Sex-Differences in Pain and Opioid Use Disorder Management: A Cross-Sectional Real-World Study

Background: It is essential to focus attention on sex-specific factors which are clinically relevant in pain management, especially with regards to opioid use disorder (OUD) risk. The aim of this study was to explore potential sex-differences in chronic non-cancer pain (CNCP) outpatients. (2) Methods: An observational cross-sectional study was conducted under CNCP outpatients with long-term prescribed opioids (n = 806), wherein 137 patients had an OUD diagnosis (cases, 64% females) and 669 did not (controls, 66% females). Socio-demographic, clinical, and pharmacological outcomes were analyzed. (3) Results: Female controls presented an older age and less intensive pain therapy but higher psychotropic prescriptions and emergency department visits compared to male controls. Meanwhile, cases demonstrated a younger age, higher work disability, double morphine equivalent daily dose, and benzodiazepine use compared with controls. Here, female cases showed an 8% greater substance use disorder (OR 2.04 [1.11-3.76]) and 24% lower tramadol use, while male cases presented a 22% higher fentanyl use (OR 2.97 [1.52-5.81]) and reported the highest number of adverse drug reactions (24%, OR 2.40 [1.12-5.16]) compared with controls. (4) Conclusions: An OUD individual risk profile was evidenced with sex-differences to take into consideration to design equal prevention programs

Pharmacogenetic Guided Opioid Therapy Improves Chronic Pain Outcomes and Comorbid Mental Health: A Randomized, Double-Blind, Controlled Study

Interindividual variability in analgesic response is at least partly due to well-characterized polymorphisms that are associated with opioid dosing and adverse outcomes. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has put forward recommendations for the CYP2D6 phenotype, but the list of studied drug-gene pairs continues to grow. This clinical trial randomized chronic pain patients (n = 60), referred from primary care to pain unit care into two opioid prescribing arms, one guided by CYP2D6, μ-opioid receptor (OPRM1), and catechol-O-methyl transferase (COMT) genotypes vs. one with clinical routine. The genotype-guided treatment reduced pain intensity (76 vs. 59 mm, p < 0.01) by improving pain relief (28 vs. 48 mm, p < 0.05), increased quality of life (43 vs. 56 mm p < 0.001), and lowered the incidence of clinically relevant adverse events (3 [1-5] vs. 1 [0-2], p < 0.01) and 42% opioid dose (35 [22-61] vs. 60 [40-80] mg/day, p < 0.05) as opposed to usual prescribing arm. The final health utility score was significantly higher (0.71 [0.58-0.82] vs. 0.51 [0.13-0.67] controls, p < 0.05) by improving sleepiness and depression comorbidity, with a significant reduction of 30-34% for headache, dry mouth, nervousness, and constipation. A large-scale implementation analysis could help clinical translation, together with a pharmaco-economic evaluation

Mindfulness and job control as moderators of the relationships between demands and innovative work behaviours

Innovation enables organizations to respond successfully to rapid changes in a business environment. This innovation capability largely relies on employees. Although workers are required to be innovative, their jobs frequently contain higher demands that might make it difficult for them to innovate at work. The Job Demands-Control model active hypothesis suggests that highly demanding jobs that allow individuals enough discretion enhance innovative performance. Improving an important attentional resource such as mindfulness at work might also play a similar role, although there is a need for more research at this level. The main aim of this study is to examine the relative contribution of job control and increases in mindfulness as moderators in the job demands-innovation work behaviours relationship. The results obtained with 221 workers indicated that in previous situations characterized by high job demands (T1), workers who increase their capacity for mindfulness are more innovative in the future (T2)

Systemic transport of Alfalfa mosaic virus can be mediated by the movement proteins of several viruses assigned to five genera of the 30K family

We previously showed that the movement protein (MP) gene of Alfalfa mosaic virus (AMV) is functionally exchangeable for the cell-to-cell transport of the corresponding genes of Tobacco mosaic virus (TMV), Brome mosaic virus, Prunus necrotic ringspot virus, Cucumber mosaic virus and Cowpea mosaic virus. We have analysed the capacity of the heterologous MPs to systemically transport the corresponding chimeric AMV genome. All MPs were competent in systemic transport but required the fusion at their C terminus of the coat protein-interacting C-terminal 44 aa (A44) of the AMV MP. Except for the TMV MP, the presence of the hybrid virus in upper leaves correlated with the capacity to move locally. These results suggest that all the MPs assigned to the 30K superfamily should be exchangeable not only for local virus movement but also for systemic transport when the A44 fragment is present.We thank L. Corachan for her excellent technical assistance. This work was supported by the Spanish granting agency DGICYT via grant BIO2011-25018 and by the Generalitat Valenciana via grant PROMETEO 2011-003.Fajardo, TVM.; Peiró Morell, A.; Pallás Benet, V.; Sanchez Navarro, JA. (2013). Systemic transport of Alfalfa mosaic virus can be mediated by the movement proteins of several viruses assigned to five genera of the 30K family. Journal of General Virology. 94:677-681. https://doi.org/10.1099/vir.0.048793-0S6776819

Opioid Monitoring in Clinical Settings: Strategies and Implications of Tailored Approaches for Therapy

This review emphasises the importance of opioid monitoring in clinical practice and advocates for a personalised approach based on pharmacogenetics. Beyond effectively managing pain, meticulous oversight is required to address concerns about side effects, specially due to opioidcrisis- related abuse and dependence. Various monitoring techniques, along with pharmacogenetic considerations, are critical for personalising treatment and optimising pain relief while reducing misuse and addiction risks. Future perspectives reveal both opportunities and challenges, with advances in analytical technologies holding promise for increasing monitoring efficiency. The integration of pharmacogenetics has the potential to transform pain management by allowing for a precise prediction of drug responses. Nevertheless, challenges such as prominent pharmacogenetic testing and guideline standardisation persist. Collaborative efforts are critical for transforming scientific advances into tangible improvements in patient care. Standardised protocols and interdisciplinary collaboration are required to ensure consistent and evidence-based opioid monitoring. Future research should look into the long-term effects of opioid therapy, as well as the impact of genetic factors on individual responses, to help guide personalised treatment plans and reduce adverse events. Lastly, embracing innovation and collaboration can improve the standard of care in chronic pain management by striking a balance between pain relief and patient safet

Therapeutic alliance impact on analgesic outcomes in a real-world clinical setting: An observational study

A good therapeutic alliance is relevant for healthcare providers exposed to patients\u27 suffering, especially since patients and physicians may understand the painful experience differently. Our aim was to explore the impact of therapeutic alliance on analgesic outcomes in a real-world interdisciplinary pain unit (PU). A cross-sectional observational study was conducted on outpatients (n = 69) using opioids on a long-term basis for the treatment of chronic non-cancer pain, where clinical pharmacologists and pharmacists advised patients about their opioid treatment. Responses to the patient-doctor relationship questionnaire (PDRQ), sociodemographic and clinical information (pain level, quality of life and hospital use) were collected, whereas pharmacology data (analgesic prescription, adverse events, and compliance) were obtained from electronic health records. Patients were predominantly middle-aged (75 % women, 72 % retired), experiencing moderate pain (VAS 40–70 mm) on average, and under a high morphine equianalgesic dosage (95 ± 88 mg per day, mainly tapentadol or fentanyl). Patients with better PDRQ outcomes, and therefore better therapeutic alliance, showed lower pain intensity than patients with worse PDRQ outcomes (pain intensity: high scores 60 ± 47 mm and medium scores 60 ± 45 mm vs. low scores 80±75 mm, p < 0.01). Along with this, pain intensity was lower when patients affirmed that, thanks to the healthcare providers, they “gained new insight”, “felt better”, or “felt content with their doctor’s treatment”. What´s more, patients who affirmed “I benefit from the treatment” experienced increased pain relief (benefit 40 ± 30 vs. non-benefit 19 ± 26 mm, p = 0.010) and improved quality of life (benefit 33 ± 25 vs. non-benefit 18 ± 16 mm, p = 0.031). However, there was a percentage of patients who did not fully understand the provided information, which is something to be taken into account to improve in clinical routine. Therapeutic alliance supported by pharmacist experts on pain management can be an effective strategy to improve analgesic outcomes. Further efforts are needed to improve communication strategies for pain management. Future directions of research should include the analysis of the role of the pharmacist in poly-professional consultations as related to the advice of patients about their medication, and the mutual trust with the patients

Gender bias in therapeutic effort: from research to health care

Existen dimensiones relevantes desde una perspectiva de género relacionadas con el esfuerzo terapéutico. Se pretende ilustrar y traer a debate posibles sesgos de género relacionados con los medicamentos, mediante el análisis del consumo en las mujeres, la prescripción de fármacos biológicos según sexo, la potencial desigualdad de género en las reacciones adversas a los medicamentos y la investigación con ensayos clínicos, así como las decisiones de las instituciones internacionales en la comercialización de medicamentos. Se observa una mayor tendencia a prescribir analgésicos, con independencia del dolor, y fármacos para síntomas depresivos de baja intensidad en mujeres que en hombres. Lo contrario sucede en la prescripción de estatinas y dosis adecuadas, y con la mayor probabilidad de prescripción de antifactor de necrosis tumoral en hombres que en mujeres con espondilitis anquilosante, pese a la similar carga de la enfermedad. Las reacciones adversas a los medicamentos se observan con más frecuencia en mujeres que en hombres, donde determinantes como el peso corporal están influyendo poco en la dosificación. En la actualidad se considera escasamente en la prescripción que las mujeres presentan diferencias en la actividad de las enzimas del citocromo CYPP450, que puede afectar a la velocidad del metabolismo hepático. Incluso hay efectos inmunológicos, genéticos y epigenéticos (por la herencia y la dosificación desigual de los genes ubicados en los cromosomas X e Y) que pueden influir en estas diferencias por sexo. Por último, mediante los casos de ensayos clínicos de la terapia hormonal, un fármaco para el deseo sexual inhibido de las mujeres y un anticonceptivo para hombres, se muestran sesgos y estereotipos de género que influyen en una potencial generación de desigualdades, especialmente en las reacciones adversas a los medicamentos en perjuicio de las mujeres. Concluyendo, los profesionales sanitarios atribuyen con frecuencia a la emocionalidad de las mujeres lo que son síntomas físicos, influyendo en la mayor prescripción de fármacos sintomáticos en ellas. Debe analizarse si la misma razón influye en la menor prescripción de fármacos terapéuticos en mujeres que en hombres. Existen determinantes biológicos a considerar por su influencia en una mayor toxicidad farmacológica en las mujeres. Los ensayos clínicos deben mejorar atendiendo a las recomendaciones de género de la Food and Drug Administration.There are relevant dimensions from a gender perspective related to therapeutic effort. To illustrate and discuss possible gender bias related to medicines, through the consumption analysis in women, the prescription of biological drugs according to sex, the potential gender inequality in adverse drug reactions, and research with clinical trials, as well as the decisions of international institutions in the marketing of medicinal products. There is greater tendency to prescribe pain relievers, regardless of pain, and drugs for low intensity depressive symptoms in women than in men. The opposite occurs in the prescription of statins and adequate doses, and with the greater probability of prescribing anti-tumor necrosis factor in men than in women with ankylosing spondylitis, despite a similar disease burden. Adverse drug reactions are observed more frequently in women than in men, where determinants such as body weight are having little influence on the dosage. It is currently scarcely considered in the prescription that women have differences in the activity of cytochrome CYPP450 enzymes, which can affect the liver’s metabolism rate. There are even immunological, genetic and epigenetic effects (due to heredity and uneven gene dosing located in the X and Y chromosomes) that can influence these differences by sex. Finally, through cases of hormonal therapy clinical trials, a drug for women’s inhibited sexual desire and a contraceptive for men, gender bias and stereotypes are shown to influence a potential generation of inequalities, especially in adverse drug reactions to the detriment of women. In conclusion, health professionals frequently attribute physical symptoms to women’s emotionality, influencing their greater prescription of symptomatic drugs. Whether the same reason influences the lower prescription of therapeutic drugs in women than in men should be analyzed. There are biological determinants to consider due to their influence on a greater pharmacological toxicity in women. Clinical trials should improve according to the gender recommendations by the Food and Drugs Administration

Effect of Cytochrome P450 and ABCB1 Polymorphisms on Imatinib Pharmacokinetics After Single-Dose Administration to Healthy Subjects

Background: Validated genomic biomarkers for oncological drugs are expanding to improve targeted therapies. Pharmacogenetics research focusing on the mechanisms underlying imatinib suboptimal response might help to explain the different treatment outcomes and drug safety profiles. Objective: To investigate whether polymorphisms in genes encoding cytochrome P450 (CYP) enzymes and ABCB1 transporter affect imatinib pharmacokinetic parameters.Methods: A prospective, multicenter, pharmacogenetic pilot study was performed in the context of two separate oral imatinib bioequivalence clinical trials, which included 26 healthy volunteers. DNA was extracted in order to analyze polymorphisms in genes CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5 and ABCB1. Imatinib plasma concentrations were measured by HPLC-MS/MS. Pharmacokinetic parameters were calculated by non-compartmental methods using WinNonlin software. Results: Volunteers (n = 26; aged 24 ± 3 years; 69% male) presented regular pharmacokinetic imatinib data (concentration at 24 h, 436 ± 140 ng/mL and at 72 h, 40 ± 26 ng/mL; AUC0-72 32,868 ± 10,713 ng/mL⋅h; and Cmax 2074 ± 604 ng/mL). CYP2B6 516GT carriers showed a significant reduction of imatinib concentration at 24 h (23%, 391 ng/dL vs 511 ng/dL in 516GG carriers, p = 0.005) and elimination half-life (11%, 12.6 h vs 14.1 h in 516GG carriers, p = 0.041). Carriers for CYP3A4 (*22/*22, *1/*20 and *1/*22 variants) showed a reduced frequency of adverse events compared to *1/*1 carriers (0 vs 64%, p = 0.033). The other polymorphisms analyzed did not influence pharmacokinetics or drug toxicity. Conclusion: CYP2B6 G516T and CYP3A4 *20,*22 polymorphisms could influence imatinib plasma concentrations and safety profile, after single-dose administration to healthy subjects. This finding needs to be confirmed before it is implemented in clinical practice in oncological patients under treatment with imatinib

β2‑adrenergic receptor functionality and genotype in two different models of chronic inflammatory disease: Liver cirrhosis and osteoarthritis

The present study was designed to investigate the functional status of β2 adrenoceptors (β2AR) in two models of chronic inflammatory disease: liver cirrhosis (LC) and osteoarthritis (OA). The β2AR 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 β2AR 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% Kellgren‑Lawrence 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 10‑9 to 10‑4 mM), and β2AR allelic variants (rs1042713, rs1042714, rs1800888) were determined. β2AR 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 β2AR response to adrenergic stimulation was very limited. Adrenergic modulation of PBMC function through the β2AR 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