Impact of CYP2D6 genotype on opioid use disorder deprescription: an observational prospective study in chronic pain with sex-differences.

Introduction: Opioid deprescription is the process of supervised tapering and safe withdrawal when a potentially inappropriate use is detected. This represents a challenge in chronic non-cancer pain (CNCP) patients who may respond differently to the procedure. Our aim was to analyze the potential impact of CYP2D6 phenotypes and sex on the clinical and safety outcomes during an opioid use disorder (OUD) tapering process. Methods: A prospective observational study was conducted on CNCP ambulatory OUD patients (cases, n = 138) who underwent a 6-month opioid dose reduction and discontinuation. Pain intensity, relief and quality of life (Visual analogue scale, VAS 0-100 mm), global activity (GAF, 0-100 scores), morphine equivalent daily dose (MEDD), analgesic drugs adverse events (AEs) and opioid withdrawal syndrome (OWS, 0-96 scores) were recorded at basal and final visits. Sex differences and CYP2D6 phenotypes (poor (PM), extensive (EM) and ultrarapid (UM) metabolizers based on CYP2D6*1, *2, *3, *4, *5, *6, *10, *17, *41, 2D6*5, 2D6 × N, 2D6*4 × 2 gene variants) were analyzed. Results: Although CYP2D6-UM consumed three-times less basal MEDD [40 (20-123) mg/day, p = 0.04], they showed the highest number of AEs [7 (6-11), p = 0.02] and opioid withdrawal symptoms (46 ± 10 scores, p = 0.01) after deprescription. This was inversely correlated with their quality of life (r = -0.604, p < 0.001). Sex-differences were evidenced with a tendency to a lower analgesic tolerability in females and lower quality of life in men. Discussion: These data support the potential benefits of CYP2D6-guided opioid deprescription, in patients with CNCP when OUD is detected. Further studies are required to understand a sex/gender interaction.

Should We be Concerned with Nicotine in Sport? Analysis from 60,802 Doping Control Tests in Italy.

BACKGROUND: Nicotine is a psychostimulant drug with purported use in sports environments, though the use of nicotine among athletes has not been studied extensively. OBJECTIVE: The aim of this study was to assess the nicotine positivity rate in 60,802 anti-doping urine samples from 2012 to 2020. METHODS: Urine samples obtained in-competition at different national and international sports events held in Italy during the period 2012-2020 were analysed. All samples were from anonymous athletes that were collected and analysed at the WADA-accredited antidoping laboratory in Rome, Italy. Samples were analysed by gas chromatography coupled with mass spectrometry, with a cut-off concentration for nicotine of > 50 ng/mL. Results were stratified by year, sport and sex. RESULTS: An overall mean of 22.7% of the samples (n = 13,804; males: n = 11,099; females: n = 2705) showed nicotine intake, with male samples also displaying higher positivity rates than female (24.1% vs 18.5%). Sample positivity was higher during 2012-2014 (25-33%) than 2015-2020 (15-20%). Samples from team sports displayed a higher positivity rate than those from individual sports (31.4 vs 14.1%). CONCLUSIONS: The current data demonstrates that one in five samples from a range of 90 sports test positive for nicotine in-competition. There is a lower positivity rate in endurance versus power/strength athletes and higher positivity rate in team versus individual sports, probably accounted for by differences in physiological and psychological demands and the desire for socialisation. WADA, international and national sports federations should consider these findings with concern, proactively investigate this phenomenon and act in order to protect the health and welfare of its athletes.

Benzodiazepines in sport, an underestimated problem: Recommendations for sports medicine physicians' practice.

In the last years, only few studies in literature have focused on the use and abuse of benzodiazepines (BZDs) in sport. Benzodiazepine-related problems include misuse, addiction, driving impairments, and morbidity and mortality related to overdose and withdrawal. Two clinical cases regarding elite endurance athletes evidenced that they had started to use BZDs to counteract insomnia, to recover faster from training sessions and to manage muscle pain. One of the important points that emerged from their stories was that their sports doctors did not recognize the drugs' addictive properties, and did not intervene to gradually reduce the dosage. Experts have previously provided recommendations for BZD therapy management in clinical practice. In this article, we would like to address sports medicine physicians specifically and provide guidelines to help them manage situations involving BZD prescription, the recognition of addiction, and intervention strategies.

The effect of benzodiazepines on exercise in healthy adult participants: A systematic review.

The use of benzodiazepines among athletes is a new and growing phenomenon according to the recent case reports published. Therefore, there is an urgent need to identify if there is rationale for the use of benzodiazepines and its effects on exercise. This review aims to provide an overview of the effects of benzodiazepine in exercise among healthy adult participants and if they might have an additional ergogenic or ergolytic effect. Electronic searches were conducted in Pubmed, Scopus and Web of Science databases up to December 2020. Search terms covered all active substance names of benzodiazepine class and search terms about sport, exercise performance and athletes. We used the Physiotherapy Evidence Database (PEDro) to assess the methodological quality of the studies included in the qualitative synthesis. The methods and planned analyses of this systematic review were pre-registered at Open Science Framework (OSF: https://osf.io/uq6j8). A total of thirty-one full articles were assessed for eligibility and ten of them were included in the qualitative analysis. We found 7 studies which investigated benzodiazepine effects after an acute dose administered, whereas only 3 studies studied long-term effects after several doses used. According to our findings it does not seem that benzodiazepines might have an ergogenic or ergolytic effect on exercise performance. The small number of articles included (n = 10) with a relatively low sample of participants (N = 16, range = 6-58) does invite us to take our results with caution. This review evidences valuable insights into the use of benzodiazepines from a physical performance point of view. Our findings highlight the unclear effects benzodiazepines might have on exercise performance and its possible mechanisms of actions. Hence, the need to conduct new studies to understand its possible effects becomes essential to protect the health of athletes of all levels.

Multimorbidity and psychotropic polypharmacy among participants with autism spectrum disorder with intellectual disability.

Nowadays, adults with autism spectrum disorder (ASD) experience several comorbidities whose treatment implies a wide range of psychotropic prescriptions. This study aimed to evaluate medication-related safety, drug-drug interactions, and psychotropics prescription trends. We conducted an observational and multicentric pharmacovigilance study in subjects with ASD and Intellectual disability (ID, n = 83). Clinical information (diagnoses, ongoing medications, comorbidities [multimorbidity ≥ 4 chronic health conditions]) and psychotropic prescriptions (polypharmacy ≥ 4 chronic drugs, daily drug doses, co-prescription) were registered. Ethical approval for this study was obtained. Participants (30±10 years old, 86% men, BMI 27±6 kg/m2) displayed 37% multimorbidity (mean of 3, IQR 2-4), and 57% polypharmacy (13% out of dose recommended range). Most drugs prescribed were psychotropic risperidone which is related to nervous system comorbidities (18% epilepsy, 16% insomnia, and 14% psychotic agitations). Risperidone and quetiapine were co-prescribed in 60% of the cases without any monitoring adverse event routine. The rates of multimorbidity and polypharmacy, among our young adults with ASD and ID, are concerning. Data suggest the need to develop a pharmacovigilance monitoring system to evaluate prescription accuracy, long-term safety of ongoing medications, and the fixed doses in this autistic population with associated ID.

Efectividad y farmacogenética en un protocolo de desprescripción en pacientes con dolor crónico y dependencia iatrogénica a opioides / Effectiveness and pharmacogenetics in a deprescription protocol in chronic pain patients and iatrogenic opioid dependence

Los protocolos de desprescripción deberían formar parte del cuidado de pacientes con dolor crónico no oncológico que hayan desarrollado dependencia iatrogénica a opioides. Nuestro objetivo es evaluar la implantación de un protocolo de desprescripción individualizado (PDI) incluyendo marcadores farmacogenéticos. Se llevó a cabo un estudio observacional prospectivo, de 6 meses de seguimiento con pacientes con dependencia iatrogénica a opioides (n=88). Una vez finalizado el PDI, los pacientes se agruparon en "respondedores" o "no respondedores" al protocolo. Las variantes de los genes OPRM1 (A118G), OPRD1 (T921C), COMT (G472A), ABCB1 (C3435T), ARRB2 (C8622T) y CYP2D6 se determinaron por PCR a tiempo real. Al concluir el estudio, el PDI alcanzó un 64% de respondedores con una reducción de dosis equivalente de morfina diaria (DEMD) significativa (visita basal vs. final, 167 vs. 87 mg/día, p=0.007) sin presentar síndrome de abstinencia, manteniendo un dolor, alivio, calidad de vida y funcionalidad moderados. El porcentaje de pacientes usando buprenorfina o sin opioides fue significativamente mayor en la visita final (65% vs. 22%, p<0.001). Los portadores del genotipo nativo 118-AA OPRM1 requirieron una DEMD menor en la visita inicial (modelo dominante, p=0.018 y superdominante, p=0.020) y en la final (modelo codominante, p=0.032 y recesivo, p=0.032). Nuestro PDI mostró efectividad y seguridad reduciendo la DEMD con una buena conversión a buprenorfina, especialmente en pacientes con genotipo 118-AA OPRM1

Deprescription protocols should be part of chronic non-cancer pain patients’ care in those cases where iatrogenic dependence is present. Our aim is to assess the implementation of a individualized deprescription protocol (IDP) including pharmacogenetic markers. An observational prospective study was carried out in patients presenting prescription opioid dependence (n=88) during 6 months of followup. Once the IDP was ended, patients were grouped in "responders" or "non-responders" to IDP. Genetic variants from OPRM1 (A118G), OPRD1 (T921C), COMT (G472A), ABCB1 (C3435T) and ARRB2 (C8622T) and CYP2D6 genes, were determined by real time PCR. At the end of the study, PDI achieved a 64 % of responders with a significant morphine equivalent daily dose (MEDD) reduction (basal visit vs. final, 167 vs. 87 mg/day, p=0.007) without presenting opiate withdrawal syndrome, keeping a moderate pain intensity, pain relief, quality of life and functionality. Frequency of patients using buprenorphine or without opioids was significantly higher in the last visit than in basal visit (65 % vs. 22 %, p<0.001). Carriers of wild type genotype 118-AA OPRM1 required lower MEDD in the basal visit (dominant, p=0.018 and overdominant models, p=0.020) and in the final visit (codominant, p=0.032 and recessive models, p=0.032). Our IDP showed efectiveness and security in reducing MEDD with a good conversion to buprenorphine, even more in naïve 118-AA OPRM1 genotype

Opioids Increase Sexual Dysfunction in Patients With Non-Cancer Pain.

INTRODUCTION: Long-term opioid therapy has been found to have a strong impact on the hypothalamic-pituitary-gonadal axis that can be manifested clinically by sexual dysfunction (SD). This event is rarely reported and thus unnoticed and undertreated. AIM: To analyze the presence of SD in a large group of patients receiving long-term opioids. METHODS: A descriptive, cross-sectional pilot study of sexual health was conducted for 2 years in 750 consecutive ambulatory patients with chronic non-cancer pain (CNP) receiving opioids for at least 12 months. Cases that reported SD and matched controls were included. Standardized questionnaires and medical record reviews were used to assess rates of pain at diagnosis, daily morphine equivalent doses, and opioid adverse effects. MAIN OUTCOME MEASURES: Sexual function was determined by the Female Sexual Function Index (FSFI; scores = 2-36) and the International Index of Erectile Function erectile function domain (IIEF-EF; scores = 1-30). RESULTS: Thirty-three percent of 33% of 750 patients with CNP recorded SD based on their spontaneous notification at the pain unit. Men reported SD significantly more frequently than women (33% vs 25%, respectively, P < .05), although they reported having a regular partner (84% vs 70%, P = .03) and a sexually active life (69% vs 34%, respectively, P = .00) significantly more often. FSFI scores were significantly influenced by sexual activity in lubrication and arousal. IIEF scores were significantly determined by age in satisfaction with sexual intercourse and overall satisfaction. The morphine equivalent dose was significant higher in men than in women (38%; median = 70 mg/d, interquartile range = 43.1-170, 115.5 ± 110.3 mg/d vs median = 60 mg/d, interquartile range = 30-100.6, 76.67 ± 63.79 mg/d, P = .016) at the same mean intensity of pain (P = .54), which correlated to FSFI scores (r = -0.313, P = .01). CONCLUSION: SD is prevalent in patients with CNP and higher in men who received a significantly higher mean opioid dose at the same intensity pain level than women. The morphine equivalent dose was correlated to SD intensity. Evidence-based interventions to support sexual activity and function in CNP are needed.