OPRM1 118A Research Articles

Functional differences in the mu opioid receptor SNP 118A>G are dependent on receptor splice-variant andagonist-specific recruitment of β-arrestin.

The OPRM1 gene codes for the mu opioid receptor (MOR) and polymorphisms are associated with complex patient clinical responses. The most studied single nucleotide polymorphism (SNP) in OPRM1 is adenine (A) substituted by guanine (G) at position 118 (118A>G, rs1799971) leading to a substitution of asparagine (Asn) for aspartic acid (Asp) at position 40 in the N terminus of the resulting protein. To date, no structural explanation for the associated clinical responses resulting from the 118A>G polymorphism has been proposed. We utilized computational modeling paired with functional cellular assays to predict unstructured N- and C-terminal regions of MOR-1. Using molecular docking and post-docking energy minimizations with morphine, we show that the extracellular substitution of Asn at position 40 alters the cytoplasmic C-terminal conformation, while leaving the G-protein binding interface unaffected. A real-time BRET assay measuring G-protein and β-arrestin association with MOR r generated data that tested this prediction. Consistent with this in silico prediction, we show changes in morphine-mediated β-arrestin association with receptor variants with little change in morphine-mediated G-protein association comparing MOR-1 wild type (WT) to MOR-1118A>G. We tested the system with different opioid agonists, the OPRM1 118A>G SNP, and different MOR splice variants (MOR-1 and MOR-1O). These results are consistent with the observation that patients with the 118A>G OPRM1 allele respond more readily to fentanyl than to morphine. In conclusion, the 118A>G substitution alters receptor responses to opioids through variable C-terminal domain movements that are agonist and splice variant dependent.

The effects of OPRM1 118A>G on methadone response in pain management in advanced cancer at end of life

Cancer pain is the most feared symptom at end of life. Methadone has advantages over other opioids but is associated with significant variability in clinical response, making dosing challenging in practice. OPRM1 is the most studied pharmacogene associated with the pharmacodynamics of opioids, however reports on the association of the A118G polymorphism on opioid dose requirements are conflicting, with no reports including methadone as the primary intervention. This association study on OPRM1 A118G and response to methadone for pain management, includes a review of this genetic factor’s role in inter-patient variability. Fifty-four adult patients with advanced cancer were recruited in a prospective, multi-centre, open label dose individualization study. Patient characteristics were not shown to influence methadone response, and no significant associations were observed for methadone dose or pain score. The findings of our review of association studies for OPRM1 A118G in advanced cancer pain demonstrate the importance of taking ancestry into account. While our sample size was small, our results were consistent with European populations, but in contrast to studies in Chinese patients, where carriers of the A118G polymorphism were associated with higher opioid dose requirements. Pharmacogenetic studies in palliative care are challenging, continued contribution will support future genotype-based drug dosing guidelines.

MDR1 and OPRM1 genetic polymorphisms on the pharmacodynamics of propofol-remifentanil TIVA in pediatrics.

Aims: To investigate the roles of MDR1 (1236C>T, 2677G>T/A, and 3435C>T) and OPRM1 (118A>G) gene polymorphisms on the anesthetic and adverse effects of propofol-remifentanil total intravenous anesthesiain pediatric surgery. Materials & methods: The genotypes were identified through Sanger sequencing. The clinical data including hemodynamics on anesthesia, postanesthesia pain and sedation score and the occurrence of adverse effects were recorded and compared against the genetic data. Results: A total of 72 pediatric patients undergoing surgery were recruited. A weak to no association was found between the genetic polymorphisms of MDR1 and OPRM1 and the anesthetic and adverse effects of propofol-remifentanil. Conclusion: Genetic polymorphisms in OPRM1, but not in MDR1, gene polymorphism, demonstrated plausible association with the effects of propofol-remifentanil.

Effects of mu-opioid receptor, ATP-banding cassette, subfamily B, member 1 gene, CYP3A genetic polymorphisms on sufentanil consumption in postoperative tumor patients

Objective To investigate the association between postoperative sufentanil consumption and genetic polymorphisms of mu-opioid receptor (OPRM1), ATP-banding cassette, subfamily B, member 1 gene(ABCB1) and CYP3A in postoperative tumor patients. Methods A total of one hundred and twenty patients [American Society of Anesthesiologists (ASA) Ⅰor Ⅱ, aging 19 to 65] who were scheduled to undergo tumor surgery under general anesthesia were enrolled in this study. Intravenous patient-controlled analgesia with sufentanil was provided postoperatively. Cumulative sufentanil consumption was measured 2, 6, 12, 24 h and 48 h after surgery. The severity of pain was assessed with the Visual Analogue Scale(VAS), while OPRM1 118A>G, ABCB1 2677G>A/T, ABCB1 3435C>T, and CYP3A4*1G and CYP3A5*3 variant alleles were detected. The effects of genetic and non-genetic factors on sufentanil requirements were evaluated with multiple linear regression analysis. Results Patient VAS scores 2, 6, 12, 24 h and 48 h after surgery were obviously associated with cumulative sufentanil doses (P<0.05). The 48 h cumulative sufentanil dose after surgery was associated with age(P<0.05). Conclusions There was no association between OPRM1, ABCB1, CYP3A genetic polymorphisms and postoperative sufentanil consumption in tumor patients. Key words: Pharmacogenetics; Sufentanil; CYP3A; Mu-opioid receptor; ATP-banding cassette, subfamily B, member 1 gene

The Relevance of the OPRM1 118A&gt;G Genetic Variant for Opioid Requirement in Pain Treatment: A Meta-Analysis

Background: There is obvious difference in individual response to opioids. Many studies have examined the correlation between the μ-opioid receptor 1 (OPRM1) 118A&gt;G genetic variation and opioid requirement in pain treatment, but the conclusion remains elusive. Objectives: To investigate whether the OPRM1 118A&gt;G genetic variation is associated with the opioid requirement. Study Design: Systematic review and meta-analysis. Methods: PubMed, Cochrane library, and EMBASE databases were systematically searched up to May 5, 2018, using the keywords “OPRM1,” “genetic variant,” “opioid,” and “pain” to identify reviews or meta-analyses on this topic. Two independent reviewers performed the data extraction and assessed study quality. The authors investigated the standardized mean difference (SMD) of opioid requirement between AA homozygotes and G allele carriers. The authors also examined the association between the OPRM1 118A&gt;G genetic variation and adverse effects such as nausea and vomiting. Potential bias was assessed using the Egger’s test and the Begg’s test. Results: A total of 530 articles were retrieved from the databases searched, and 36 studies involving 8,609 patients were included in the final analysis. G allele carriers required a higher mean opioid dose (SMD: 0.17; 95% confidence interval [CI]: [0.12, 0.22]; P &lt; 0.001) and displayed less nausea risk difference (RD): –0.04; 95% CI: [–0.06, –0.01]), but the incident rate of vomiting has no relationship with the genetic variant than AA homozygotes in a random-effects meta-analysis. Although there was no evidence of publication bias (Begg’s test: P = 0.333; Egger’s: P = 0.561), heterogeneity was present among studies (I2 = 54.3%). In the subgroup meta-analyses, there was also significance observed in the postoperative pain setting. Limitations: In all of the articles reviewed, postoperative pain and cancer pain were mostly discussed except for one in other pain setting. Conclusions: In this meta-analysis, the results indicate the OPRM1 A118G polymorphism was associated with the opioid requirement and the adverse effects in pain treatment especially in postoperative pain. This may provide valuable information for clinicians to adopt personalized pain management by properly using the opioids in individual patients. Key words: OPRM1, genetic variation, opioid, pain, side effect, review, meta-analysis

μ-opioid receptor genetic polymorphisms and duration of epidural fentanyl analgesia during early labor.

Epidural fentanyl is commonly used for initiation of early labor analgesia. The aim of this prospective study is to test the hypothesis that duration of epidural fentanyl analgesia differs in nulliparous women requesting epidural analgesia in early labor who are variant allele carriers of the OPRM1 SNVs 118A>G rs1799971, IVS2+31G>A rs9479757, and IVS2+691G>C rs2075572. Two hundred and twenty parturients who received epidural analgesia with fentanyl were included in the 118A>G analysis, and a 196 sub-cohort was included in the IVS2+31G>A and IVS2+691G>C exploratory analysis. Peripheral blood DNA was genotyped using Taqman allele discrimination assays. One hundred and seventy-four subjects (79%; 95% CI: 74-84) were homozygous for the wild type OPRM1 118A>G SNV (AA), and forty-six subjects (21%; 95% CI: 16-26) were heterozygous AG (N.=40) or homozygous GG (N.=6) for the variant allele. The minor allele frequency (MAF) was hence 12%. The MAFs for the IVS2+31G>A and IVS2+691G>C SNVs in the sub-cohort of 196 participants were 5% and 59% respectively. There was no significant difference in duration of epidural fentanyl analgesia for the three SNVs (161±68 and 143±51 min for wild type and allele carriers of the 118A>G SNV respectively [P=0.08]). Similarly, no significant differences were shown with the visual analog scale scores, side effects, and satisfaction for each of the three SNVs. OPRM1 SNVs did not affect the duration of epidural fentanyl administered for early labor analgesia in nulliparous women. These results should be confirmed in patients receiving epidural opioids in other clinical settings.

Association of OPRM1 Polymorphisms With DSM-5–Defined Prescription Opioid Use Disorder Among Chronic Pain Patients on Opioid Therapy for Noncancer Pain

Background/Aims: The OPRM1 118A>G polymorphism (rs1799971) has been associated with susceptibility to drug misuse. Previously we assessed the association between single nucleotide polymorphisms (SNPs) located in OPRM1 genetic locus, including rs1799971 and rs6923231, and susceptibility to substance misuse among outpatients receiving long-term opioid therapy.

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.

Pharmacogenetics of opioid response.

For opioids requiring CYP2D6 O-demethylation to active metabolites, poor metabolizers have reduced metabolite formation and minimal pain reduction. Clinically, this has only reliably been shown for tramadol. Ultra-rapid metabolizers have an increased risk of toxicity especially for codeine. ABCB1 genetics show no consistent findings. In Asian populations, the high OPRM1 118A>G frequency associates with higher opioid dosage requirements. Clinical translation of opioid genetics is premature because many important pain and addiction phenotype factors contribute.

How Much Oxycodone Is Needed for Adequate Analgesia After Breast Cancer Surgery: Effect of the OPRM1 118A>G Polymorphism

Most clinically used opioids are mu-opioid receptor agonists. Therefore, genetic variation of the OPRM1 gene that encodes the mu-opioid receptor is of great interest for understanding pain management. A polymorphism 118A>G (rs1799971) within the OPRM1 gene results in a missense mutation and affects the function of the receptor. We studied the association between the 118A>G polymorphism and oxycodone analgesia and pain sensitivity in 1,000 women undergoing breast cancer surgery. Preoperatively, experimental cold and heat pain sensitivities were tested. Postoperative pain was assessed at rest and during motion. Intravenous oxycodone analgesia was titrated first by a research nurse and on the ward using a patient-controlled analgesia device. The primary endpoint was the amount of oxycodone needed for the first state of adequate analgesia. For each patient, the 118A>G polymorphism was genotyped using the Sequenom MassARRAY (Sequenom, San Diego, CA). The association between this variant and the pain phenotypes was tested using linear regression. The 118A>G variant was associated significantly with the amount of oxycodone requested for adequate analgesia (P = .003, β = .016). Collectively, oxycodone consumption was highest in individuals having the GG genotype (.16 mg/kg), lowest for those with the AA genotype (.12 mg/kg), and moderate for those having the AG genotype (.13 mg/kg). Furthermore, the G allele was associated with higher postoperative baseline pain ratings (P = .001, β = .44). No evidence of association with other pain phenotypes examined was observed. PerspectiveThis study demonstrates that the OPRM1 118A>G polymorphism was associated with the amount of oxycodone required in the immediate postoperative period. Although a significant factor for determining oxycodone requirement, the 118A>G polymorphism alone explained less than 1% of the variance. No association was found between 118A>G and experimental pain.

Rescue morphine in mechanically ventilated newborns associated with combined OPRM1 and COMT genotype.

Determine whether SNPs of OPRM1 118A>G (asn(40)asp), COMT 472G>A (val(158)met) and ARRB2 8622C>T are associated with morphine rescue in newborns on mechanical ventilation. This is a pharmacogenetic analysis of a randomized controlled trial in (pre)term newborns (n = 64) at a level III Neonatal Intensive Care Unit (NICU) who received placebo infusion and for whom need and dose for rescue morphine was documented. For OPRM1 and COMT separately, the expected risk for rescue morphine or morphine dose was not significantly increased. However, the combined OPRM1/COMT 'high-risk' genotype lead to a significant association with the need for rescue (OR: 5.12; 95% CI: 1.12-23.3; p = 0.035). No association was found between OPRM1/COMT 'high-risk' genotype and total morphine dose administered. Combined OPRM1 118A>G and COMT 472G>A genotype might serve as a predictor for the need of rescue morphine in premature and term newborns on mechanical ventilation.

Influence of UGT2B7,OPRM1 and ABCB1 Gene Polymorphisms on Postoperative Morphine Consumption

Therapeutic modulation of pain with morphine and other opioids is associated with significant variation in both effects and adverse effects in individual patients. Many factors including gene polymorphisms have been shown to contribute to the interindividual variability in the response to opioids. The aim of this study was to investigate the significance of UGT2B7, OPRM1 and ABCB1 polymorphisms for interindividual variability in morphine-induced analgesia in patients undergoing hysterectomy. The frequency of these polymorphisms was also investigated in forensic autopsies as morphine is also a very commonly abused drug. Blood samples were collected from 40 patients following abdominal hysterectomy, 24hr after initiation of analgesia through a patient-controlled analgesia (PCA) pump. Samples were genotyped and analysed for morphine and its metabolites. We also genotyped approximately 200 autopsies found positive for morphine in routine forensic analysis. Patients homozygous for UGT2B7 802C needed significantly lower dose of morphine for pain relief. The same trend was observed for patients homozygous for ABCB1 1236T and 3435T, as well as to OPRM1 118A. The dose of morphine in patients included in this study was significantly related to variation in UGT2B7 T802C. Age was significantly related to both dose and concentration of morphine in blood. Regression analysis showed that 30% of differences in variation in morphine dose could be explained by SNPs in these genes. The genotype distribution was similar between the forensic cases and the patients. However, the mean concentration of morphine was higher in forensic cases compared to patients. We conclude that gene polymorphisms contribute significantly to the variation in morphine concentrations observed in individual patients.

Association of OPRM1 and COMT Single-Nucleotide Polymorphisms With Hospital Length of Stay and Treatment of Neonatal Abstinence Syndrome

Neonatal abstinence syndrome (NAS) caused by in utero opioid exposure is a growing problem; genetic factors influencing the incidence and severity have not been previously examined. Single-nucleotide polymorphisms (SNPs) in the μ-opioid receptor (OPRM1), multidrug resistance (ABCB1), and catechol-o-methyltransferase (COMT) genes are associated with risk for opioid addiction in adults. To determine whether SNPs in the OPRM1, ABCB1, and COMT genes are associated with length of hospital stay and the need for treatment of NAS. Prospective multicenter cohort study conducted at 5 tertiary care centers and community hospitals in Massachusetts and Maine between July 2011 and July 2012. DNA samples were genotyped for SNPs, and then NAS outcomes were correlated with genotype. Eighty-six of 140 eligible mother-infant dyads were enrolled. Infants were eligible if they were 36 weeks' gestational age or older and exposed to methadone or buprenorphine in utero . Primary outcome measure was length of hospital stay, with between-group differences expressed as β and calculated with linear regression models. Secondary outcome measures included need for any medical treatment for NAS and treatment with 2 or more medications. Infants with the OPRM1 118A>G AG/GG genotype had shortened length of stay (β = -8.5 days; 95% CI, -14.9 to -2.1 days; P = .009) and were less likely to receive any treatment than AA infants (48% vs 72%; adjusted odds ratio, 0.76; 95% CI, 0.63-0.96; P = .006). The COMT 158A>G AG/GG genotype was associated with shortened length of stay (β = -10.8 days; 95% CI, -18.2 to -3.4 days; P = .005) and less treatment with 2 or more medications (18% vs 56%; adjusted odds ratio, 0.68; 95% CI, 0.55-0.86; P = .001) than the AA genotype. Associations with the ABCB1 SNPs were not significant. Among infants with NAS, variants in the OPRM1 and COMT genes were associated with a shorter length of hospital stay and less need for treatment. These preliminary findings may provide insight into the mechanisms underlying NAS.

Effects of genetic polymorphisms of OPRM1, ABCB1, CYP3A4/5 on postoperative fentanyl consumption in Korean gynecologic patients

Fentanyl, a μ-opioid receptor agonist, is a substrate of P-glycoprotein. Its metabolism is catalyzed by CYP3A4 and CYP3A5. The aim of this study was to investigate the association between postoperative fentanyl consumption and genetic polymorphisms of μ-opioid receptor (OPRM1), ABCB1 (gene encoding P-glycoprotein), CYP3A4 and CYP3A5 in Korean patients. 196 female patients scheduled to undergo total abdominal hysterectomy or laparoscopic assisted vaginal hysterectomy under general anesthesia were enrolled in this study. Intravenous patient-controlled analgesia with fentanyl was provided postoperatively. Cumulative fentanyl consumption was measured during the first 48 hours postoperatively. The severity of pain at rest was assessed with the visual analogue scale. OPRM1 118A>G, ABCB1 2677G>A/T, ABCB1 3435C>T, CYP3A4*18 and CYP3A5*3 variant alleles were genotyped. The effects of genetic and non-genetic factors on fentanyl requirements were evaluated with multiple linear regression analysis. The 24-hour cumulative fentanyl doses were significantly associated with pain core, weight and type of surgery (p < 0.05). The 48-hour cumulative fentanyl doses were significantly associated with pain score, type of surgery and history of PONV or motion sickness (p < 0.05). Genetic polymorphisms were not associated with fentanyl requirements. In Korean gynecologic patients, no association was found between genetic factors and postoperative fentanyl consumption.

Genetic–epigenetic interaction modulates µ-opioid receptor regulation

Genetic and epigenetic mechanisms play important roles in protein expression, although at different levels. Genetic variations can alter CpG sites and thus influence the epigenetic regulation of mRNA expression, providing an increasingly recognized mechanism of functional consequences of genetic polymorphisms. One of those genetic effects is the association of reduced μ-opioid receptor expression with the functional genetic variant N40D (OPRM1 118A>G, rs1799971) that causes an amino acid exchange in the extracellular terminal of the μ-opioid receptor. We report that the nucleotide exchange at gene position +118 introduces a new CpG-methylation site into the OPRM1 DNA at position +117. This leads to an enhanced methylation of the OPRM1 DNA at this site and downstream. This epigenetic mechanism impedes μ-opioid receptor upregulation in brain tissue of Caucasian chronic opiate addicts, assessed postmortem. While in wild-type subjects, a reduced signalling efficiency associated with chronic heroin exposure was compensated by an increased receptor density, this upregulation was absent in carriers of the 118G receptor variant due to a diminished OPRM1 mRNA transcription. Thus, the OPRM1 118A>G SNP variant not only reduces µ-opioid receptor signalling efficiency, but, by a genetic-epigenetic interaction, reduces opioid receptor expression and therefore, depletes the opioid system of a compensatory reaction to chronic exposure. This demonstrates that a change in the genotype can cause a change in the epigenotype with major functional consequences.

Micro Opioid Receptor A118G Polymorphism and Post-Operative Pain: Opioids' Effects on Heterozigous Patients

The single-nucleotide-polymorphism (SNP) 118A>G in the micro-1 opioid receptor gene (OPRM1) is associated with a decrease in the analgesic effects of opioids. The aim of this study is to assess whether 118A >G polymorphism could influence the analgesic response to opioid-based postoperative pain (POP) therapy. The study consisted of two parts: section alpha, observational, included 199 subjects undergoing scheduled surgical procedures with pain management standardized on surgery invasiveness and on expected level of postoperative pain; section beta, randomized, included 41 women undergoing scheduled caesarean delivery with continuous intra-operative epidural anesthesia and post-operative analgesia (CEA). In both sections, POP was measured over 48 h (T6h-T24h-T48h) by the visual analogue scale (VAS). In section beta we also tested the responsiveness of hypothalamic-pituitary-adrenal axis (HPA) expressed by cortisol levels. In section alpha, with cluster analysis, subjects were analyzed according to their genotype: a group (no. 1) of 34 patients reporting VAS score >3 at every time lapse was identified and included only A118G carriers, while wild-type (A118A - absence of 118A>G polymorphism) patients were unevenly distributed between those with cluster no. 2 (VAS score <3 at every study steps) and those with cluster no. 3 (VAS score progressively reducing from T6h). In section beta, A118G carriers receiving epidural sufentanil had the lowest VAS scores at T24h; also in these patients, cortisol levels remained more stable, with a mild decrease at T6h. This study shows that the OPRM1 118A>G polymorphism affects postoperative pain response in heterozygous patients: they have a different postoperative pain response than patients with wild-type genes, which may affect the efficacy of the analgesic therapy.

Polymorphism of the μ-Opioid Receptor Gene (OPRM1 118A&gt;G) Affects Fentanyl-Induced Analgesia During Anesthesia and Recovery

There is much variation in the response of both individuals and different ethnic populations to opioids, with genetic differences being responsible for interindividual variation. The micro-opioid receptor single nucleotide polymorphism (rs number 1799971) at nucleotide position 118 (OPRM1 118A>G) affects the analgesic response to opioids. This study aimed to investigate the association between the OPRM1 118A>G polymorphism and the effects of fentanyl-induced analgesia, respiratory depression, and anesthetic recovery responses in a population of Han Chinese patients. The study was a case series in a hospital setting, with 1 year of study and 1 year of follow-up. A total of 189 patients (92 males and 97 females; American Society of Anesthesiologists Physical Status I or II, Glasgow Coma Scale = 15) who were scheduled for laparoscopic abdominal surgery received intravenous midazolam (Versed) 0.08-0.01 mg/kg and fentanyl (Duragesic) 5.0 microg/kg. The main outcome measure was the degree of postoperative pain, as assessed using the Visual Analog Scale (VAS). VAS scores were recorded 5, 15, 30, 45, and 60 minutes after a fentanyl bolus injection in the post-anesthesia care unit (PACU). The minute expiratory volume, end-tidal carbon dioxide concentration (EtCO(2)) and respiratory rate (RR) were measured continuously. The incidence of fentanyl-induced respiratory depression (RR <8/min and EtCO(2) >45 mmHg) was recorded at its appearance and treated with respiratory assistance. Blood gas analysis was done 15, 30, 45, and 60 minutes after extubation. These parameters were correlated with genotyping results of genomic DNA extracted from whole blood. Patients with the OPRM1 118 AG or GG genotypes had significantly higher VAS pain scores 15 and 30 minutes after a fentanyl bolus injection in the PACU than AA genotype patients (p < 0.05). A small but statistically significant difference was observed between the 118 AA and 118 AG/GG genotypes with regard to the carbon dioxide arterial pressure (PaCO(2)) at 15 and 30 minutes from the fentanyl bolus injection after extubation (p < 0.05); however, no clinically significant difference in the frequency of respiratory depression was seen. Homozygous 118 GG genotype patients had a significantly shorter time to awakening (p = 0.018) and extubation (p = 0.024) than patients with the 118 AA genotype. When the 118 GG and 118 AG genotypes were combined for analysis, a significantly shorter time to awakening (p = 0.011) and extubation (p = 0.010), compared with the 118 AA genotype, was also seen. The OPRM1 118A>G polymorphism lessens the analgesic response to fentanyl and the time to awakening and extubation but has no clinically significant effect on the incidence of respiratory depression.

Meta-analysis of the relevance of the OPRM1 118A>G genetic variant for pain treatment

Regard of functional pharmacogenetic polymorphisms may further the success of pain therapy by adopting individualized approaches. The μ-opioid receptor gene ( OPRM1) 118A >G polymorphism is a promising candidate for both opioid effects and pain because of both biological reasonability and apparent experimental and clinical evidence. We analyzed its importance for pain therapy using a meta-analytic approach to studies relating it to opioid pain therapy. Data from suitable studies selected from hits of a PubMed search for “OPRM1” were independently extracted by two authors. The meta-analysis included phenotypes by OPRM1 genotype (opioid dosing, pain, and side effects), publication year, diagnostic status, proportion of male study participants, and whether genotype frequencies agreed with Hardy–Weinberg equilibrium. We found no consistent association between OPRM1 118A >G genotypes and most of the phenotypes in a heterogeneous set of eight clinical studies. Only weak evidence of an association with less nausea (effect size, Cohen’s d = −0.21, p = 0.037) and of increased opioid dosage requirements ( d = 0.56, p = 0.018) in homozygous carriers of the G allele was obtained. This indicates that despite initially promising results, available evidence of the clinical relevance of the OPRM1 118A >G polymorphism does not withhold a meta-analysis. This discourages basing personalized therapeutic concepts of pain therapy on OPRM1 118A >G genotyping at the present state of evidence.

Cross-sectional analysis of the influence of currently known pharmacogenetic modulators on opioid therapy in outpatient pain centers

A finite number of variants in the OPRM1, COMT, MC1R, ABCB1 and CYP2D6 genes has been identified to significantly modulate the effects of opioids in controlled homogenous settings. We analyzed the imprint of these variants in opioid therapy in a highly variable cohort of pain patients treated in outpatient units to test whether genotyping may play a role in this clinical setting. In a multicenter study conducted in tertiary care outpatient pain centers, 352 patients (156 men and 196 women, aged 58.5+/- 14.6 years) treated for 1-600 months (63.4 +/- 92.4 months) with various opioids for pain of various origins were included. Genotyping was performed for all the variants reportedly modulating pain in well-defined cohorts. Association analyses focused on opioid dosing, the actual 24-h pain score on a 0-10 rating scale and the occurrence of side effects. The frequency of the genetic variants in the patients did not significantly differ from that in the average Caucasian population. Daily opioid doses ranged from 4 to 1750 mg oral morphine equivalents (133.4 +/- 203.2 mg) and significantly decreased in a gene dose-dependent manner with the P-glycoprotein variant ABCB1 3435C>T. Pain was rated on average at 3.7 +/- 2.6. There was a tendency towards increased pain in a gene dose-dependent manner with the mu-opioid receptor variant OPRM1 118A>G. Genetics were reflected in the outpatient pain therapy only to a modest degree. The need of outpatient therapy of pain of various causes guided by the presently known functional genetic variants cannot be convincingly concluded from the present data. Using the ABCB1 3435 genotype to predefine lower individual opioid doses barely merits the laboratory effort. If any, the results suggest that a genetics guided outpatient pain therapy may be based on ABCB1 and OPRM1 variants.

Differential Opioid Action on Sensory and Affective Cerebral Pain Processing

Low doses of morphine, the most commonly used opioid analgesic, have been shown to significantly reduce the affective but not the sensory intensive dimension of pain. This suggests differential dose-response relationships of opioid analgesia on the sensory and affective components of pain. We investigated the effects of different alfentanil plasma concentration levels (0, 19.6+/-2.7, 47.2+/-7.6, and 76.6+/-11.3 ng/ml) on pain-related brain activation achieved by short pulses of gaseous CO(2) delivered to the nasal mucosa, using functional magnetic resonance imaging (fMRI) on a 3.0 T MRI scanner in 16 non-carriers and 9 homozygous carriers of the mu-opioid receptor gene variant OPRM1 118A>G. Increasing opioid concentrations had differential effects in brain regions processing the sensory and affective dimensions of pain. In brain regions associated with the processing of the sensory intensity of pain (primary and secondary somatosensory cortices, posterior insular cortex), activation decreased linearly in relation to alfentanil concentrations, which was significantly less pronounced in OPRM1 118G carriers. In contrast, in brain regions known to process the affective dimension of pain (parahippocampal gyrus, amygdala, anterior insula), pain-related activation disappeared at the lowest alfentanil dose, without genotype differences.