OPRM1, OPRK1, and COMT genetic polymorphisms associated with opioid effects on experimental pain: a randomized, double-blind, placebo-controlled study.
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SUBMITTER: Ho KWD
PROVIDER: S-EPMC7260086 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:mu-opioid receptor ( OPRM1) and catechol-O-methyltransferase ( COMT) contribute to the neurotransmission pathway of pain. COMT affects mu receptor expression and density in the brain. The aim of this study was to explore the OPRM1 and COMT interaction effects on postoperative pain and opioid consumption. METHODS:This cross-sectional exploratory study used genotype and clinical data from 153 postoperative patients. Using multiple regression analyses, four single-nucleotide polymorphisms of COMT (rs6269, rs4633, rs4818, and rs4680), their haplotypes, and diplotypes were considered for their interactions with A118G of OPRM1 regarding postoperative pain and opioid consumption. RESULTS:For opioid consumption, significant interactions were found between OPRM1 A118G and COMT rs4680 ( p = .037) and between OPRM1 and COMT rs4633 ( p = .037). Patients having Met158Met of COMT rs4680 and AG/GG of OPRM1 or TT of COMT rs4633 and AG/GG of OPRM1 consumed the largest amount of opioid compared to those having other combinations. For postoperative pain, a significant interaction was found between OPRM1 and the low pain sensitivity (LPS; GCGG) haplotype of COMT ( p = .017). For patients with no copies of the LPS haplotype, AA of OPRM1 A118G was significantly associated with higher pain scores compared to the variant AG/GG. However, the opposite direction was observed for patients with at least one copy of the LPS haplotype. CONCLUSIONS:The interaction of OPRM1 with COMT may contribute to variability in postoperative pain and opioid consumption. Additional larger studies are needed to confirm findings.
| S-EPMC5942486 | biostudies-literature
Project description:ObjectiveWe investigated whether single nucleotide polymorphisms (SNPs) associated with neuroplasticity and activity of monoamine neurotransmitters, such as the brain-derived neurotrophic factor (BDNF, rs6265), the serotonin transporter (SLC6A4, rs25531), the tryptophan hydroxylase 1 (TPH1, rs1800532), the 5-hydroxytryptamine receptor 2A (HTR2A, rs6311, rs6313, rs7997012), and the catechol-O-methyltransferase (COMT, rs4680) genes, are associated with efficacy of transcranial direct current stimulation (tDCS) in major depression.MethodsData from the Escitalopram vs. Electrical Current Therapy for Treating Depression Clinical Study (ELECT-TDCS) were used. Participants were antidepressant-free at baseline and presented with an acute, moderate-to-severe unipolar depressive episode. They were randomized to receive escitalopram/tDCS-sham (n=75), tDCS/placebo-pill (n=75), or placebo-pill/sham-tDCS (n=45). General linear models assessed the interaction between treatment group and allele-wise carriers. Additional analyses were performed for each group and each genotype separately.ResultsPairwise group comparisons (tDCS vs. placebo, tDCS vs. escitalopram, and escitalopram vs. placebo) did not identify alleles associated with depression improvement. In addition, exploratory analyses also did not identify any SNP unequivocally associated with improvement of depression in any treatment group.ConclusionLarger, combined datasets are necessary to identify candidate genes for tDCS response.
| S-EPMC7115450 | biostudies-literature
Project description:Background: Kratom has a long history of traditional medicine use in Southeast Asia. Consumption of kratom products has also been reported in the US and other regions of the world. Pain relief is among many self-reported kratom effects but have not been evaluated in controlled human subject research. Methods: Kratom effects on pain tolerance were assessed in a randomized, placebo-controlled, double-blind study. During a 1-day inpatient stay, participants received a randomized sequence of kratom and placebo decoctions matched for taste and appearance. Pain tolerance was measured objectively in a cold pressor task (CPT) as time (seconds) between the pain onset and the hand withdrawal from the ice bath. Health status, vital signs, objective, and subjective indicators of withdrawal symptoms, self-reported data on lifetime kratom use patterns, and assessments of blinding procedures were also evaluated. Results: Twenty-six males with the mean (SD) age 24.3 (3.4) years were enrolled. They reported the mean (SD) 6.1 (3.2) years of daily kratom consumption. Pain tolerance increased significantly 1 hour after kratom ingestion from the mean (SD) 11.2 (6.7) seconds immediately before to 24.9 (39.4) seconds 1 hour after kratom consumption (F(2,53.7)=4.33, p=0.02). Pain tolerance was unchanged after consuming placebo drinks: 15.0 (19.0) seconds immediately before and 12.0 (8.1) seconds 1 hour after consumption of placebo (F(2,52.8)=0.93, p=0.40). No discomfort or signs of withdrawal were reported or observed during 10-20 hours of kratom discontinuation. Conclusions: Kratom decoction demonstrated a substantial and statistically significant increase in pain tolerance. Further rigorous research on kratom pain-relieving properties and a safety profile is needed.
| S-EPMC7309661 | biostudies-literature
Project description:Mu-opioid receptors (MOPRs) are critically involved in the modulation of pain and analgesia, and represent a candidate mechanism for the development of biomarkers of pain conditions and their responses to treatment. To further understand the human implications of genetic variation within the opioid system in pain and opioid-mediated placebo responses, we investigated the association between the functional single-nucleotide polymorphism (SNP) in the μ-opioid receptor gene (OPRM1), A118G, and psychophysical responses, personality traits, and neurotransmitter systems (dopamine (DA), opioid) related to pain and placebo analgesia. OPRM1 G carriers, compared with AA homozygotes, showed an overall reduction of baseline μ-opioid receptor availability in regions implicated in pain and affective regulation. In response to a sustained painful stimulus, we found no effect of A118G on pain-induced endogenous opioid release. Instead, AA homozygotes showed a blunted DA response in the nucleus accumbens (NAc) in response to the pain challenge. After placebo administration, G carriers showed more pronounced mood disturbances and lower placebo-induced μ-opioid system activation in the anterior insula (aINS), the amygdala (AMY), the NAc, the thalamus (THA), and the brainstem, as well as lower levels of DA D2/3 activation in the NAc. At a trait level, G carriers reported higher NEO-Neuroticism scores; a personality trait previously associated with increased pain and lower placebo responses, which were negatively correlated with baseline μ-opioid receptor availability in the aINS and subgenual anterior cingulate cortex (sgACC). Our results demonstrate that the A118G OPRM1 polymorphism contributes to interindividual variations in the function of neurotransmitters responsive to pain (endogenous opioid and dopamine), as well as their regulation through cognitive-emotional influences in the context of therapeutic expectations, the so-called placebo effect. These effects are relevant to human vulnerability to disease processes where these neurotransmitters have a role, such as persistent pain, mood, and substance use disorders, and responses to their treatments.
| S-EPMC4330509 | biostudies-literature
Project description:Genetics studies on the placebo hypoalgesic effect highlight a promising link between single nucleotide polymorphisms (SNPs) in the dopamine, opioid, and endocannabinoid genes and placebo hypoalgesia. However, epistasis and replication studies are missing. In this study, we expanded on previous findings related to the 3 SNPs in the opioid receptor mu subunit (OPRM1 rs1799971), catechol-O-methyltransferase (COMT rs4680), and fatty acid amide hydrolase (FAAH rs324420) genes associated with placebo hypoalgesia and tested the effect of a 3-way interaction on placebo hypoalgesia. Using 2 well-established placebo procedures (verbal suggestion and learning paradigm), we induced significant placebo hypoalgesic effects in 160 healthy participants. We found that individuals with OPRM1 AA combined with FAAH Pro/Pro and those carrying COMT met/met together with FAAH Pro/Pro showed significant placebo effects. Participants with COMT met/val alleles showed significant placebo effects independently of OPRM1 and FAAH allele combinations. Finally, the model that included the placebo procedure and genotypes predicted placebo responsiveness with a higher accuracy (area under the curve, AUC = 0.773) as compared to the SNPs alone indicating that genetic variants can only partially explain the placebo responder status. Our results suggest that the endogenous mu-opioid system with a larger activation in response to pain in the met/val allele carriers as well as the synergism between endogenous mu-opioid system and cannabinoids might play the most relevant role in driving hypoalgesic responses. Future epistasis studies with larger sample sizes will help us to fully understand the complexity of placebo effects and explain the mechanisms that underlie placebo responsiveness.
| S-EPMC6668362 | biostudies-literature
Project description:Analgesic-response variability in chronic noncancer pain (CNCP) has been reported due to several biological and environmental factors. This study was undertaken to explore sex differences linked to OPRM1 and COMT DNA methylation changes and genetic variants in analgesic response. A retrospective study with 250 real-world CNCP outpatients was performed in which data from demographic, clinical, and pharmacological variables were collected. DNA methylation levels (CpG island) were evaluated by pyrosequencing, and their interaction with the OPRM1 (A118G) and COMT (G472A) gene polymorphisms was studied. A priori-planned statistical analyses were conducted to compare responses between females and males. Sex-differential OPRM1 DNA methylation was observed to be linked to lower opioid use disorder (OUD) cases for females (p = 0.006). Patients with lower OPRM1 DNA methylation and the presence of the mutant G-allele reduced opioid dose requirements (p = 0.001), equal for both sexes. Moreover, COMT DNA methylation levels were negatively related to pain relief (p = 0.020), quality of life (p = 0.046), and some adverse events (probability > 90%) such as constipation, insomnia, or nervousness. Females were, significantly, 5 years older with high anxiety levels and a different side-effects distribution than males. The analyses demonstrated significant differences between females and males related to OPRM1 signalling efficiency and OUD, with a genetic-epigenetic interaction in opioid requirements. These findings support the importance of sex as a biological variable to be factored into chronic pain-management studies.
| S-EPMC10219447 | biostudies-literature
Project description:The potential synergistic effects of combining cannabinoids and opioids for analgesia has received considerable attention. No studies to date have evaluated this combination in patients with chronic pain. The present study aimed to evaluate the combined analgesic and drug effects of oral opioid (hydromorphone) and delta-9-tetrahydrocannabinol (dronabinol), as well as their effects on physical and cognitive functioning, and human abuse potential (HAP) outcomes among individuals with knee osteoarthritis (KOA). This was a within-subject, double-blind, randomized, placebo-controlled study. Participants (N = 37; 65% women; mean age = 62) diagnosed with knee osteoarthritis of ≥3/10 average pain intensity were included. Participants received (1) placebo-placebo, (2) hydromorphone (4 mg)-placebo; (3) dronabinol (10 mg)-placebo, and (4) hydromorphone (4 mg)-dronabinol (10 mg). Clinical and experimentally-induced pain, physical and cognitive function, subjective drug effects, HAP, adverse events, and pharmacokinetics were evaluated. No significant analgesic effects were observed for clinical pain severity or physical functioning across all drug conditions. Little enhancement of hydromorphone analgesia by dronabinol was observed on evoked pain indices. While subjective drug effects and some HAP ratings were increased in the combined drug condition, these were not significantly increased over the dronabinol alone condition. No serious adverse events were reported; hydromorphone produced more mild adverse events than placebo, but hydromorphone + dronabinol produced more moderate adverse events than both placebo and hydromorphone alone. Only hydromorphone impaired cognitive performance. Consistent with laboratory studies on healthy adults, the present study shows minimal benefit of combining dronabinol (10 mg) and hydromorphone (4 mg) for analgesia and improving physical functioning in adults with KOA.
| S-EPMC10516978 | biostudies-literature
Project description:Objective. To investigate the effects of modified Hungqi Guizhi Wuwu Tang (MHGWT), a formula that comprises Chinese medicinal herbs, in relieving neuropathic pain in diabetics. Method. Between March 2008 and April 2009, 112 participants were randomly assigned to either the MHGWT group, whose members received MHGWT (n = 56), or the control group, whose members received a placebo (n = 56). Diabetic neuropathic pain (DNP) was rated using the 15-item Short-Form Brief Pain Inventory (SF-BPI), the 17-item Short-Form McGill Pain Questionnaire (SF-MPQ), the 13-item Modified Michigan Neuropathy Screening Instrument (MMNSI), and the 36-item "SF-36." Nerve conduction studies (NCSs) were performed before and after treatment. Results. After 12 weeks of treatment, the SF-MPQ and SF-BPI scores of the MHGWT group were significantly (P < 0.05) reduced and a significant difference between the groups was observed (P < 0.05). The levels of NCS in the MHGWT group were nonsignificantly (P > 0.05) reduced, and no significant difference in NCS level was observed between the groups (P > 0.05). Conclusions. MHGWT shows promise in relieving DNP and deserves further investigation.
| S-EPMC3766986 | biostudies-other
Project description:BackgroundOsteoarthritis (OA) of the knee is a common and increasingly prevalent condition that is one of the primary causes of chronic pain. Staying physically active protects against disability from knee OA but is also very challenging. A critical but unexamined question is whether patients at greatest risk for becoming less active are those with a genetic predisposition for greater sensitivity to daily pain.AimsWe examined day-to-day variability in knee OA pain for patients with different variants of catechol-O-methyltransferase (COMT) and mu-opioid receptor (OPRM1) single nucleotide polymorphisms (SNPs), and whether patients with a specific genotype experience more pain following daily physical activity. We predicted that patients having one or more copies of the Met158 allele of COMT rs4680 (A-A or A-G) and one or more copies of the Asp40 allele of OPRM1 rs1799971 (A-G or G-G) would show greater pain variability. We expected to see the same pattern for these SNPs with regard to moderation (i.e., exacerbation) of the activity-pain association.MethodsA total of 120 knee OA patients reported on their pain 3 times per day over 22 days using handheld computers, and wore an accelerometer to capture daily physical activity. Multilevel modeling was used to examine the magnitude of within-person variability in pain by genetic group. We also examined whether lagged, within-patient associations between level of activity in the afternoon (i.e., minutes of moderate intensity activity, and number of steps) and knee pain at the end-of-day were moderated by between-patient differences in genotype.ResultsRegarding OPRM1 rs1799971 (Asn40Asp), patients with two copies of the Asn40 allele showed the greatest day-to-day pain variability. Regarding COMT rs4680 (Val158Met), patients with the Val/Val genotype showed the greatest pain variability and also experienced the greatest increase in pain as a result of physical activity. A similar pattern of findings across bi-directional temporal lags was consistent with a negative feedback loop between daily physical activity and pain according to genotype. Consistent with some previous studies, there were no significant between-person differences in daily pain when comparing patients according to COMT rs4680, or OPRM1 rs1799971.ConclusionThis study provides preliminary evidence that patients with certain genotypes for COMT rs4680 and OPRM1 rs1799971 (G-G and A-A, respectively) experience more variability in their day-to-day pain and exacerbation of pain after daily physical activity compared to patients with other genotypes. Our findings should be replicated in larger study populations.ImplicationsPrevious clinical research has focused primarily on differences in average level of pain between patients with and without a specific genotype. Assessment of within-person variability through repeated measurements in daily life enhances the reliability, power, and ecological validity of phenotypic measurement.
| S-EPMC4548933 | biostudies-literature
Project description:Chronic shoulder pain and disability is a common adverse effect experienced by >40% of breast cancer survivors (BCS). Pain management protocols for acute and chronic pain include the use of opioids and opioid derivatives. Furthermore, pain-modulating genes, such as COMT and OPRM1, have been linked to the aetiology of chronic pain. This study aimed to investigate the association between genetic variants of major pain modulator genes and chronic pain/disability in BCS. Assessment of pain, disability and combined (pain and disability) symptoms were determined using the Shoulder Pain and Disability Index (SPADI). Participants were grouped according to their scores such as no-low (<30%) and moderate-high (≥30%) groups of pain, disability and combined (pain and disability). Genotyping of the COMT rs6269 (A > G), rs4633 (C > T), rs4818 (C > G) and the functional rs4680(G > A) SNPs within the BCS (N = 252) cohort were conducted using TaqMan® SNP assays. Genotype, allele, haplotype, and allele-allele combination frequencies were evaluated. Statistical analysis was applied, with significance accepted at p < 0.05. The COMT rs4680:A/A genotype was significantly associated with moderate-high pain (p = 0.024, OR: 3.23, 95% CI: 1.33-7.81) and combined (pain and disability) (p = 0.015, OR: 3.81, 95% CI: 1.47-9.85). The rs4680:A allele was also significantly associated with moderate-high pain (p = 0.035, OR: 1.58, 95% CI: 1.03-2.43) and combined (pain and disability) (p = 0.017, OR: 1.71, 95% CI: 1.07-2.71). For the inferred COMT (rs6269 A > G-rs4680 G > A) haplotype analyses, the G-G (p = 0.026, OR: 0.67, 95% CI: 0.38-1.18) and A-A (p = 0.007, OR: 2.09, 95% CI: 0.89-4.88) haplotypes were significantly associated with reduced and increased likelihoods of reporting moderate-high pain, respectively. The inferred A-A (p = 0.003, OR: 2.18, 95% CI: 0.92-5.17) haplotype was also significantly associated with combined (pain and disability). Gene-gene interaction analyses further showed allele-allele combinations for COMT (rs4680 G > A)-OPRM1 (rs1799971 A > G) and COMT (rs4680 G > A)-OPRM1(rs540825 T > A) were associated with reporting pain and combined (pain and disability) symptoms, p < 0.05. The findings of this study suggest that COMT and OPRM1 SNPs play a role in the development of chronic shoulder pain/disability in BCS in a unique South African cohort from the Western Cape.
| S-EPMC9858584 | biostudies-literature