>G G-allele carriers (AG and GG) rated the hot stimulus as significantly less painful than did OPRM1 118A>G AA genotyped individuals (2[1-5] vs 7 [3-9], respectively; P = 0.00005). Additionally, OPRM1 118G allele carriers reached more frequently the minimum temperature limit (44% vs 17%, respectively; P = 0.003) and maximum temperature limit (52% vs 24%, respectively; P = 0.0052), indicative for lower pain sensitivity. The combined genotype, based on expected pain sensitivity, OPRM1 118AA/COMT 472 GA or AA genotyped children, was associated with lower pain thresholds (ie, higher pain sensitivity) than were the OPRM1 118GA or GG/COMT 472GG genotyped children. This is the first study reporting on genetic variants and experimental thermal pain in children and adolescents. OPRM1 rs1799971 and the combined OPRM1/COMT genotype could serve as biomarkers for pain sensitivity.

Acute effect of intravenously applied alcohol in the human striatal and extrastriatal D2 /D3 dopamine system.

Investigations on the acute effects of alcohol in the human mesolimbic dopamine D2 /D3 receptor system have yielded conflicting results. With respect to the effects of alcohol on extrastriatal D2 /D3 dopamine receptors no investigations have been reported yet. Therefore we applied PET imaging using the postsynaptic dopamine D2 /D3 receptor ligand [18 F]fallypride addressing the question, whether intravenously applied alcohol stimulates the extrastriatal and striatal dopamine system. We measured subjective effects of alcohol and made correlation analyses with the striatal and extrastriatal D2 /D3 binding potential. Twenty-four healthy male μ-opioid receptor (OPRM1)118G allele carriers underwent a standardized intravenous and placebo alcohol administration. The subjective effects of alcohol were measured with a visual analogue scale. For the evaluation of the dopamine response we calculated the binding potential (BPND ) by using the simplified reference tissue model (SRTM). In addition, we calculated distribution volumes (target and reference regions) in 10 subjects for which metabolite corrected arterial samples were available. In the alcohol condition no significant dopamine response in terms of a reduction of BPND was observed in striatal and extrastriatal brain regions. We found a positive correlation for 'liking' alcohol and the BPND in extrastriatal brain regions (Inferior frontal cortex (IFC) (r = 0.533, p = 0.007), orbitofrontal cortex (OFC) (r = 0.416, p = 0.043) and prefrontal cortex (PFC) (r = 0.625, p = 0.001)). The acute alcohol effects on the D2 /D3 dopamine receptor binding potential of the striatal and extrastriatal system in our experiment were insignificant. A positive correlation of the subjective effect of 'liking' alcohol with cortical D2 /D3 receptors may hint at an addiction relevant trait.

A gene-by-sex interaction for nicotine reward: evidence from humanized mice and epidemiology.

It has been proposed that vulnerability to nicotine addiction is moderated by variation at the μ-opioid receptor locus (OPRM1), but results from human studies vary and prospective studies based on genotype are lacking. We have developed a humanized mouse model of the most common functional OPRM1 polymorphism rs1799971_A>G (A118G). Here we use this model system together with a cohort of German youth to examine the role of the OPRM1 A118G variation on nicotine reward. Nicotine reinforcement was examined in the humanized mouse model using i.v. self-administration. Male (n=17) and female (n=26) mice homozygous either for the major human A allele (AA) or the minor G allele (GG) underwent eight daily 2 h sessions of nicotine self-administration. Furthermore, male (n=104) and female (n=118) subjects homozygous for the A allele or carrying the G allele from the Mannheim Study of Children at Risk were evaluated for pleasurable and unpleasant experiences during their initial smoking experience. A significant sex-by-genotype effect was observed for nicotine self-administration. Male 118GG mice demonstrated higher nicotine intake than male 118AA mice, suggesting increased nicotine reinforcement. In contrast, there was no genotype effect in female mice. Human male G allele carriers reported increased pleasurable effects from their first smoking experience, as compared to male homozygous A, female G and female homozygous A allele carriers. The 118G allele appears to confer greater sensitivity to nicotine reinforcement in males, but not females.

A prospective study of genetic factors, human laboratory phenotypes, and heavy drinking in late adolescence.

Subjective responses to alcohol are considered candidate endophenotypes for alcohol use disorder and appear to anticipate future consumption. However, prospective studies have been rare, and laboratory research has typically examined subjective responses absent measures of self-administration. This study examined the association of subjective responses with subsequent laboratory self-administration, also evaluating laboratory phenotypes in relation to putative genetic risk factors [family history (FH) of alcohol dependence and OPRM1 genotype] and subsequent heavy drinking. Participants (N = 61, M = 19.89 years, SD = 0.86) completed laboratory sessions involving intravenous alcohol challenge (Session 1) and free-access intravenous self-administration (Session 2), followed by prospective assessments. Multilevel modeling showed that higher reported stimulation and lower sedation during Session 1 independently predicted greater alcohol self-administration during Session 2. Although self-administration did not differ by FH group, participants with the OPRM1 118G allele evidenced steeper breath alcohol concentration (BrAC) trajectories and greater peak BrAC relative to 118A homozygous participants. Prospective analyses supported significant indirect associations between Session 1 subjective responses and 6-month heavy drinking via peak BrAC in Session 2. Additionally, significant indirect associations of FH (via Session 1 stimulation and Session 2 peak BrAC) and OPRM1 (via peak BrAC) with follow-up heavy drinking were observed. These results further support the utility of human laboratory phenotypes in prospective studies of alcohol use disorder risk and highlight the potential role of self-administration phenotypes in longitudinal research.

Functional mu opioid receptor polymorphism (OPRM1 A(118) G) associated with heroin use outcomes in Caucasian males: A pilot study.

Heroin's analgesic, euphoric and dependence-producing effects are primarily mediated by the mu opioid receptor (MOR). A single gene, OPRM1, encodes the MOR. The functional polymorphism A(118)G, located in exon 1 of the OPRM1 gene, results in anatomically-specific reductions in MOR expression, which may alter an individual's response to heroin. In prior studies 118G (rare allele) carriers demonstrated significantly greater opioid tolerance, overdose vulnerability, and pain sensitivity than 118AA homozygotes. Those findings suggest OPRM1 genotype may impact characteristics of heroin use. The present pilot study characterized the impact of OPRM1 genotype (rs1799971, 118G allele carriers vs. 118AA homozygotes) on heroin-use phenotypes associated with heroin dependence severity in a sample of male, Caucasian chronic heroin users (n = 86). Results indicate that 118G allele carriers reported significantly more heroin use-related consequences and heroin-quit attempts, and were more likely to have sought treatment for their heroin use than 118AA homozygotes. These preliminary findings, consistent with extant data, illustrate a role for OPRM1 allelic variation on heroin use characteristics, and provide support for considering genotype in heroin treatment and relapse prevention.

Alcohol Consumption in Healthy OPRM1 G Allele Carriers and Its Association with Impulsive Behavior.

A link between alcohol use disorders (AUD) and impulsivity is well established. As there is evidence for the heritability of AUD, the investigation of the underlying genetic disposition for both conditions is an important issue. An association between AUD and a coding single nucleotide polymorphism (SNP) (rs1799971 encoding an Asn40Asp amino acid substitution, A118G) within the µ-opioid receptor 1 gene (OPRM1) has been reported. Therefore we tested the association between the OPRM1 A118G polymorphism and drinking as well as impulsive behavior in social drinkers. A total of 214 healthy male social drinkers were recruited. Each participant was genotyped for the OPRM1 A118G variant. Alcohol use was assessed with items of the Alcohol Use Disorders Identification Test (AUDIT). Impulsivity was assessed using the UPPS impulsive behavior scale. For statistical analyses, we considered correlations, t-tests and ordinal regression models using SPSS V21. In total, 49 out of 214 participants were carriers of the OPRM1 118G allele. On average the OPRM1 118G carriers showed a slightly higher propensity for alcohol drinking. Higher drinking frequency among the G allele carriers was linked with higher urgency and perseveration subscores of impulsivity. Our results suggest a genetically influenced higher propensity for alcohol drinking among social drinkers carrying the 118G allele of the OPRM1 gene. The positive correlation between urgency and a higher drinking frequency among the OPRM1 118G hint towards a functional meaning of the opioid system in the regulation of impulsivity.

The Impact of Genetic Variation on Sensitivity to Opioid Analgesics in Patients with Postoperative Pain: A Systematic Review and Meta-Analysis

Background: Individual response to opioid analgesics varies among patients. Objective: This study sought to clarify the impact of distinct genetic variations on pain, opioid consumption, and opioid side effects in patients with postoperative pain. Study Design: A systematic review and meta-analysis of associations between genetic singlenucleotide polymorphisms (SNPs) and opioids used for acute postoperative pain. Setting: This meta-analysis examined all studies involving an association between genetic polymorphisms and the analgesic efficacy or clinical outcome of opioid analgesics for postoperative pain. Methods: A literature search was performed up to January 31, 2014, using the PubMed, EMBase, ISI Web of Science, and Cochrane Library databases. Results: Fifty-nine studies were included in this systematic review, and 23 studies (a total of 5,902 patients) were included in the final meta-analysis. The results showed that human μ-opioid receptor gene (OPRM1) 118G allele variant carriers consumed more opioids for analgesia (SMD = -0.17, 95% CI = [-0.25, -0.10], P &lt; 0.00001), but reported higher pain scores (MD = -0.11, 95% CI = [-0.17, -0.04], P = 0.002) and less nausea and vomiting (odds ratio = 1.30, 95% CI = [1.08, 1.55], P = 0.005) than the homozygous 118AA patients during the first 24 hour but not the 48 hour postoperative period. Moreover, CYP3A4*1G carriers consumed less opioids than homozygous CYP3A4*1/*1 patients during the first 24 hours postoperative period (MD = 45.12, 95% CI = [36.17, 54.06], P &lt; 0.00001). No significant differences were found in CYP3A5*3, ABCB1 C3435T, and G2477T/A genetic polymorphisms. Limitations: Some potential non-genetic factors can modify the effects of gene SNP on pain and opioid consumption during the postoperative period, such as age, gender, mood, anxiety, and drug-drug interactions. But further analyses could not be performed in the present meta-analysis due to limited information. Conclusion: The results indicate that among the genetic SNPs we studied which include those affecting analgesic drug metabolism, transport of analgesic agents across the blood-brain barrier, and their activity at target receptors and ion channels and in the modulation of neurotransmitter pathways, the A118G allele variant of OPRM1 has the most potent influence on pain management of postoperative patients. Opioid receptor gene information may provide valuable information for clinicians to properly manage the analgesic use of opioids individually for better pain management. Key words: Postoperative pain, meta-analysis, single-nucleotide polymorphism, opioid

Cocaine-induced suppression of saccharin intake and morphine modulation of Ca2 + channel currents in sensory neurons of OPRM1 A118G mice

Several studies have shown that human carriers of the single nucleotide polymorphism of the μ-opioid receptor, OPRM1 A118G, exhibit greater drug and alcohol use, increased sensitivity to pain, and reduced sensitivity to the antinociceptive effects of opiates. In the present study, we employed a ‘humanized’ mouse model containing the wild-type (118AA) or variant (118GG) allele to examine behavior in our model of drug-induced suppression of a natural reward cue and to compare the morphine pharmacological profile in acutely isolated sensory neurons. Compared with 118AA mice, our results demonstrate that homozygous 118GG mice exhibit greater avoidance of the cocaine-paired saccharin cue, a behavior linked to an aversive withdrawal-like state. Electrophysiological recordings confirmed the reduced modulation of Ca2+ channels by morphine in trigeminal ganglion (TG) neurons from 118GG mice compared to the 118AA control cells. However, repeated cocaine exposure in 118GG mice led to a leftward shift of the morphine concentration–response relationship when compared with 118GG control mice, while a rightward shift was observed in 118AA mice. These results suggest that cocaine exposure of mice carrying the 118G allele leads to a heightened sensitivity of the reward system and a blunted modulation of Ca2+ channels by morphine in sensory neurons.

Assessment of opioid receptor μ1 gene A118G polymorphism and its association with pain intensity in patients with fibromyalgia

Fibromyalgia may present with widespread pain and tenderness, fatigue, anxiety, and depression and is associated with a low pain threshold. The etiology of fibromyalgia is yet to be ascertained, although both genetic and environmental factors may play a role in the susceptibility of patients to fibromyalgia. Various genetic variations have been investigated to explain fibromyalgia susceptibility and differences in pain sensitivity, pain threshold, and tolerance. The A118G rs1799971 polymorphism in the opioid receptor μ1 gene (OPRM1) is one of the candidate genes. We hypothesized that the OPRM1 polymorphism may play a role in fibromyalgia susceptibility and impact the pain intensity and pain-related symptoms in fibromyalgia patients. This study comprised of 108 patients with fibromyalgia and 100 healthy controls. Overall, the 118G allele frequency was 16.3 % and was significantly lower in patients with fibromyalgia than in the control group (13.9 and 19 %, respectively). No difference was observed between fibromyalgia patients with and without the A118G allele with regard to the Beck Depression Inventory, widespread pain index, symptom severity, and Fibromyalgia Impact Questionnaire scores. All body parts of patients with fibromyalgia demonstrated lower pressure pain thresholds (PPT) compared to controls. The PPTs were higher in the 118 A/A genotype carrier fibromyalgia patients than in 118*/G carriers; however, the differences were not significant. As the A118G polymorphism frequency was lower in fibromyalgia patients, this polymorphism may exert a protective effect against fibromyalgia in Turkish women. However, the OPRM1 polymorphism does not have a significant effect on pressure pain and fibromyalgia severity.

Association of μ-opioid receptor gene polymorphism (A118G) with variations in fentanyl analgesia consumption after total abdominal hysterectomy in female Egyptian patients

Opioid analgesics are widely used for the treatment of moderate to severe pain. However, the analgesic efficacy of opioids is well known to vary widely among individuals, making it difficult to predict optimal pain management for each patient. The current clinical study was designed to investigate the association of the A118G single nucleotide polymorphism of the μ-opioid receptor gene with the individual variation in pain sensitivity and fentanyl consumption with patient-controlled analgesia (PCA) in 60 adult female Egyptian patients after total abdominal hysterectomy. All patients received general anesthesia according to the same protocol. During the first 24 h after surgery, pain was assessed using a visual analogue scale. In addition, total amount of fentanyl consumption, sedation score, and any other side effects of opioids were recorded; the A118G single nucleotide polymorphism of the μ-opioid receptor gene was detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Our main finding was that in Egyptian gynecological patients, subjects homozygous for the 118G allele needed more fentanyl (488.5 ± 23.91 μg) for 24-h postoperative analgesia than 118A homozygotes (359.82 ± 19.63 μg) and heterozygotes (400± 8.99 μg) (P = 0.001). There was no association of G or A allele and opioid side effects. This study may provide support for the potential use of genetic data in predicting patient’s individual fentanyl doses for adequate postoperative pain control.

A118G polymorphism in the μ-opioid receptor gene and levels of β-endorphin are associated with provoked vestibulodynia and pressure pain sensitivity

Background and aimsProvoked vestibulodynia (PVD) is the most common cause of dyspareunia among young women. The aetiology is largely unknown and treatment is often extensive and longstanding with varying outcomes. Patients display general pain hypersensitivity and there are correlations with other chronic pain syndromes such as fibromyalgia later in life. The A118G polymorphism in the μ-opioid receptor (OPRM1) gene influences endogenous pain regulation and pain sensitivity, but has not been studied in this patient group before. We aimed to investigate a possible association between A118G polymorphism and PVD, with correlation to plasma levels of β-endorphin, and to explore relationships between this polymorphism and pain sensitivity among women with PVD and healthy controls. MethodsThis case–control study included 98 women with PVD and 103 controls. Participants filled out study-specific questionnaires and underwent quantitative sensory testing of pressure pain thresholds on the arm, leg and in the vestibular area. Levels of β-endorphin were analyzed by radioimmunoassay using the EURIA-beta-endorphin kit, and the A118G single-nucleotide polymorphism (SNP; rs1799971) in the OPRM1 gene was analyzed using the TaqMan SNP genotyping assay. ResultsThe 118G allele was more common in controls (44%) than in patients (30%) (p=0.042). The odds ratio of having PVD was 1.8 in participants carrying the 118A allele compared to participants hetero- or homozygous for the 118G allele (OR=1.846, CI: 1.03–3.31, p=0.039). Pressure pain thresholds on the leg were higher for participants carrying the 118G allele (mean 480kPa, SD 167.5) than for those carrying the 118A allele (mean 419, SD 150.4, p=0.008). Levels of β-endorphin were higher in patients (mean 17.9fmol/ml, SD 4.71) than in controls (mean 15.8fmol/ml, SD 4.03) (p<0.001). ConclusionWe found an association between the A118G polymorphism in the OPRM1 gene and an increased risk of PVD and increased pain sensitivity among participants carrying the 118A allele. PVD patients were more sensitive to pressure pain and had higher levels of plasma β-endorphin than controls. The results indicate that differences in endogenous pain modulation involving the opioid system could contribute to the pathophysiology of PVD and the general pain hypersensitivity seen in these women. ImplicationsThe data support the conceptualization of PVD as part of a general pain disorder with a possible genetic predisposition. The age of onset of PVD is usually between 18 and 25 years and already at this age general pain hypersensitivity is present but rarely causing disability. We believe that early recognition and treatment, with the risk of further development of chronic pain taken into consideration, might prevent future aggravated pain problems in this patient group.

Can Mu-opioid Receptor A118G Gene Polymorphism be Predictive of Acute Poisoning Severity in the Emergency Department?

To the Editor,We have read with a great interest the manuscript by Maninietal.[1]reportingtheassociationofmu-opioidreceptorgene(OPRM1) A118G polymorphism with clinical severity ofacute poisonings admitted to the emergency department. Inpatients carrying at least one G allele of the c.A118G poly-morphism (rs1799971), these authors reported increasedpoisoning severity defined as the occurrence of respiratoryarrest, cardiac arrest, or in-hospital mortality with an adjust-ed 5.3 odds ratio whatever the responsible drug was.This finding is quite promising since suggesting that onesimple test could be helpful in identifying acutely poisonedpatients with major risk for severe outcome. However, sev-eral significant biases may temperate possible enthusiasm.The association between the 118G allele and poisoningseverity may have resulted from a confounding factor, i.e.,the surprising severity of poisonings with opioids and benzo-diazepines reported in Manini’s patient population as assessedin the univariate analysis (Table 2) and confirmed in themultivariate analysis identifying a significant link betweenthe clinical outcome and recreational intent of drug abuse(Table4).Toouropinion,theauthorsshouldhavelimitedtheiranalysisto the group oftoxicants witheither obvious(opioids)or possible molecular interactions with MOR like previouslyreported(benzodiazepines)[2],whileothertoxicantslikesym-pathomimetics, antipsychotics, and antidepressants do notclearly interact with MOR.Previous studies have associated the 118G allele with lessmorphine-related pupil-constricting and gastrointestinaleffects [3] and no increased respiratory depression [4]. Amore recent study has evidenced that infants with neonatalabstinence syndrome due to in utero exposure to opioidsneeded less treatments and presented shortened length ofstay, if carrying almost one 118G allele [5]. Taken together,all these data support increased resistance rather than in-creased susceptibility or vulnerability to opioids in the pres-ence of the 118G allele, in contrast to Manini’s findings [1].Additionally, as partly acknowledged by the authors, wecannot exclude that ethnical differences according to severityexplain the observed association between the 118G allele andsevere poisoning outcome, sin cethe118Galleleismorecom-moninAsiandescent( http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1799971).Thus,webelievethatdeterminationofpatients’ ethnical origin is mandatory to allow any definitiveconclusion, even though the Hardy –Weinberg Equilibrium isrespected. Moreover, we cannot e xclude that ethnical origin isassociated with socioeconomical factors or morbidities thatmayhavecontributedtoworsenthefinaloutcomeofpoisoning.Inconclusion,Manini’sdataarequitepromisingtoperson-alizemonitoringofpoisonedpatients,especiallythatthe118Gallele is frequent in the general population. However, consid-ering possible major limitations of their study, a reproductionin a well-characterized independent cohort appears necessary.References

On the Role of Genetic Testing for Personalized Drug Overdose Management

Author Reply: We thank our colleagues for their interest in our study entitled “Opioid Receptor Polymorphism A118G Associated with Clinical Severity in a Drug Overdose Population.” Our results add to the growing literature over the past decade that implicate a handful of promising single nucleotide polymorphisms (SNPs) of the mu opioid receptor gene (OPRM1) as candidates for clinically relevant variability in baseline mesolimbic reward neurobiology (dopamine–opioid interaction), opioid sensitivity, and addiction [1]. Our findings warrant further research to understand the mechanisms underlying specific at-risk overdose populations. We completely concur that results of our pilot study, as with all such investigations, will require validation in larger populations, an effort which is currently being addressed at our institution. Confirming our results would have significant impact in the field of addiction to pave the way for personalized prescription practices not only for opioids, but for those at risk for drug overdose. Our data which demonstrated higher overdose severity in G allele subjects, not limited to opioid drugs, is likely due to dopamine–opioid interactions in the mesolimbic/striatal pathways relevant to reward and habit formation. Indeed, several lines of evidence have established significant disturbances of the opioid system in association with various drugs of abuse [2, 3]. We therefore chose not to limit the analysis to only opioids given the biologic plausibility of enhanced abuse and addiction behaviors which apply for all drugs, not limited to opioids. To address our colleagues’ suggestion to eliminate sympathomimetics, such as cocaine, from the analysis, we would argue that it is equally plausible that OPRM1 variants affect the same reward pathways for sympathomimetics, and thus arbitrary removal of these exposures would actually introduce, not eliminate, bias. A question was also raised as to whether the 118G allele confers resistance rather than increased susceptibility as suggested by the findings of our study. Consistent with the results of our study, multiple investigations have reported an association of the 118G allele with opioid abuse [4–6]. However, the mu opioid receptor is involved in multiple physiological functions, thus the 118G allele could be beneficial for some processes, but adverse for others. Our colleagues also question whether race/ethnicity may have introduced confounding into our analysis. To truly control for the effect of racial bias, it would be necessary to not only gather self-reported data, which is difficult to gather on critically ill patients with altered mental status due to overdose, but also it would be necessary to perform additional analyses such as ancestral informative markers (AIMs), which we did not have available at the time. The poor specificity of racial/ethnic variables in addiction research is often compounded by failure to measure social and environmental exposures that track with self-identified race in the USA, thereby masking important gene–environment effects. Missing these effects means missing an opportunity to disentangle the complex social, environmental, behavioral, and genetic factors that interact to create disease and determine treatment outcomes [7]. To account for this, future studies of OPRM1 variants in overdose populations should gather social and environmental variables as well as perform AIMs analysis.

Gene Polymorphisms of OPRM1 A118G and ABCB1 C3435T May Influence Opioid Requirements in Chinese Patients with Cancer Pain

Polymorphisms of OPRM1 A118G and ABCB1 C3435T have been suggested to contribute to inter-individual variability regarding pain sensitivity, opioid usage, tolerance and dependence and incidence of adverse effects in patients with chronic pain. This study aimed to investigate the association of both two polymorphisms with opioid requirements in Chinese patients with cancer pain. The genotypes of rs1799971 (OPRM1) and rs1045642 (ABCB1) were determined by PCR-RFLP and direct sequencing methods respectively in 112 patients with cancer-related pain. Comparisons between the different genotype or allele groups were performed with t-tests or one-way ANOVA tests, as appropriate. The potential relationship of allele number with opioid response was performed with a trend Jonckheere-Terpstra test. In the 112 subjects, the frequencies of variant 118 G and 3435T allele were 38.4% and 37.9%, respectively. Significant higher 24h-opioid doses were observed in patients with GG (P=0.0004) and AG + GG (P=0.005) genotypes than the AA carriers. The dominant mutant 118G allele tended to be associated with progressively increasing 24h-opioiddoses (P=0.001). Compared with CC/CT, patients with ABCB1 TT genotype received higher 24h- and weight-surface area-adjusted-24h- opioids doses (P=0.057 and 0.028, respectively). The OPRM1 A118G single nucleotide polymorphism (SNP) is a key contributor for the inter-individual variability in opioidrequirements in Chinese cancer pain patients. This may possibly extend to the ABCB1 C3435T SNP.