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Management of Iatrogenically induced opioid dependence
Oral Communications Management of Iatrogenically induced opioid dependence A.M. Peiró1; C. Puga2; B. Planelles3; L. Mira2; M. Puerto2; L. Gómez1; J.F. Horga1; and C. Margarit1 1 Hospital General Universitario de Alicante (HGUA), Spain; 2 The Foundation for the Promotion of Health and Biomedical Research of the Valencian. Community (FISABIO), Spain; and 3Occupational Observatory, University Miguel Hernández (UMH), Spain Introduction: Opioids are valuable analgesics, capable of providing pain relief and functional improvement also in chronic non–cancerrelated pain (NCP) patients. However, recent data have shown that the increasing prescription of opioids is associated with a rise in aberrant drug-related behaviour. Methodology: A prospective study was performed with 70 NCP outpatients diagnosed with opioid iatrogenic DSMIV dependence and severe pain intensity. The study focused on analgesic efficacy, opioid withdrawal syndrome prevention, adverse side effects, functional status, and aberrant drug-related behaviour. We design a contractual agreement on opioid therapy, including goals, side effects, and criteria to finish the opioid therapy. Genotyping of the OPRM (rs1799971), COMT (rs4680), and ABCB (rs1045642) genes was performed. Results: Results from 73% (50 of 70) of the patients are presented. After a structured and progressive opioid conversion to buprenorphine/tramadol, a significant reduction of 47% of the total daily dose (TDD) with no withdrawal symptoms (OWS reduction of 9 points) was achieved, maintaining a moderate relief and pain intensity score. Quality of life tends to improve, as do the number of adverse reactions reported by the patients throughout the visits. OPRM and COMT gene variant distribution but ABCB variants were more prevalent (9% C/C, 65% C/T, 26% T/T) vs general population distribution (21% C/C, 49% C/T, 25% T/T). Psychosocial risk was associated to a high prevalence of opioid iatrogenic dependence. Conclusions: The indication for the prescription of opioids must be very carefully weighed in the presence of any risk factors. In these cases the integration into a multimodal, interdisciplinary therapy program is mandatory.
β 2-Adrenergic receptor functionality and genotype in two different models of chronic inflammatory diseases: Liver Cirrhosis and Osteoarthrosis Ana Peiró1; Pedro Zapater1,2; Reyes Roca3; Annaluciana Comte4; M. Angeles Pena1; José María Palazón1; and José F. Horga1 1 Hospital General Universitario de Alicante (HGUA), Spain; 2 Institute of Health Carlos III, ISCIII, Madrid, Spain; 3The Foundation for the Promotion of Health and Biomedical Research of the Valencian Community (FISABIO), Spain; and 4 Occupational Observatory, University Miguel Hernández (UMH), Spain Background: This study was designed to investigate the contribution of polymorphic b2 adrenoceptors (b2AR) to the proinflammatory effects of the sympathetic nervous system in two models of chronic inflammatory disease: liver cirrhosis (LC) and osteoarthrosis (OA). The b2AR gene contains three single-nucleotide polymorphisms (SNPs) at amino acid positions 16, 27, and 164. Our aim was to study the potential influence of genotype on lymphocytes b2AR functionality in LC and OA development/progression. Methods: We compared 52 cirrhotic patients with esophageal varices and portal hypertension (hepatic venous pressure gradient [HVPG] 13 ± 4 mm Hg, CHILD 7 ± 2, and MELD 11 ± 4 scores), 32 OA
August 2015
(84% Kellgren-Lawrence [KL] severity 4 grade, 14% knee replacement joint), and 26 healthy volunteers as controls. Mononuclear cells were isolated from the whole blood. Basal and stimulated intracellular cAMP levels (isoproterenol stimulus from 10−8 to 10−3) and b2AR allelic variants (Arg16Gly, rs1042713; Gln27Glu, rs1042714; Thr164Ile, rs1800888) were determined. Results: b2AR functionality was significantly decreased in LC and OA vs control (14 ± 15.5 pmol/mL, 38 ± 21 pmol/mL vs 90 ± 66 pmol/mL at ISO 10-5 stimulus, respectively, P < 0.05). This decreased b2AR functionality was similar in LC patients: (i) in primary or secondary prophylaxis (15 ± 19 and 14 ± 13 pmol/mL, respectively) and (ii) in responder or non-responder to propranolol during HVPG (14 ± 16 and 14 ± 15 pmol/mL, respectively). The prevalence of different genotypes did not differ between patients stratified according to any clinical variable. In cirrhotic patients, the decreased in b2AR functionality was the same for all the studied allelic variants (naive vs SNP, 15 ± 17 vs 13 ± 16 pmol/mL). Conclusions: In patients with cirrhosis and portal hypertension, the functionality of b2AR is significantly decreased. This change is not related to b2AR allelic variants.
Gene expression of anaesthetic and analgesic drug targets in Breast tumours predicts metastasis: relevance to personalized, therapeutic intervention in the peri-operative period H.C. Gallagher1,2 University College Dublin, Belfield, Dublin 4, Ireland; and 2 UCD-Mater Clinical Research Centre, Nelson St, Dublin 7, Ireland Introduction: Mortality associated with breast cancer is due, invariably, to the burden of metastasis. Virtually all patients with breast cancer undergo surgery, which may result in release of tumor cells into the bloodstream. Thus, perioperative factors, including drugs, are important in minimizing metastatic risk during tumor resection. However, retrospective clinical trials suggest that combined volatile general anesthesia and opioid analgesia, which is routinely used during cancer surgery, may promote metastasis. The current study investigated a pharmacogenetic basis for this phenomenon. Methods: The publically accessible transcriptomic database, Breastmark, was interrogated. It currently employs 26 breast cancer genechip data sets (~17,000 genes in ~4738 samples). Gene expression levels were dichotomized on the basis of median, high, and/ or low stratification, and a global pooled survival analysis was performed for distant disease-free survival (metastasis) and overall survival. Kaplan-Meier estimates and the log-rank P value indicated differences in survival, with values less than 0.05 considered significant. Cox regression analysis was used to calculate hazard ratios. Results: Bioinformatic analysis revealed that patients whose breast tumors overexpress mu and delta opioid receptors have a shorter disease-free survival and shorter overall survival than those with low expression of these analgesic drug targets. Importantly, these are not established oncogenes, and no such effect is seen for kappa opioid receptors. Furthermore, low expression of the glycine β -receptor was strongly associated with metastasis. This receptor is a key target for volatile anesthetic agents, such as sevoflurane. Conclusions: The data presented here suggest that the gene expression profile of breast tumors determines the therapeutic response to anesthetics and analgesics. Thus, an opportunity exists to specifically address the prometastatic changes occurring in the critical, perioperative period via personalized, therapeutic intervention. It may be possible to pharmacogenetically stratify patients who would most benefit 1
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β 2-Adrenergic receptor functionality and genotype in two different models of chronic inflammatory diseases: Liver Cirrhosis and Osteoarthrosis Ana Peiró1; Pedro Zapater1,2; Reyes Roca3; Annaluciana Comte4; M. Angeles Pena1; José María Palazón1; and José F. Horga1 1 Hospital General Universitario de Alicante (HGUA), Spain; 2 Institute of Health Carlos III, ISCIII, Madrid, Spain; 3The Foundation for the Promotion of Health and Biomedical Research of the Valencian Community (FISABIO), Spain; and 4 Occupational Observatory, University Miguel Hernández (UMH), Spain Background: This study was designed to investigate the contribution of polymorphic b2 adrenoceptors (b2AR) to the proinflammatory effects of the sympathetic nervous system in two models of chronic inflammatory disease: liver cirrhosis (LC) and osteoarthrosis (OA). The b2AR gene contains three single-nucleotide polymorphisms (SNPs) at amino acid positions 16, 27, and 164. Our aim was to study the potential influence of genotype on lymphocytes b2AR functionality in LC and OA development/progression. Methods: We compared 52 cirrhotic patients with esophageal varices and portal hypertension (hepatic venous pressure gradient [HVPG] 13 ± 4 mm Hg, CHILD 7 ± 2, and MELD 11 ± 4 scores), 32 OA
August 2015
(84% Kellgren-Lawrence [KL] severity 4 grade, 14% knee replacement joint), and 26 healthy volunteers as controls. Mononuclear cells were isolated from the whole blood. Basal and stimulated intracellular cAMP levels (isoproterenol stimulus from 10−8 to 10−3) and b2AR allelic variants (Arg16Gly, rs1042713; Gln27Glu, rs1042714; Thr164Ile, rs1800888) were determined. Results: b2AR functionality was significantly decreased in LC and OA vs control (14 ± 15.5 pmol/mL, 38 ± 21 pmol/mL vs 90 ± 66 pmol/mL at ISO 10-5 stimulus, respectively, P < 0.05). This decreased b2AR functionality was similar in LC patients: (i) in primary or secondary prophylaxis (15 ± 19 and 14 ± 13 pmol/mL, respectively) and (ii) in responder or non-responder to propranolol during HVPG (14 ± 16 and 14 ± 15 pmol/mL, respectively). The prevalence of different genotypes did not differ between patients stratified according to any clinical variable. In cirrhotic patients, the decreased in b2AR functionality was the same for all the studied allelic variants (naive vs SNP, 15 ± 17 vs 13 ± 16 pmol/mL). Conclusions: In patients with cirrhosis and portal hypertension, the functionality of b2AR is significantly decreased. This change is not related to b2AR allelic variants.
Gene expression of anaesthetic and analgesic drug targets in Breast tumours predicts metastasis: relevance to personalized, therapeutic intervention in the peri-operative period H.C. Gallagher1,2 University College Dublin, Belfield, Dublin 4, Ireland; and 2 UCD-Mater Clinical Research Centre, Nelson St, Dublin 7, Ireland Introduction: Mortality associated with breast cancer is due, invariably, to the burden of metastasis. Virtually all patients with breast cancer undergo surgery, which may result in release of tumor cells into the bloodstream. Thus, perioperative factors, including drugs, are important in minimizing metastatic risk during tumor resection. However, retrospective clinical trials suggest that combined volatile general anesthesia and opioid analgesia, which is routinely used during cancer surgery, may promote metastasis. The current study investigated a pharmacogenetic basis for this phenomenon. Methods: The publically accessible transcriptomic database, Breastmark, was interrogated. It currently employs 26 breast cancer genechip data sets (~17,000 genes in ~4738 samples). Gene expression levels were dichotomized on the basis of median, high, and/ or low stratification, and a global pooled survival analysis was performed for distant disease-free survival (metastasis) and overall survival. Kaplan-Meier estimates and the log-rank P value indicated differences in survival, with values less than 0.05 considered significant. Cox regression analysis was used to calculate hazard ratios. Results: Bioinformatic analysis revealed that patients whose breast tumors overexpress mu and delta opioid receptors have a shorter disease-free survival and shorter overall survival than those with low expression of these analgesic drug targets. Importantly, these are not established oncogenes, and no such effect is seen for kappa opioid receptors. Furthermore, low expression of the glycine β -receptor was strongly associated with metastasis. This receptor is a key target for volatile anesthetic agents, such as sevoflurane. Conclusions: The data presented here suggest that the gene expression profile of breast tumors determines the therapeutic response to anesthetics and analgesics. Thus, an opportunity exists to specifically address the prometastatic changes occurring in the critical, perioperative period via personalized, therapeutic intervention. It may be possible to pharmacogenetically stratify patients who would most benefit 1
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