RESUMO
Safety data in chronic non-cancer pain (CNCP) with long-term opioid therapy has been poorly studied and can be differently influenced by gender. Furthermore, pharmacogenetics (PGx) could possibly be used to tailor pain medication based on the individual's genetic background. The aim was to assess whether PGx applied to a pharmacovigilance system could help to improve a patient's security profile. A pharmacovigilance data recording system was conducted over 24 months, including genotyping of OPRM1 variants (opioid receptor, A118G) and COMT (enzyme that degrades catecholamines such as norepinephrine, G1947A). Pain intensity (visual analogue scale, VAS), morphine equivalent daily dose (MEDD), adverse events (AEs) and suspected adverse drug reactions (ADRs) were recorded and analysed by gender. The Ethics Committee approved the study and data were analysed with R 3.6.0 software. A total of 748 patients were recruited in the study (67% female, VAS 62 ± 29 mm, MEDD 119 ± 114 mg/day) reporting a median of 6 (3.5-9) AEs/patient. Women presented more nausea, headaches, insomnia, loss of appetite, weight change, depression and dizziness than men. Analysis by genotype demonstrated that PGx influenced the prevalence of vomiting and depression in men, dizziness in women and sexual dysfunction in both. Physicians notified 150 ADRs mostly in females (79%) related to nervous system disorders. PGx applied to a pharmacovigilance recording system provides important information to achieve a better knowledge about AEs in CNCP pharmacological therapy. OPRM1 and COMT polymorphisms were associated with AEs in CNCP patients that differed according to gender.
Assuntos
Analgésicos Opioides/efeitos adversos , Dor Crônica/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Manejo da Dor/métodos , Farmacogenética/métodos , Caracteres Sexuais , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/administração & dosagem , Dor Crônica/tratamento farmacológico , Dor Crônica/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor/métodos , Polimorfismo de Nucleotídeo Único/genética , Espanha/epidemiologiaRESUMO
BACKGROUND: Safety data from long-term opioid therapy in the real world has been poorly studied in chronic non-cancer pain (CNCP). The aim was to design a pharmacovigilance data recording system and assess whether participation in this recording system improves pain management, enhancing patient's health status. METHODS: A pharmacovigilance data recording system was conducted during 24 months. Data were self-reported by patients (pain, adverse events [AEs] and healthcare resources use) and physicians (morphine equivalent daily dose [MEDD] prescribed and suspected adverse drug reaction [ADRs]). Outcomes from patients with (case) or without (controls) suspected ADRs and cases follow-up were also compared with Spanish Pharmacovigilance System data. RESULTS: A total of 753 patients were recruited in 897 visits. Fentanyl and tramadol were the most prescribed opioids, 89% with concomitant drugs, pregabalin being the one with the most potential drug interactions. Cases presented significantly higher pain intensity (VAS 67 ± 26 vs 59 ± 30 mm, P < 0.05), number of AEs (8 ± 6 vs 5 ± 3 AEs/patient, P < 0.01), polypharmacy related to pain (65% vs 34%, P < 0.01) and MEDD (139 ± 130 vs 106 ± 99 mg/d, P < 0.01) than controls. Furthermore, cases presented significant higher changes in pharmacological pain therapy due to pain, unplanned emergency visits and hospital admission than controls. Physicians notified 168 suspected ADRs mostly related to neurological or psychiatric events and 8% of them were previously unknown. CONCLUSIONS: This data recording system provided important information to achieve a better control of CNCP pharmacological pain therapy, improving patient's health status and reducing costs to the Health System.
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Sistemas de Notificação de Reações Adversas a Medicamentos , Analgésicos Opioides/efeitos adversos , Dor Crônica/complicações , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/uso terapêutico , Dor Crônica/tratamento farmacológico , Feminino , Fentanila/efeitos adversos , Fentanila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Manejo da Dor , Farmacovigilância , Médicos , Estudos Retrospectivos , Autorrelato , Tramadol/efeitos adversos , Tramadol/uso terapêuticoRESUMO
OBJECTIVES: Chronic pain is one of the most common reasons individuals seek medical attention. It is a major issue because of the wide interindividual variability in the analgesic response. This might be partly explained by the presence of variants in genes encoding molecules involved in pharmacodynamics and pharmacokinetics. The aim was to analyze opioid effectiveness in chronic low back pain (CLBP) relief after opioid titration, unveiling the impact of pharmacogenetics. METHODS: The study included 231 opioid-naïve patients from the Spine Unit; age 63 ± 14 years, 64% female, body mass index 29 ± 6 kg/m2 , visual analog scale pain intensity score 73 ± 16 mm. Clinical data were collected at baseline, 3 months after opioid titration, and after 2 to 4 years of follow-up concerning pain (intensity and relief), quality of life, disability, comorbidities, and drug prescription (opioid dose, rotations, and adverse events). The genotype influence of OPRM1, COMT, UGT2B7, ABCB1, KCNJ6, and CYP3A5*3A in analgesic response was analyzed by reverse-transcription polymerase chain reaction genotyping. RESULTS: Patients with the COMT G472A-AA genotype (rs4680) and KCNJ6 A1032G-A allele (rs2070995) CLBP responded differently to opioid titration, with higher pain intensity requiring higher dosing. Furthermore, GG- genotypes of A118G (OPRM1, rs1799971) and A854G (UGT2B7, rs776746) influenced the neuropathic component. After opioid titration, CLBP intensity, neuropathic component, low back pain disability, anxiety, and depression significantly decreased, while quality of life improved. CONCLUSION: Single-nucleotide polymorphisms in genes involved in pain transmission and opioid metabolism might predispose to exaggerated sensitivity and differences in the opioid analgesic effect in patients with CLBP. We encourage clinical trials for their clinical application in chronic pain management.
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Analgésicos Opioides/uso terapêutico , Dor Crônica/genética , Estudos de Associação Genética/métodos , Dor Lombar/genética , Polimorfismo de Nucleotídeo Único/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Dor Crônica/diagnóstico , Dor Crônica/tratamento farmacológico , Feminino , Seguimentos , Humanos , Dor Lombar/diagnóstico , Dor Lombar/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Farmacogenética/métodos , Estudos Prospectivos , Qualidade de Vida , Receptores Opioides mu/genéticaRESUMO
CONTEXT: Opioids decrease pain and improve functional capacity and quality of life; however, they are not always effective and are associated with harmful side effects. Few studies have shown that relaxation-based therapies, in comparison with usual care, can decrease pain. OBJECTIVE: The objective of the study was to investigate whether a controlled relaxation treatment, Jacobson progressive muscular relaxation (PMR), was effective in relieving chronic low-back pain (CLBP) and reducing pain comorbidities. The research team hypothesized that PMR-controlled relaxation could be more effective in reducing CLBP than music. DESIGN: The research team designed a randomized, controlled, crossover study. SETTING: The study took place in the pain unit, a clinic, in the Department of Health at Alicante-General Hospital (Alicante, Spain). PARTICIPANTS: Participants in this study were 58 adults with nononcological CLBP, secondary to lumbar canal stenosis, who had been treated with opioids without any changes in the 3 mo prior to the study. INTERVENTION: Participants were randomly assigned to 1 of 2 groups, each of which received 2 treatments, but in a different order (ie, either AB or BA where A was the standardized PMR, the intervention, and B was relaxing music, the control. For both groups, the 2 treatment periods were 8 wk in length, with a 1-mo washout period between them. OUTCOME MEASURES: The primary outcome measures included (1) a visual analogue scale-pain and relief intensity; (2) the 12-item short form health survey-quality of life; (3) the hospital anxiety and depression scale-anxiety and depression; and (4) the medical outcomes study sleep scale-sleep disturbances. Secondary outcome measures included a self-efficacy scale and a measure of satisfaction with treatment and compliance. RESULTS: Pain was mostly mild to moderate. Greater decreases in pain between baseline and postintervention were observed for the PMR vs the control treatment in the mild pain category, with a VAS difference of 1.8 cm and P = .018. Significant differences were also found in anxiety, depression, quality of life, and sleep between participants in the 3 pain categories. Self-rated adherence was high. CONCLUSIONS: Findings support the efficacy and acceptability of a self-guided PMR intervention for reducing CLBP with minimal time with a therapist.
Assuntos
Dor Crônica/terapia , Dor Lombar/terapia , Manejo da Dor/métodos , Terapia de Relaxamento/métodos , Adulto , Estudos Cross-Over , Terapia por Exercício , Humanos , Qualidade de Vida , Espanha , Resultado do TratamentoRESUMO
Human solid tumors frequently have pronounced heterogeneity of both neoplastic and normal cells on the histological, genetic, and gene expression levels. While current efforts are focused on understanding heterotypic interactions between tumor cells and surrounding normal cells, much less is known about the interactions between and among heterogeneous tumor cells within a neoplasm. In glioblastoma multiforme (GBM), epidermal growth factor receptor gene (EGFR) amplification and mutation (EGFRvIII/DeltaEGFR) are signature pathogenetic events that are invariably expressed in a heterogeneous manner. Strikingly, despite its greater biological activity than wild-type EGFR (wtEGFR), individual GBM tumors expressing both amplified receptors typically express wtEGFR in far greater abundance than the DeltaEGFR lesion. We hypothesized that the minor DeltaEGFR-expressing subpopulation enhances tumorigenicity of the entire tumor cell population, and thereby maintains heterogeneity of expression of the two receptor forms in different cells. Using mixtures of glioma cells as well as immortalized murine astrocytes, we demonstrate that a paracrine mechanism driven by DeltaEGFR is the primary means for recruiting wtEGFR-expressing cells into accelerated proliferation in vivo. We determined that human glioma tissues, glioma cell lines, glioma stem cells, and immortalized mouse Ink4a/Arf(-/-) astrocytes that express DeltaEGFR each also express IL-6 and/or leukemia inhibitory factor (LIF) cytokines. These cytokines activate gp130, which in turn activates wtEGFR in neighboring cells, leading to enhanced rates of tumor growth. Ablating IL-6, LIF, or gp130 uncouples this cellular cross-talk, and potently attenuates tumor growth enhancement. These findings support the view that a minor tumor cell population can potently drive accelerated growth of the entire tumor mass, and thereby actively maintain tumor cell heterogeneity within a tumor mass. Such interactions between genetically dissimilar cancer cells could provide novel points of therapeutic intervention.
Assuntos
Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioblastoma/fisiopatologia , Mutação/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/fisiologia , Receptor gp130 de Citocina/metabolismo , Citocinas/metabolismo , Glioblastoma/genética , Glioma/fisiopatologia , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Fator Inibidor de Leucemia/genética , Fator Inibidor de Leucemia/metabolismo , Ligantes , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/patologia , Regulação para CimaRESUMO
BACKGROUND: Opioids are an effective treatment for chronic non-malignant pain (CNP). Long-term use risks and side effects such as opioid-induced androgen deficiency (OPIAD) exist. This could be measured by saliva testosterone (Sal-T). OBJECTIVES: To evaluate OPIAD in long-term opioid use in CNP patients. METHODS: A cross-sectional study included CNP male outpatients under opioid treatment. Total-Testosterone (Total-T), Free-Testosterone (Free-T), Bio-Testosterone (Bio-T) and Sal-T were measured. Correlations were calculated by Spearman's rho (SPSS 20). RESULTS: From 2012 to 2014, 134 from 249 (54%) consecutive male outpatients reported erectile dysfunction (ED), 37% of them related to opioids and 19% evidenced OPIAD. A total of 120 subjects (94 cases and 26 matched-controls) were included. A significantly lower luteinizing hormone, Total-T and Free-T were found, as well as, a significant correlation between Sal-T and Total-T (r = 0.234, p = 0.039), Bio-T (r = 0.241, p = 0.039), IIEF (r = 0.363, p = 0.003) and HAD-anxiety (r = -0.414, p = 0.012) in OPIAD patients. Sal-T levels were significantly lower in patients with severe-moderate ED versus mild ED (p = 0.045) and in patients with severe ED versus moderate-mild ED (p = 0.036). CONCLUSIONS: These data demonstrate the high prevalence of ED in long-term use of opioids, part of this is associated to OPIAD, which can be tested by Sal-T as a non-invasive approach.
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Analgésicos Opioides/efeitos adversos , Androgênios/deficiência , Dor Crônica/tratamento farmacológico , Disfunção Erétil/induzido quimicamente , Saliva/química , Testosterona/deficiência , Idoso , Analgésicos Opioides/administração & dosagem , Estudos de Casos e Controles , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Inquéritos e QuestionáriosRESUMO
Glioblastoma multiforme (GBM) is the most aggressive of the astrocytic malignancies and the most common intracranial tumor in adults. Although the epidermal growth factor receptor (EGFR) is overexpressed and/or mutated in at least 50% of GBM cases and is required for tumor maintenance in animal models, EGFR inhibitors have thus far failed to deliver significant responses in GBM patients. One inherent resistance mechanism in GBM is the coactivation of multiple receptor tyrosine kinases, which generates redundancy in activation of phosphoinositide-3'-kinase (PI3K) signaling. Here we demonstrate that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is frequently phosphorylated at a conserved tyrosine residue, Y240, in GBM clinical samples. Phosphorylation of Y240 is associated with shortened overall survival and resistance to EGFR inhibitor therapy in GBM patients and plays an active role in mediating resistance to EGFR inhibition in vitro. Y240 phosphorylation can be mediated by both fibroblast growth factor receptors and SRC family kinases (SFKs) but does not affect the ability of PTEN to antagonize PI3K signaling. These findings show that, in addition to genetic loss and mutation of PTEN, its modulation by tyrosine phosphorylation has important implications for the development and treatment of GBM.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Glioblastoma/tratamento farmacológico , PTEN Fosfo-Hidrolase/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Animais , Astrócitos/citologia , Astrócitos/fisiologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/fisiologia , Receptores ErbB/metabolismo , Cloridrato de Erlotinib , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Camundongos , Camundongos Mutantes , Camundongos Nus , PTEN Fosfo-Hidrolase/genética , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Transplante Heterólogo , Células Tumorais Cultivadas , Tirosina/metabolismoRESUMO
Tapentadol (TAP) and oxycodone/naloxone (OXN) potentially offer an improved opioid tolerability. However, real-world studies in chronic non-cancer pain (CNCP) remain scarce. Our aim was to compare effectiveness and security in daily pain practice, together with the influence of pharmacogenetic markers. An observational study was developed with ambulatory test cases under TAP (n = 194) or OXN (n = 175) prescription with controls (prescribed with other opioids (control), n = 216) CNCP patients. Pain intensity and relief, quality of life, morphine equivalent daily doses (MEDD), concomitant analgesic drugs, adverse events (AEs), hospital frequentation and genetic variants of OPRM1 (rs1799971, A118G) and COMT (rs4680, G472A) genes, were analysed. Test CNCP cases evidenced a significantly higher pain relief predictable due to pain intensity and quality of life (R2 = 0.3), in front of controls. Here, OXN achieved the greatest pain relief under a 28% higher MEDD, 8-13% higher use of pregabalin and duloxetine, and 23% more prescription change due to pain, compared to TAP. Whilst, TAP yielded a better tolerability due the lower number of 4 [0-6] AEs/patient, in front of OXN. Furthermore, OXN COMT-AA homozygotes evidenced higher rates of erythema and vomiting, especially in females. CNCP real-world patients achieved higher pain relief than other traditional opioids with a better tolerability for TAP. Further research is necessary to clarify the potential influence of COMT and sex on OXN side-effects.
Assuntos
Dor do Câncer , Dor Crônica , Analgésicos Opioides/efeitos adversos , Dor do Câncer/tratamento farmacológico , Dor do Câncer/genética , Dor Crônica/induzido quimicamente , Dor Crônica/tratamento farmacológico , Dor Crônica/genética , Constipação Intestinal/tratamento farmacológico , Preparações de Ação Retardada , Combinação de Medicamentos , Feminino , Humanos , Morfina/efeitos adversos , Naloxona/efeitos adversos , Oxicodona/efeitos adversos , Testes Farmacogenômicos , Qualidade de Vida , TapentadolRESUMO
The prevalence of personality disorders (PDs) and sexual dysfunction in chronic pain patients is higher than in general population. Our main objective was to analyse the influence of PD in patients with erectile dysfunction and chronic non-cancer pain and their response to andrological treatment. One-hundred one patients were included along 30 months. Pain intensity, quality of life, sexual life quality, anxiety and depression were analysed together with opioid dose. Erectile functioning was measured with the International Index of Erectile Function (IIEF) and PDs with Millon Clinical Multiaxial Inventory (MCMI-III). The mean age was 57 ± 12 years old, with moderate to severe pain, 70% were sexually active and presented moderate to severe ED. PDs were very frequent (31%, cut-off 85 and 84% cut-off 75 scores) mostly anxiety, compulsive, though disorder, somatoform and narcissistic. Self-defeating feature presence was significantly correlated (r = -0.4, 95% CI = -0.605 to -0.145, p = 0.002) with a more severe baseline ED and narcissistic, and a better response to andrological treatment (p = 0.010, d = 1.082). Patients with dysthymia features required significantly higher opioid doses vs. control (238 vs. 102 mg/day, respectively). These findings underline the importance of diagnosing PDs to rigorously treat patients with chronic pain and ED.
Assuntos
Dor Crônica , Disfunção Erétil , Idoso , Analgésicos Opioides/uso terapêutico , Dor Crônica/complicações , Disfunção Erétil/complicações , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Personalidade , Transtornos da Personalidade/complicações , Transtornos da Personalidade/epidemiologia , Estudos Prospectivos , Qualidade de VidaRESUMO
OBJECTIVES: The use of opioids to relieve pain is a challenge because of the high variability in dose requirements and tolerance profiles. Among potential modulators are the individual's genetic background and being female. Our aim was to evaluate sex bias and genotype-related influence on opioid titration safety, in chronic low back pain (CLBP), the most frequent chronic noncancer pain. METHODS: A 3-year prospective study was developed in opioid-naive CLBP patients. Data were self-reported by patients (pain [Visual Analogy Scale], adverse events [AEs], and health care resource utilization) and physicians (analgesic prescription, morphine equivalent daily dose, and suspected adverse drug reactions [ADRs]). Outcomes were analyzed as patients with AEs (case) or without (control) together with patients' sex and genotype. Gene variants in OPRM1 (rs1799971), COMT (rs4680), ABCB1 (rs1045642), UGT2B7 (rs12233719 and rs7438135), KCNJ6 (rs2070995 and rs6517442), and CYP3A5*3 (rs776746) were assessed. The hospital ethics committee approved the study, and statistical analyses were performed with R, v.3.2.4. RESULTS: A total of 179 patients were included (64% female, mean pain intensity 73±16 mm), and 90% of them presented at least 1 AE (median of 3 (1 to 6) AEs/patient) with a rate of 5 AEs: 1 ADR without differences due to sex. However, there is a significant delay in referral of female patients (a mean of 6 years) to the Pain Unit, being significantly 3 to 5 times more likely to present sleep or psychiatric disorders. Meanwhile male individuals showed more sexual and reproductive system disorders. Genotypes influenced skin (COMT, G472A-GG) and gastrointestinal (ABCB1, C3435T-CC) related problems. CONCLUSIONS: Sex bias affects female patients resulting in a CLBP diagnostic delay and a different analgesic safety profile. Moreover, the individual's genetic background might be useful to predict certain AEs in opioid-naive patients under an opioid titration procedure. Addressing sex in necessary to resolve inequalities in health care access.
Assuntos
Dor Crônica , Dor Lombar , Analgésicos Opioides/efeitos adversos , Dor Crônica/tratamento farmacológico , Dor Crônica/genética , Diagnóstico Tardio , Feminino , Genótipo , Humanos , Dor Lombar/tratamento farmacológico , Dor Lombar/genética , Masculino , Estudos Prospectivos , Receptores Opioides mu/genética , SexismoRESUMO
OBJECTIVES: To investigate whether endothelial nitric oxide synthase (eNOS) T786C, 4VNTR and G894â¯T gene polymorphisms could mediate in andrological treatment response in Spaniards. SUBJECT PATIENTS/METHODS: The study participants were Spaniard males with erectile dysfunction (ED) and chronic pain (nâ¯=â¯105) recruited at the Pain Unit. eNOS polymorphisms were genotyped by quantitative polymerase chain reaction using Taqman specific probes. Statistical analyses were carried out using R-3.2.4 software. RESULTS: A total of 69 patients required andrological treatment and 76% of them improved ED upon iPED5 (20%), testosterone (35%) or iPDE5/testosterone treatment (45%); being significantly better in T786C-CC patients. Multivariate regression analysis indicated that age, opioid daily dose and carriage of T786C-C allele influenced the risk and ED severity in Spaniard chronic pain patients. CONCLUSION: T786C polymorphism at eNOS locus appeared to be a major contributor in the variable erectile function iPDE5/testosterone response in Spaniards.
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Sleep problems (SP) are recognized as a common comorbid condition in autism spectrum disorder (ASD) and can influence core autism symptoms and mental and physical health. SPs can be lifelong and have been reported that adults on the autistic spectrum with and without intellectual disability (ID) present SPs (longer sleep latency, frequent night awakenings, and circadian rhythm sleep-wake disorders). A prospective, objective sleep study was conducted in 41 adults with ASD (33 ± 6 years old) and ID and 51 typically developing adults (33 ± 5 years old) using ambulatory circadian monitoring (ACM) recording wrist temperature, motor activity, body position, sleep, and light intensity. The findings indicated that individuals with ASD presented sleep difficulties including low sleep efficiency, prolonged sleep latency and increased number and length of night awakenings, together with daily sedentary behavior, and increased nocturnal activity. Furthermore, indications of an advanced sleep-wake phase disorder were found in these autistic adults. Examining sleep and markers of the circadian system showed significant differences between adults with ASD and ID and an age-matched, healthy adult population. The sleep disturbances described for this sample of adults with ASD and ID are similar to those of already described for adults with ASD without ID; their relationship with intellectual ability should be further studied. Improving knowledge of sleep patterns in ASD adults with ID might help to designed targeted interventions to improve their functioning and reduce family stress. Autism Research 2019, 12: 66-79. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: SPs are very frequent in autism from childhood to adulthood. We recorded sleep with a watch-like device in adults with autism and ID and compared sleep patterns with nonautistic volunteers. Results showed poorer sleep conditions in adults with autism (increased sleep latency and number/length of night awakenings) that resulted in decreased sleep efficiency. Increasing knowledge of the SPs in adults on the autism spectrum will allow to improve their and their families' quality of life.
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Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/fisiopatologia , Deficiência Intelectual/complicações , Deficiência Intelectual/fisiopatologia , Transtornos do Sono-Vigília/complicações , Transtornos do Sono-Vigília/fisiopatologia , Adulto , Feminino , Humanos , Masculino , Estudos ProspectivosRESUMO
BACKGROUND: The experience of chronic non-cancer pain (CNCP) is one of the most common reasons individuals seek medical attention. Patients with CNCP frequently experience concomitant sleep-related problems. OBJECTIVES: The aim was to evaluate sleep problems in opioid naïve CNCP patients, before and after opioid titration, analyzing the influence of OPRM1 gene variants. STUDY DESIGN: A prospective, cohort, observational study. SETTING: This study was performed at the Pain Unit of the Alicante University General Hospital. METHODS: Pain and Medical Outcomes Study Sleep questionnaire (MOS-Sleep) were assessed at baseline and 3 months after opioid titration in 231 opioid naïve CNCP patients. Sleep data was compared with a matched-control group (n = 64). Morphine equivalent daily doses, adverse events, and drugs prescribed for pain were also registered. OPRM1 polymorphism rs1799971 was analyzed by RT-PCR. Ethics Committee approved the study and results were analyzed by R software. RESULTS: After 3 months of opioid titration, patients with CNCP (63 ± 14 years, 64% female, VAS 74 ± 17 mm) significantly decreased pain intensity, anxiety and depression, and increased quality of life. Sleep problems were significantly more frequent in females (P = 0.002). Age, quality of life, anxiety, and depression all influenced sleep disturbances and problems indices, which were significantly different from the control group. Furthermore, the OPRM1 118-GG genotype was also associated with significantly lower sleep adequacy, and more sleep problems. LIMITATIONS: Total number of subjects studied was relatively small and most patients were on other non-opioid centrally-acting medications. CONCLUSIONS: Opioids decreased CNCP severity, improving patients' psychological areas, and quality of life. However, patients with OPRM1 118-GG genotype indicated an increase in sleep problems and worsening sleep pattern while taking opioids. KEY WORDS: OPRM1, pharmacogenetics, MOS-Sleep, opioids, chronic noncancer pain, sleep related problems, sleep problem index SLP-6 and SLP-9.
Assuntos
Analgésicos Opioides/uso terapêutico , Dor Crônica/tratamento farmacológico , Receptores Opioides mu/genética , Sono/efeitos dos fármacos , Sono/genética , Adulto , Idoso , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de VidaRESUMO
OBJECTIVES: To investigate whether endothelial nitric oxide synthase (eNOS) T786C, 4VNTR and G894â¯T gene polymorphisms could mediate in andrological treatment response in Spaniards. SUBJECT PATIENTS/METHODS: The study participants were Spaniard males with erectile dysfunction (ED) and chronic pain (nâ¯=â¯105) recruited at the Pain Unit. eNOS polymorphisms were genotyped by quantitative polymerase chain reaction using Taqman specific probes. Statistical analyses were carried out using R-3.2.4 software. RESULTS: A total of 69 patients required andrological treatment and 76% of them improved ED upon iPED5 (20%), testosterone (35%) or iPDE5/testosterone treatment (45%); being significantly better in T786C-CC patients. Multivariate regression analysis indicated that age, opioid daily dose and carriage of T786C-C allele influenced the risk and ED severity in Spaniard chronic pain patients. CONCLUSION: T786C polymorphism at eNOS locus appeared to be a major contributor in the variable erectile function iPDE5/testosterone response in Spaniards.
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PURPOSE: Intellectual disability (ID) and autism spectrum disorder (ASD) are common, co-occurring developmental disorders and are frequently associated with sleep problems. This study aimed to assess the effectiveness and tolerability of agomelatine as a pharmacotherapy for sleep problems in ASD adults with ID. METHOD: A randomised, crossover, triple-blind, placebo-controlled clinical trial, with two three-month periods of treatment starting with either agomelatine or placebo and a washout period of two weeks. Ambulatory circadian monitoring (24 hours/7 days) evaluated total sleep time (TST) as the primary outcome variable. RESULTS: Participants (N=23; 35±12 years old; 83% male) had a median of three (interquartile range (IQR) 1-4) co-morbidities and were taking a median of five (IQR 2-7) prescribed drugs. Before agomelatine or placebo treatment, all subjects presented with insomnia symptoms, including sleep latency (100% abnormal, 55±23 minutes) or TST (55% abnormal, 449±177 minutes), and 66% had circadian rhythm sleep-wake abnormalities with rhythm phase advancements according to the M5 sleep phase marker values. During the three-month agomelatine treatment, night TST significantly increased by a mean of 83 minutes (16% abnormal, 532±121 minutes), together with a phase correction (M5 1:45±2:28 hours vs. 3:15±2:20 hours), improving sleep stability in wrist temperature rhythm (0.43±0.29 vs. 0.52±0.18 AU). Adverse events were mild and transient. CONCLUSIONS: Agomelatine was effective and well tolerated for treating insomnia and circadian rhythm sleep problems present in adults with ASD and ID.
Assuntos
Acetamidas/administração & dosagem , Transtorno do Espectro Autista/tratamento farmacológico , Hipnóticos e Sedativos/administração & dosagem , Deficiência Intelectual/tratamento farmacológico , Transtornos do Sono-Vigília/tratamento farmacológico , Acetamidas/efeitos adversos , Adulto , Transtorno do Espectro Autista/complicações , Ritmo Circadiano , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Deficiência Intelectual/complicações , Masculino , Pessoa de Meia-Idade , Transtornos do Sono-Vigília/etiologia , Fatores de Tempo , Adulto JovemRESUMO
Screening for opioid use disorder should be considered in chronic non-cancer pain (CNCP) patients with long-term use of opioids. The aim of our study was to assess the effectiveness of an individualized treatment plan (ITP) for prescription opioid dependence that included screening of pharmacogenetic markers. An observational prospective study was performed using prescription opioid-dependent CNCP outpatients (n = 88). Patients were divided into nonresponders, responders, or high responders according to their response to the ITP. Genotyping of OPRM1 (A118G), OPRD1 (T921C), COMT (G472A), ABCB1 (C3435T), and ARRB2 (C8622T) was performed by real-time PCR. Our ITP achieved a significant reduction of the morphine equivalent daily dose (MEDD) in 64% of responders, including 33% of high responders. Nonopioid medication or buprenorphine use was significantly higher at final versus basal visit. 118-AA OPRM1 patients required significantly lower MEDD at basal and final visits. Our ITP showed effectiveness and security in reducing MEDD in opioid-dependent patients, with good conversion to buprenorphine that was more pronounced in 118-AA OPRM1 patients.
Assuntos
Analgésicos Opioides/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Receptores Opioides mu/genética , Adulto , Idoso , Buprenorfina/uso terapêutico , Dor Crônica/tratamento farmacológico , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Opioides/diagnóstico , Transtornos Relacionados ao Uso de Opioides/genética , Farmacogenética/métodos , Polimorfismo de Nucleotídeo Único , Estudos ProspectivosRESUMO
The present study was designed to investigate the functional status of ß2 adrenoceptors (ß2AR) in two models of chronic inflammatory disease: liver cirrhosis (LC) and osteoarthritis (OA). The ß2AR gene contains three single nucleotide polymorphisms at amino acid positions 16, 27 and 164. The aim of the present study was to investigate the potential influence of lymphocyte ß2AR receptor functionality and genotype in LC and OA patients. Blood samples from cirrhotic patients (n=52, hepatic venous pressure gradient 13±4 mmHg, CHILD 7±2 and MELD 11±4 scores), OA patients (n=30, 84% KellgrenLawrence severity 4 grade, 14% knee replacement joint) and healthy volunteers as control group (n=26) were analyzed. Peripheral blood mononuclear cells (PBMC) were isolated from whole blood and basal and isoproterenol induced adenylate cyclase activity (isoproterenol stimulus from 109 to 104 mM), and ß2AR allelic variants (rs1042713, rs1042714, rs1800888) were determined. ß2AR functionality was decreased in the two different models of chronic inflammatory disease studied, OA (50% vs. control) and LC (85% vs. control). In these patients, the strength of the ß2AR response to adrenergic stimulation was very limited. Adrenergic modulation of PBMC function through the ß2AR stimulus is decreased in chronic inflammatory processes including LC and OA, suggesting that the adrenergic system may be important in the development of these processes.
Assuntos
Genótipo , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Osteoartrite/etiologia , Osteoartrite/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores , Estudos de Casos e Controles , Doença Crônica , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Leucócitos Mononucleares/metabolismo , Cirrose Hepática/diagnóstico , Masculino , Pessoa de Meia-Idade , Osteoartrite/diagnósticoRESUMO
BACKGROUND: Video-assisted thoracic surgery (VATS) emerged as a minimally invasive surgery for diseases in the field of thoracic surgery. We herein reviewed our experience on thoracoscopic lobectomy for early lung cancer and evaluated Health System use. METHODS: A cost-effectiveness study was performed comparing VATS vs. open thoracic surgery (OPEN) for lung cancer patients. Demographic data, tumor localization, dynamic pulmonary function tests [forced vital capacity (FVC), forced expiratory volume in one second (FEV1), diffusion capacity (DLCO) and maximal oxygen uptake (VO2max)], surgical approach, postoperative details, and complications were recorded and analyzed. RESULTS: One hundred seventeen patients underwent lung resection by VATS (n=42, 36%; age: 63±9 years old, 57% males) or OPEN (n=75, 64%; age: 61±11 years old, 73% males). Pulmonary function tests decreased just after surgery with a parallel increasing tendency during first 12 months. VATS group tended to recover FEV1 and FVC quicker with significantly less clinical and post-surgical complications (31% vs. 53%, P=0.015). Costs including surgery and associated hospital stay, complications and costs in the 12 months after surgery were significantly lower for VATS (P<0.05). CONCLUSIONS: The VATS approach surgery allowed earlier recovery at a lower cost than OPEN with a better cost-effectiveness profile.
RESUMO
INTRODUCTION AND OBJECTIVE: Chronic pain is associated with comorbidities that have an impact on the quality of life of patients and, among others, affect their sexual functioning. One of the most relevant side effects of opioid analgesics is erectile dysfunction (ED), due in part to the inhibition of the gonadal-pituitary-hypothalamic axis and the decline in testosterone levels. To evaluate ED and effectiveness of treatment in men with chronic pain treated with long-term opioids. MATERIAL AND METHODS: Prospective observational study lasting 3 years, where the intensity of pain (visual analogue scale, 0-10cm), erectile function (IIEF-EF, range 1-30 points), quality of life (EQ-VAS, 0-100mm), quality of sexual life (MSLQ-QOL, 0-100 points), anxiety/depression (HAD, 0-21 points) and testosterone levels, was assessed in patients who reported sexual dysfunction (ED or libido modification). A 6-month follow-up was applied to each patient after administering the usual treatment in the Andrology Unit. The study was approved by the Clinical Research Ethics Committee and data were statistically analyzed with the GraphPad Prism 5 software. RESULTS: ED was observed in 27.6% of patients (n=105, 57±12.2 years, mean dose of morphine equivalent=107.1±107.9mg/day, 84.3% adjuvant analgesics). After 6 months, 42% of patients showed a significant improvement after being treated with iPDE5 (48.5%) and/or testosterone gel (81.8%), with a resolution rate of 31% (p=0.000). A positive correlation was observed between the improvement of IIEF and quality of sexual life (55.5±25.7 points, p=0.000), as well as anxiety (7.4±4.3 points, p=0.048). No significant changes were observed in the levels of testosterone, in the levels of pain nor in the quality of life, which remained moderate. CONCLUSIONS: Erectile function and quality of sexual life, as well as anxiety, improved in patients treated chronically with opioids after administering andrological treatment. The management of patients with pain should include a review of their sexual health history given the significant emotional impact posed to the patient, the impact on their overall quality of life and its good clinical response to an interdisciplinary treatment.
Assuntos
Analgésicos Opioides/efeitos adversos , Dor Crônica/tratamento farmacológico , Disfunção Erétil/induzido quimicamente , Morfina/efeitos adversos , Adulto , Idoso , Analgésicos Opioides/uso terapêutico , Androgênios/uso terapêutico , Dor Crônica/diagnóstico , Dor Crônica/psicologia , Disfunção Erétil/diagnóstico , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/epidemiologia , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/uso terapêutico , Medição da Dor , Inibidores da Fosfodiesterase 5/uso terapêutico , Prevalência , Estudos Prospectivos , Qualidade de Vida/psicologia , Testosterona/uso terapêutico , Resultado do TratamentoRESUMO
Heterogeneity is a hallmark of tumors and has a crucial role in the outcome of the malignancy, because it not only confounds diagnosis, but also challenges the design of effective therapies. There are two types of heterogeneity: inter-tumor and intra-tumor heterogeneity. While inter-tumor heterogeneity has been studied widely, intra-tumor heterogeneity has been neglected even though numerous studies support this aspect of tumor pathobiology. The main reason has been the technical difficulties, but with new advances in single-cell technology, intra-tumor heterogeneity is becoming a key area in the study of cancer. Several models try to explain the origin and maintenance of intra-tumor heterogeneity, however, one prominent model compares cancer with a tree where the ubiquitous mutations compose the trunk and mutations present in subpopulations of cells are represented by the branches. In this review we will focus on the intra-tumor heterogeneity of glioblastoma multiforme (GBM), the most common brain tumor in adults that is characterized by a marked heterogeneity at the cellular and molecular levels. Better understanding of this heterogeneity will be essential to design effective therapies against this devastating disease to avoid tumor escape.