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1.
Medicine (Baltimore) ; 99(5): e18924, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32000405

RESUMO

Adiponectin is an adipose tissue-derived cytokine that exerts its antiinflammatory effects by binding to 2 adiponectin receptors, adiponectin receptor 1 (ADIPOR1) and adiponectin receptor 2 (ADIPOR2). However, the role of these adiponectin receptors on inflammatory pain remains unclear. We investigated the association between single nucleotide polymorphisms (SNPs) of these genes and inflammatory pain, such as postoperative pain and cancer pain.We analyzed 17 SNPs of the ADIPOR1 gene and 27 SNPs of the ADIPOR2 gene in 56 adult patients with postlaparotomy pain. We compared these genotypes with pain intensity and opioid consumption, adjusting for multiple testing. We analyzed the genotypes of 88 patients with cancer pain and examined the association of the relevant SNP(s) with pain intensity and opioid consumption.One variant of the ADIPOR1 gene (rs12045862) showed significant association with postoperative pain intensity; patients with minor allele homozygote (n = 7) demonstrated significantly worse pain intensity than that of combined patient group exhibiting major allele homozygote or the heterozygote (n = 49; Mann-Whitney test, P < .00002), although their opioid consumptions were comparable. Cancer pain intensity between minor allele homozygote patients (n = 7) and other 2 genotype patients (n = 81) were comparable.The rs12045862 SNP of the ADIPOR1 gene was associated with postoperative pain but not cancer pain. This might result from functional alteration of the ADIPOR1 signalling pathways, which influence the inflammatory process. ADIPOR1 may be a novel potential target for developing analgesics of postoperative pain.


Assuntos
Dor do Câncer/genética , Dor Pós-Operatória/genética , Polimorfismo de Nucleotídeo Único , Receptores de Adiponectina/genética , Analgésicos Opioides/uso terapêutico , Dor do Câncer/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/cirurgia , Feminino , Estudos de Associação Genética , Humanos , Inflamação/genética , Laparotomia , Masculino , Pessoa de Meia-Idade , Medição da Dor , Dor Pós-Operatória/tratamento farmacológico
2.
Anaesthesia ; 75 Suppl 1: e111-e120, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31903573

RESUMO

Chronic postoperative pain is common and can have a negative impact on quality of life. Recent studies show that genetic risk factors are likely to play a role, although only gene-targeted analysis has been used to date. This is the first genome-wide association study to identify single-nucleotide polymorphisms associated with the development of chronic postoperative pain based on two independent cohorts. In a discovery cohort, 330 women scheduled for hysterectomy were genotyped. A case-control association analysis compared patients without chronic postoperative pain and the 34 who had severe chronic postoperative pain 3 months after surgery. No single-nucleotide polymorphisms reached genome-wide significance, but several showed suggestive associations with chronic postoperative pain (p < 1 × 10-5 ). Single-nucleotide polymorphisms with significance p < 1 × 10-5 were followed up in a replication cohort consisting of 203 men and women scheduled for orthopaedic or abdominal surgery. Ten of these patients developed severe chronic postoperative pain. A single-nucleotide polymorphism in NAV3 was significantly replicated with chronic postoperative pain in the replication cohort (p = 0.009). Meta-analysis revealed that two loci (IQGAP1 and CRTC3) were significantly associated with chronic postoperative pain at 3 months (IQGAP1 p = 3.93 × 10-6 ß = 2.3863, CRTC3 p = 2.26 × 10-6 , ß = 2.4209). The present genome-wide association study provides initial evidence for genetic risk factors of chronic postoperative pain and supports follow-up studies.


Assuntos
Dor Crônica/genética , Estudo de Associação Genômica Ampla/métodos , Dor Pós-Operatória/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos
3.
Br J Anaesth ; 123(6): 853-864, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31558312

RESUMO

Chronic post-surgical pain (CPSP) is a debilitating condition affecting 10-50% of surgical patients. The current treatment strategy for CPSP is not optimal, and the identification of genetic variation in surgical patients might help to improve prediction and treatment of CPSP. The neurotransmitter dopamine (DA) has been associated with several chronic pain disorders. This narrative review focuses on DA neurotransmission as a potential target in the treatment of CPSP. The current knowledge on genetic variation within DA neurotransmission and its role in CPSP susceptibility are reviewed. Three genes involved in DA neurotransmission (COMT, GCH1, and DRD2) have been associated with variability in pain sensitivity, development of CPSP, and analgesic requirement. The direction of the effect of the association is sometimes inconclusive because of contradictory results, but ample evidence suggests a modulatory role of DA. Because of this modulatory role, DA is an excellent pharmacological target in the treatment of pain. Pharmacotherapy focused on DA neurotransmission has potential in both prevention (via D1-like receptors) and treatment (via D2-like receptors and DA reuptake inhibitors) of CPSP. The development of prediction models including genetic risk factors is necessary to better identify patients at risk.


Assuntos
Dopamina/metabolismo , Variação Genética/genética , Dor Pós-Operatória/genética , Dor Pós-Operatória/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Dor Crônica/genética , Dor Crônica/metabolismo , Dopamina/genética , Humanos , Transmissão Sináptica/genética
4.
Medicine (Baltimore) ; 98(34): e16706, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31441843

RESUMO

OBJECTIVE: Postoperative chronic pain is characterized by high incidence, long duration, and complex pathogenesis. The purpose of this study was to investigate the correlation between the single nucleotide polymorphisms of the CCL2 gene rs4586 (g.5974T>C), CALCA rs3781719 (-692T>C), CX3CL1 rs614230 (2342C>T), and the risk of postoperative chronic pain in Chinese Han women. METHODS: We analyzed the CCL2 gene rs4586, CALCA rs3781719, CX3CL1 rs614230 single nucleotide polymorphism (SNPs) of 350 Chinese Han women with chronic postsurgical pain (CPSP) 6 months after cesarean section and 350 healthy women without chronic pain (HC). The levels of CCL2, CALCA, and CX3CL1 in serum were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: The CCL2 rs4586 T allele and the CX3CL1 gene rs614230C allele were protective factors for CPSP risk (adjusted OR = 0.766, 95% CI: 0.675-0.865 and OR = 0.336, 95% CI: 0.644-0.835). The CALCA gene rs3781719C allele was a risk factor for CPSP (adjusted OR = 1.273, 95% CI: 1.125-1.424). CCL2 rs4586, CX3CL1 gene rs614230, and CALCA gene rs3781719 locus gene polymorphisms were associated with serum CCL2, CX3CL1, and CALCA protein levels. CONCLUSION: Our results support that CCL2 gene rs4586, CALCA rs3781719, CX3CL1 rs614230 gene polymorphism are associated with the occurrence of chronic pain after cesarean section in Chinese Han women.


Assuntos
Cesárea/efeitos adversos , Dor Crônica/etiologia , Dor Crônica/genética , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/genética , Adulto , Grupo com Ancestrais do Continente Asiático , Peptídeo Relacionado com Gene de Calcitonina/genética , Estudos de Casos e Controles , Quimiocina CCL2/genética , Quimiocina CX3CL1/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Polimorfismo de Nucleotídeo Único , Adulto Jovem
5.
Pain Physician ; 22(4): 331-340, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31337162

RESUMO

BACKGROUND: There is obvious difference in individual response to opioids. Many studies have examined the correlation between the mu-opioid receptor 1 (OPRM1) 118A>G genetic variation and opioid requirement in pain treatment, but the conclusion remains elusive. OBJECTIVES: To investigate whether the OPRM1 118A>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>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 < 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 (I-squared = 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.


Assuntos
Analgésicos Opioides/uso terapêutico , Predisposição Genética para Doença/genética , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/genética , Receptores Opioides mu/genética , Humanos , Manejo da Dor , Polimorfismo Genético
6.
Eur J Anaesthesiol ; 36(5): 342-350, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30882400

RESUMO

BACKGROUND: Neuropathic pain following surgery could be a useful model for the study of the genetic mechanisms of peripheral neuropathic pain. OBJECTIVE: The aim of this study was to identify genetic predictors of persistent postsurgical neuropathic pain. DESIGN: An ancillary study from a prospective cohort. SETTING: Eighteen French university hospitals. PATIENTS: Five hundred and sixty-one patients at risk of persistent postoperative pain who underwent scheduled surgery were classified as 159 cases and 402 controls. INTERVENTION: Pre-operative blood sampling for DNA analysis and questionnaires sent at the third and sixth month after surgery. MAIN OUTCOME MEASURES: The phenotype was the report of pain at the site of surgery with a positive response in the DN4 questionnaire within 6 months after surgery. Out of a list of 126 candidate genes involved in the initial processes of peripheral neuropathic pain, a set of 4599 single nucleotide polymorphisms was tested on an Illumina chip. We carried out the association tests, based on an additive model, on 4422 single nucleotide polymorphisms. RESULTS: After correcting for type-I error inflation, only one suggestive association was reached for one single nucleotide polymorphism, the rs2286614, which we had selected to tag KCNK4. This gene encodes for TRAAK, a two-pore domain background K channel involved in the modulation of the primary thermoreceptors of the transient receptor potential channels family. CONCLUSION: This is the first genetic association study specifically investigating the occurrence of persistent postsurgical neuropathic pain. Its results help target future research to better understand the mechanisms of peripheral neuropathic pain. TRIAL REGISTRATION: ClinicalTrials.gov (ref. NCT00812734).


Assuntos
Neuralgia/genética , Dor Pós-Operatória/genética , Canais de Potássio/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Neuralgia/epidemiologia , Dor Pós-Operatória/epidemiologia , Polimorfismo de Nucleotídeo Único , Prevalência , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários
7.
Reg Anesth Pain Med ; 44(5): 604-608, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30902913

RESUMO

BACKGROUND: Therapeutic ultrasound (TU) alleviates nerve injury-associated pain, while the molecular mechanisms are less clear. This is an investigator-initiated experimental study to evaluate the mechanisms and effects of ultrasound on prolonged post-thoracotomy pain in a rodent model. METHODS: The rats were randomly separated into four groups (n=8 per group): sham-operation (sham; group 1), thoracotomy and rib retraction (TRR; group 2), and TRR procedure followed by TU (TRR+TU-3; group 3) or TU with the ultrasound power turned off (TRR+TU-0; group 4). TU was delivered daily, beginning on postoperative day 11 (POD 11) for the next 2 weeks. Mechanical sensitivity, subcutaneous tissue temperature, and spinal substance P and interleukin-1 beta (IL-1ß) were evaluated on PODs 11 and 23. RESULTS: Group 3, which received ultrasound treatment (3 MHz; 1.0 W/cm2) for 5 min each day, demonstrated higher mechanical withdrawal thresholds when compared with the group without ultrasound intervention (group 2) or sham ultrasound (group 4). Ultrasound treatment also inhibited the upregulation of spinal substance P and IL-1ß measured from spinal cord dorsal horns extract and increased subcutaneous temperature. CONCLUSIONS: The results of this study suggest an increase in mechanical withdrawal thresholds and subcutaneous temperature, as well as a downregulation of spinal substance P and IL-1ß, in the group which received ultrasound treatment. The regulation of spinal substance P and IL-1ß may mediate potential effects of this non-invasive treatment.


Assuntos
Hiperalgesia/metabolismo , Medição da Dor/métodos , Dor Pós-Operatória/metabolismo , Substância P/biossíntese , Toracotomia/efeitos adversos , Terapia por Ultrassom/métodos , Animais , Expressão Gênica , Hiperalgesia/terapia , Masculino , Medição da Dor/tendências , Dor Pós-Operatória/genética , Dor Pós-Operatória/terapia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Substância P/genética , Toracotomia/tendências , Terapia por Ultrassom/tendências
8.
Medicine (Baltimore) ; 98(7): e14445, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30762755

RESUMO

The aim of this study was to investigate the association between purinergic receptor P2X7 (P2RX7) gene rs1718125 polymorphism and analgesic effect of fentanyl after surgery among patients with lung cancer in a Chinese Han population.A total of 238 patients with lung cancer who received resection were enrolled in our study. The genotype distributions of P2RX7 rs1718125 polymorphism were detected by polymerase chain reaction and direct sequencing. Postoperative analgesia was performed by patient-controlled intravenous analgesia, and the consumption of fentanyl was recorded. The postoperative pain was measured by visual analog scale (VAS). Differences in postoperative VAS score and postoperative fentanyl consumption for analgesia in different genotype groups were analyzed by analysis of variance assay.The frequencies of GG, GA, and AA genotypes were 46.22%, 44.96%, and 8.82%, respectively. After surgery, the postoperative VAS score of GA group was significantly high in the period of analepsia after general anesthesia and at 6 hours after surgery (P = .041 and P = .030, respectively), while AA group exhibited obviously high in the period of analepsia after general anesthesia (P < .001), at postoperative 6 hours (P = .006) and 24 hours (P = .016). Moreover, the patients carrying GA and AA genotypes needed more fentanyl to control pain within 48 hours after surgery (P < .05 for all).P2RX7 gene rs1718125 polymorphism is significantly associated with postoperative pain and fentanyl consumption in patients with lung cancer.


Assuntos
Analgésicos Opioides/uso terapêutico , Fentanila/uso terapêutico , Neoplasias Pulmonares/genética , Dor Pós-Operatória/genética , Receptores Purinérgicos P2X7/genética , Idoso , Analgesia Controlada pelo Paciente/estatística & dados numéricos , Grupo com Ancestrais do Continente Asiático/genética , China , Feminino , Genótipo , Humanos , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Medição da Dor , Dor Pós-Operatória/tratamento farmacológico , Polimorfismo de Nucleotídeo Único/genética , Fatores de Tempo
9.
Anesth Analg ; 128(3): 563-568, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29649030

RESUMO

BACKGROUND: Pro- and anti-inflammatory cytokines (adipokines) associated with adipose tissue can modulate inflammatory processes and lead to systemic inflammatory conditions such as metabolic syndrome. In the present pilot study, we investigated 3 major adipokines (leptin, adiponectin, and resistin) and 2 nonspecific proinflammatory cytokines (tumor necrosis factor α and interleukin-6) with regard to their association with postoperative pain intensity. METHODS: We analyzed a total of 45 single-nucleotide polymorphisms of the adipokines in 57 patients with postlaparotomy pain. We adjusted for multiple testing to reduce the chance of false-positive results by controlling the false discovery rate. Serum levels of the adipokines and proinflammatory cytokines were measured in another 36 patients undergoing laparotomy. A stepwise multiple linear regression analysis using these measurements and opioid dosages as independent variables was performed to explore the factors associated with postoperative pain. RESULTS: Only 1 variant of the resistin gene (rs3745367) demonstrated a significant association with postoperative pain (P < .002). Patients exhibiting homozygosity for the minor alleles (n = 7; numerical rating scale [NRS], 2.3 ± 1.3) demonstrated lower pain intensity compared with those exhibiting homozygosity for the major alleles (n = 29; NRS, 3.8 ± 1.0; P = .004) and heterozygosity for the minor alleles (n = 21; NRS, 4.2 ± 0.8; P < .001). Only serum resistin levels showed a positive association with postoperative pain. CONCLUSIONS: A genetic variant of resistin and serum resistin levels were associated with postoperative pain intensity, while other adipokines and cytokines exhibit no such association. Resistin can alter the inflammatory responses in postoperative wounds, although it could be a determinant factor that is independent of inflammatory processes. Resistin may be a novel marker for postoperative pain intensity.


Assuntos
Estudos de Associação Genética/métodos , Medição da Dor/métodos , Dor Pós-Operatória/sangue , Dor Pós-Operatória/genética , Resistina/sangue , Resistina/genética , Idoso , Biomarcadores/sangue , Feminino , Humanos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/diagnóstico , Projetos Piloto , Polimorfismo de Nucleotídeo Único/genética
10.
Gen Thorac Cardiovasc Surg ; 67(9): 806-810, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30073475

RESUMO

Chronic persistent surgical pain (CPSP) is a complex disease with strong genetic component. The studies on revealed association of mutations in membrane bound catechol-O-methyltransferase gene with CPSP were reported indifferent ethnic populations across the globe. We identify that one out of four patients who underwent sternotomy procedure showed CPSP even after 3 months of surgery. The Mb.COMT gene sequence analysis revealed of the four patients, three patients had no mutation in Mb.COMT gene, while in one patient exhibited G472A mutation. Interestingly, this patient showed CPSP even after 90 days of surgery. The magnitude of the CPSP was evaluated with pain questionnaires' at the end of 3 months after discharge from the hospital. In this study 25% (1/4) showed presence G472A allele correlating with CPSP. Further the study suggested that evaluation of G472A allele of Mb.COMT gene in the patients undergoing sternotomy for monitoring pain in pre and post-surgical events.


Assuntos
Alelos , Catecol O-Metiltransferase/genética , Dor Crônica/genética , Dor Pós-Operatória/genética , Esternotomia/efeitos adversos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/terapia , Projetos Piloto , Análise de Sequência de DNA , Esternotomia/métodos , Inquéritos e Questionários
11.
Pain ; 160(3): 561-568, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30371558

RESUMO

Chronic postmastectomy pain (PMP) imposes a major burden on the quality of life of the ever-increasing number of long-term survivors of breast cancer. An earlier report by Nissenbaum et al. claimed that particular polymorphisms in the gene CACNG2 are associated with the risk of developing chronic PMP after breast surgery (Nissenbaum J, Devor M, Seltzer Z, Gebauer M, Michaelis M, Tal M, Dorfman R, Abitbul-Yarkoni M, Lu Y, Elahipanah T, delCanho S, Minert A, Fried K, Persson AK, Shpigler H, Shabo E, Yakir B, Pisante A, Darvasi A. Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2. Genome Res 2010;20:1180-90). This information is important because in principle, it can inform the surgical, radiological, and chemotherapeutic decision-making process in ways that could mitigate the increased risk of chronic pain. In this study, we revisited this claim by independently evaluating the proposed marker haplotype using 2 different patient cohorts recruited in different research settings. Meta-analysis of these new postmastectomy cohorts and the original cohort confirmed significant association of the CACNG2 haplotype with PMP. In addition, we tested whether the same markers would predict chronic postsurgical pain in men who underwent surgery for inguinal hernia repair, and whether there is significant genetic association with cutaneous thermal sensitivity in postmastectomy and postherniotomy patients. We found that the biomarker is selective because it did not predict pain after laparoscopic hernia repair and was not associated with pain sensitivity to experimentally applied noxious thermal stimuli. We conclude that the A-C-C haplotype at the 3 single-nucleotide polymorphisms (rs4820242, rs2284015, and rs2284017) in the CACNG2 gene is associated with increased risk of developing PMP. This information may advance current knowledge on pathophysiology of PMP and serve as a step forward in the prediction of clinical outcomes and personalized pain management.


Assuntos
Canais de Cálcio/genética , Mastectomia/efeitos adversos , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/genética , Polimorfismo Genético/genética , Idoso , Neoplasias da Mama/cirurgia , Estudos de Coortes , Feminino , Genótipo , Humanos , Hiperalgesia/etiologia , Metanálise como Assunto , Pessoa de Meia-Idade , Medição da Dor , Limiar da Dor/fisiologia , Dor Pós-Operatória/complicações
12.
Pain Med ; 20(2): 359-368, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29546421

RESUMO

OBJECTIVE: Prospective observational study to analyze CYP2D6 pharmacogenetics in 55 Portuguese adult parturients undergoing elective cesarean section and to investigate the association between CYP2D6 alleles and pain score. METHODS: DNA was extracted from peripheral blood by standard methods. Genetic analysis included allelic discrimination (CYP2D6*1, *2, *3, *4, *5, *6, *10, *17, and *41) and copy number determination with TaqMan probes by real-time polymerase chain reaction (PCR). Allele duplications were confirmed (long PCR and PCR-restriction fragment length polymorphism). Theoretical metabolic profiles prediction was based on genetic data and activity scores. Association was investigated between genotypes and predicted phenotypes with pain scores. Statistical analysis was performed by using a χ2 test, and significance was set at P < 0.05. RESULTS: The percentage of poor, intermediate, extensive, and ultrarapid metabolizers found were 9%, 38%, 46%, and 7%, respectively. The results reveal a positive association between alleles *4, *10, and pain. CONCLUSIONS: A positive association was found between predicted reduced or null activity of CYP2D6 and increased pain. It can be hypothesized that if CYP2D6 activity is reduced, tyramine metabolism will decrease, resulting in reduced formation of endogenous dopamine. Consequently, activation of the signal transduction pathways that controls pain and analgesic effect may be reduced, leading to an increase in pain. Therefore, we would recommend CYP2D6 genotyping to anticipate the needs for analgesia, which will help to adjust opioid dose and maximize clinical efficacy while reducing side effects.


Assuntos
Cesárea/efeitos adversos , Citocromo P-450 CYP2D6/genética , Dor Pós-Operatória/genética , Adulto , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Testes Farmacogenômicos , Gravidez
13.
Curr Opin Anaesthesiol ; 31(6): 749-755, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30239351

RESUMO

PURPOSE OF REVIEW: The current review will discuss the current literature on genetics of pain and analgesia, with special emphasis on perioperative setting. We will also discuss pharmacogenetics-based management guidelines, current clinical status and future perspectives. RECENT FINDINGS: Recent literature suggests that the interindividual variability in pain and postoperative analgesic response is at least in part because of one's genetic make-up. Some of the well characterized polymorphisms that are associated with surgical pain and opioid-related postoperative adverse outcomes are described in catechol-O-methyl transferase, CYP2D6 and µ-opioid receptor (OPRM1), ATP-binding cassette subfamily B member 1, ABCC3, organic cation transporter 1 genes. Clinical Pharmacogenetics Implementation Consortium has put forth recommendations on CYP2D6 genotype-based opioid selection and dosing. The list of drug-gene pairs studied continue to expand. SUMMARY: Pharmacogenetic approach marks the dawn of personalized pain medicine both in perioperative and chronic pain settings.


Assuntos
Analgesia , Manejo da Dor/métodos , Farmacogenética/métodos , Humanos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/genética , Medicina de Precisão
14.
Neuropsychopharmacol Rep ; 38(2): 67-74, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-30106258

RESUMO

AIM: Interleukin-17A (IL-17A) plays an essential role in tissue inflammation by inducing proinflammatory cytokine and chemokine production and is related to innate immune reactions. IL-17A also contributes to neuroinflammation, neuropathic pain, and mechanical hypersensitivity after peripheral nerve injury in rodents. To clarify the contribution of IL-17A to pain-related phenotypes in humans, we investigated the association between pain-related phenotypes and the rs2275913 single-nucleotide polymorphism (SNP) of the IL-17A gene, which has been reported to be associated with rheumatoid arthritis, ulcerative colitis, and some cancers. METHODS: The present study used a correlational design to examine the impact of the rs2275913 SNP on postoperative pain-related phenotypes in a group of patients who underwent cosmetic orthognathic surgery. RESULTS: Carriers of the AA genotype had higher opioid requirements during and after surgery than carriers of the AG and GG genotypes (P = .009). Linear regression analysis indicated that opioid requirements linearly increased as the copy number of the A allele of the SNP increased (P = .008). CONCLUSIONS: Opioid requirements during and after surgery are enhanced in carriers of the AA genotype of the rs2275913 SNP of the IL-17A gene, possibly through an enhancement of IL-17A function that induces inflammation that is related to the inflammatory pain stimulus.


Assuntos
Analgésicos Opioides/uso terapêutico , Interleucina-17/genética , Procedimentos Cirúrgicos Ortognáticos/efeitos adversos , Dor Pós-Operatória/genética , Polimorfismo de Nucleotídeo Único , Cirurgia Plástica/efeitos adversos , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/tratamento farmacológico
15.
Curr Opin Anaesthesiol ; 31(5): 569-574, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29994939

RESUMO

PURPOSE OF REVIEW: The review describes recent advances in genetics and genomics of postoperative pain, the association between genetic variants and the efficacy of analgesics, and the role of pharmacogenomics in the selection of appropriate analgesic treatments for postoperative pain. RECENT FINDINGS: Recent genetic studies have reported associations of genetic variants in catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF), voltage-gated channel alpha subunit 11 (SCN11A) and µ-opioid receptor (OPRM1) genes with postoperative pain. The recent pharmacogenetics studies revealed an association of the organic cation transporter 1 (OCT1) and ATP-binding cassette C3 (ABCC3) polymorphisms with morphine-related adverse effects, an effect of polymorphisms in cytochrome P450 gene CYP2D6 on the analgesic efficacy of tramadol and no effect of CYP2C8 and CYP2C9 variants on efficacy of piroxicam. SUMMARY: Genetic variants associate with inter-individual variability in drug responses and they can affect pain sensitivity and intensity of postoperative pain. Despite the recent progress in genetics and genomics of postoperative pain, it is still not possible to precisely predict the patients who are genetically predisposed to have severe postoperative pain or who develop chronic postoperative pain.


Assuntos
Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/genética , Farmacogenética , Variação Genética , Humanos , Manejo da Dor
16.
Sci Rep ; 8(1): 8965, 2018 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-29895890

RESUMO

Novel pain killers without adverse effects are urgently needed. Opioids induce central and intestinal side effects such as respiratory depression, sedation, addiction, and constipation. We have recently shown that a newly designed agonist with a reduced acid dissociation constant (pKa) abolished pain by selectively activating peripheral µ-opioid receptors (MOR) in inflamed (acidic) tissues without eliciting side effects. Here, we extended this concept in that pKa reduction to 7.22 was achieved by placing a fluorine atom at the ethylidene bridge in the parental molecule fentanyl. The new compound (FF3) showed pH-sensitive MOR affinity, [35S]-GTPγS binding, and G protein dissociation by fluorescence resonance energy transfer. It produced injury-restricted analgesia in rat models of inflammatory, postoperative, abdominal, and neuropathic pain. At high dosages, FF3 induced sedation, motor disturbance, reward, constipation, and respiratory depression. These results support our hypothesis that a ligand's pKa should be close to the pH of injured tissue to obtain analgesia without side effects.


Assuntos
Analgésicos , Desenho de Drogas , Neuralgia/tratamento farmacológico , Dor Pós-Operatória/tratamento farmacológico , Receptores Opioides mu/agonistas , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Relação Dose-Resposta a Droga , Concentração de Íons de Hidrogênio , Masculino , Estrutura Molecular , Muramidase , Neuralgia/genética , Neuralgia/metabolismo , Neuralgia/patologia , Dor Pós-Operatória/genética , Dor Pós-Operatória/metabolismo , Dor Pós-Operatória/patologia , Fragmentos de Peptídeos , Ratos , Ratos Wistar , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo
17.
Surg Technol Int ; 32: 306-314, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29791710

RESUMO

BACKGROUND: Multiple factors have been implicated in determining why certain patients have increased postoperative pain, with the potential to develop chronic pain. The purpose of this study was to: 1) identify and describe genes that affect postoperative pain perception and control; 2) address modifiable risk factors that result in epigenetic altered responses to pain; and 3) characterize differences in pain sensitivity and thresholds between opioid-naïve and opioid-dependent patients. MATERIALS AND METHODS: Three electronic databases were used to conduct the literature search: Pubmed, EBSCO host, and SCOPUS. A total of 372 abstracts were reviewed, of which 46 studies were deemed relevant and are included in this review. RESULTS: Specific gene alterations that were shown to affect postoperative pain control included single nucleotide polymorphisms in the mu, kappa, and delta opioid receptors, ion channel genes, cytotoxic T-cells, glutamate receptors and cytokine genes, among others. Alcoholism, obesity, and smoking were all linked with genetic polymorphisms that altered pain sensitivity. Opioid abuse was found to be associated with a poorer response to analgesics postoperatively, as well as a risk for prescription overdose. CONCLUSION: Although pain perception has multiple complex influences, the greatest variability seen in response to opioids among postoperative patients known to date can be traced to genetic differences in opioid metabolism. Further study is needed to determine the clinical significance of these genetic associations.


Assuntos
Analgésicos Opioides , Dor Crônica , Dor Pós-Operatória , Polimorfismo Genético/genética , Receptores Opioides/genética , Analgésicos Opioides/metabolismo , Analgésicos Opioides/uso terapêutico , Dor Crônica/tratamento farmacológico , Dor Crônica/genética , Humanos , Manejo da Dor , Percepção da Dor , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/genética , Fatores de Risco
18.
Clin Orthop Relat Res ; 476(1): 101-109, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29529623

RESUMO

BACKGROUND: TKA pain management protocols vary widely with no current consensus on a standardized pain management regimen. Multimodal TKA pain management protocols aim to address pain control, facilitate functional recovery, and maintain patient satisfaction. QUESTIONS/PURPOSES: (1) Did changes to our pain management protocol, specifically adding liposomal bupivacaine, eliminating patient-controlled analgesia (PCA), and discontinuing femoral nerve blocks (FNBs), affect narcotic consumption after TKA? (2) Did these changes to our pain management protocols affect patient-reported pain scores? (3) Does the use of an immediate postoperative PCA affect rapid rehabilitation and functional recovery? (4) How did changes to our pain management regimen affect discharge disposition and pain-related Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores? METHODS: We retrospectively analyzed an institutional arthroplasty database between September 2013 and September 2015 containing 1808 patients who underwent primary TKA. Departmental pain management protocols were compared in 6-month periods as the protocol changed. All patients received a multimodal pain management protocol including preoperative oral medications, spinal or general anesthesia, a short-acting intraoperative pericapsular injection, and continued postoperative oral narcotics for breakthrough pain. From September 2013 to April 2014, all patients received an intraoperative FNB and a PCA for the first 24 hours postoperatively (Cohort 1). From May 2014 to October 2014, a periarticular injection of liposomal bupivacaine was added to the protocol and FNBs were discontinued (Cohort 2). After April 2015, PCA was eliminated (Cohort 3). No other major changes were made to the TKA pain management pathways. Narcotic use, pain scores on 8-hour intervals, physical therapy milestones, and discharge disposition were compared. RESULTS: Total narcotic use was the least in Cohort 3 (Cohort 3: 66 ± 54 morphine milligram equivalents versus Cohort 2: 82 ± 72 versus Cohort 1: 96 ± 62; p < 0.001). There was an increase in pain score immediately after surgery in Cohort 3 (4.0 ± 3.5 versus 1.2 ± 2.2 versus 1.2 ± 2.5, post hoc analysis of Cohort 2 versus 3: mean difference 2.6, 95% confidence interval [CI] 2.2-3.0; p < 0.001); however, it was not different for the remainder of the hospital stay. Patients who did not receive PCA reached functional milestones for both gait and stairs faster by postoperative day 1 (47% [328 of 698] versus 30% [158 of 527] versus 16% [93 of 583], p < 0.001; Cohort 3 versus 2: odds ratio 2.1, 95% CI 1.6-2.6; p < 0.001). Discharge to home occurred more frequently (84% [583 of 698] versus 78% [410 of 527] versus 72% [421 of 583], p = 0.010) in Cohort 3. There were no differences in pain-related HCAHPS scores across all cohorts. CONCLUSIONS: Discontinuing PCAs and FNBs from our multimodal TKA pain management protocols and adding liposomal bupivacaine resulted in fewer narcotics consumed with no difference in pain control and faster functional recovery while maintaining high HCAHPS scores relating to pain. LEVEL OF EVIDENCE: Level III, therapeutic study.


Assuntos
Analgesia Controlada pelo Paciente , Analgésicos Opioides/administração & dosagem , Anestésicos Locais/administração & dosagem , Artralgia/prevenção & controle , Artroplastia do Joelho/efeitos adversos , Bupivacaína/administração & dosagem , Nervo Femoral , Articulação do Joelho/inervação , Articulação do Joelho/cirurgia , Bloqueio Nervoso/métodos , Manejo da Dor/métodos , Dor Pós-Operatória/prevenção & controle , Analgesia Controlada pelo Paciente/efeitos adversos , Analgésicos Opioides/efeitos adversos , Anestésicos Locais/efeitos adversos , Artralgia/diagnóstico , Artralgia/etiologia , Artralgia/fisiopatologia , Bupivacaína/efeitos adversos , Terapia Combinada , Bases de Dados Factuais , Humanos , Lipossomos , Bloqueio Nervoso/efeitos adversos , Manejo da Dor/efeitos adversos , Medição da Dor , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/genética , Dor Pós-Operatória/fisiopatologia , Medidas de Resultados Relatados pelo Paciente , Satisfação do Paciente , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
19.
Gene ; 661: 78-84, 2018 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-29601950

RESUMO

OBJECTIVE: Our study aimed to evaluate the association between the multidrug resistance 1 (MDR1)/cytochrome P450 3A4 (CYP3A4)/µ-opioid receptor (OPRM1) gene polymorphisms and the post-caesarean analgesic effect of fentanyl on Chinese women. METHODS: We recruited 240 patients who received lower segment caesarean section surgeries. Sanger sequencing was used to analyze the MDR11236C > T/CYP3A4*1G/OPRM1A118G polymorphisms. We evaluated post-operative fentanyl consumption and the effect of intravenous analgesia in patients with different genotypes. RESULTS: 1. Subjects with the TT genotype at the 1236C > T polymorphism in the MDR1 gene consumed significantly more fentanyl than that consumed by subjects with the CC and CT genotypes in the first post-operative 24 h and 48 h (P < 0.05), and the MAP/HR/Cor/Ang-1 levels gradually increased immediately after surgery and in the first post-operative 24 h. 2. Subjects with the CYP3A4*1G/*1G genotype needed less fentanyl to achieve pain control than that needed by subjects carrying the CYP3A4*1/*1 and CYP3A4*1/*1G genotypes in the first post-operative 24 h and 48 h (P < 0.05), and the MAP/HR/Cor/Ang-1 levels gradually decreased immediately after surgery and in the first post-operative 24 h. 3. Subjects with the GG genotype at the A118G polymorphism in the OPRM1 gene consumed significantly more fentanyl than that consumed by subjects with the AA and AG genotypes in the first post-operative 24 h and 48 h (P < 0.05), and the MAP/HR/Cor/Ang-1 levels gradually increased immediately after surgery and in the first post-operative 24 h. 4. There were no significant differences in the adverse reactions to fentanyl in patients with different genotypes (P > 0.05). CONCLUSION: These results indicated that the MDR1/CYP3A4/OPRM1 gene polymorphisms influenced the fentanyl consumption and the physiological effects of intravenous analgesia in the Chinese women who received lower segment caesarean section surgeries. Moreover, the present study provides an important foundation and theoretical evidence for the gene-directed rationalization and individualization of medication before caesarean section surgeries.


Assuntos
Cesárea/efeitos adversos , Citocromo P-450 CYP3A/genética , Resistência a Medicamentos/genética , Fentanila/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Receptores Opioides mu/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Administração Intravenosa , Adolescente , Adulto , Analgesia Controlada pelo Paciente/métodos , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Fentanila/administração & dosagem , Estudos de Associação Genética , Humanos , Dor Pós-Operatória/genética , Polimorfismo de Nucleotídeo Único , Gravidez , Resultado do Tratamento , Adulto Jovem
20.
J Pharmacol Sci ; 136(3): 107-113, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29502940

RESUMO

Opioid analgesics are widely used for the treatment of moderate to severe pain. The analgesic effects of opioids are well known to vary among individuals. The present study focused on the genetic factors that are associated with interindividual differences in pain and opioid sensitivity. We conducted a multistage genome-wide association study in subjects who were scheduled to undergo mandibular sagittal split ramus osteotomy and were not medicated until they received fentanyl for the induction of anesthesia. We preoperatively conducted the cold pressor-induced pain test before and after fentanyl administration. The rs13093031 and rs12633508 single-nucleotide polymorphisms (SNPs) near the LOC728432 gene region and rs6961071 SNP in the tcag7.1213 gene region were significantly associated with the analgesic effect of fentanyl, based on differences in pain perception latency before and after fentanyl administration. The associations of these three SNPs that were identified in our exploratory study have not been previously reported. The two polymorphic loci (rs13093031 and rs12633508) were shown to be in strong linkage disequilibrium. Subjects with the G/G genotype of the rs13093031 and rs6961071 SNPs presented lower fentanyl-induced analgesia. Our findings provide a basis for investigating genetics-based analgesic sensitivity and personalized pain control.


Assuntos
Analgesia , Analgésicos Opioides/administração & dosagem , Fentanila/administração & dosagem , Estudo de Associação Genômica Ampla , Manejo da Dor , Medição da Dor/métodos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/genética , Polimorfismo de Nucleotídeo Único , Pseudogenes , Adolescente , Adulto , Feminino , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Osteotomia Mandibular , Pessoa de Meia-Idade , Percepção da Dor , Período Pré-Operatório , Adulto Jovem
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