Long-term deprescription in chronic pain and opioid use disorder patients: Pharmacogenetic and sex differences

1 Neuropharmacology applied to Pain (NED), Alicante Institute for Health and Biomedical Research (ISABIAL), c/ Pintor Baeza, 12, 03010, Alicante, Spain 2 Institute of Bioengineering, Miguel Hernández University, Avda. de la Universidad s/n, 03202, Elche, Spain 3 Pain Unit, Dr. Balmis General University Hospital, ISABIAL, c/ Pintor Baeza, 12, 03010, Alicante, Spain 4 Operations Research Centre, Miguel Hernández University, Avda. de la Universidad s/n, 03202, Elche, Spain 5 Clinical Pharmacology Department, Dr. Balmis General University Hospital, ISABIAL c/ Pintor Baeza, 12, 03010 Alicante, Spain More than half of patients with opioid use disorder for chronic non-cancer pain (CNCP) reduced their dose through a progressive opioid withdrawal supported by a rotation to buprenorphine and/or tramadol. The aim of this research is to analyse the long-term effectiveness of opioid deprescription taking into account the impact of sex and pharmacogenetics on the inter-individual variability. A cross-sectional study was carried out from October 2019 to June 2020 on CNCP patients who had previously undergone an opioid deprescription (n = 119 patients). Demographic, clinical (pain, relief and adverse events) and therapeutic (analgesic use) outcomes were collected. Effectiveness (< 50 mg per day of morphine equivalent daily dose without any aberrant opioid use behaviour) and safety (number of side-effects) were analysed in relation to sex differences and pharmacogenetic markers impact [OPRM1 genotype (rs1799971) and CYP2D6 phenotypes]. Long-term opioid deprescription was achieved in 49 % of the patients with an increase in pain relief and a reduction of adverse events. CYP2D6 poor metabolizers showed the lowest long-term opioid doses. Here, women showed a higher degree of opioid deprescription, but increased use of tramadol and neuromodulators, as well as an increased number of adverse events. Long-term deprescription was successful in half of the cases. Understanding sex and gender interaction plus a genetic impact could help to design more individualized strategies for opioid deprescription

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

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

ntroduction: 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

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

Deprescripción en pacientes con dependencia inducida a opioides: efectividad a largo plazo y validación de marcadores genéticos

Introducción: Los pacientes con dolor crónico no oncológico (DCNO) que desarrollan dependencia iatrogénica a opioides de prescripción (DOP), en la Unidad del Dolor (UDO), se someten de forma ambulatoria a un plan terapéutico individualizado (PTI) desde hace más de 5 años. Este programa contó con un 70% de pacientes respondedores a corto plazo. Asimismo, el genotipo OPRM1 influyó en la efectividad y seguridad de la respuesta analgésica, sugiriéndose una posible influencia del sexo. Sin embargo, se desconoce la persistencia de estos resultados de efectividad y seguridad del PTI a largo plazo. Objetivos: Caracterizar los patrones de respuesta al PTI a largo plazo (≥24 meses) en pacientes con DOP, analizando las posibles asociaciones con las variantes genéticas involucradas en la respuesta farmacológica de los analgésicos opioides. Metodología: Estudio observacional, transversal, en pacientes con DOP que fueron sometidos al PTI y caracterizados como respondedores (sí/no). Se registraron sus variables sociodemográficas (edad, sexo), clínicas (intensidad y alivio del dolor, calidad de vida, funcionalidad, eventos adversos (EA) y sospechas de reacciones adversas a medicamentos (RAM)), así como farmacológicas (prescripción de opioides (sí/no), dosis equivalente diaria de morfina (DDEM), tipo de medicación analgésica o concomitante, entre otros). A su vez, se realizó un estudio farmacogenético de las variantes del gen OPRM1 (rs1799971, A118G) y fenotipo CYP2D6; y se analizaron si existían diferencias según el sexo del paciente. Resultados: La respuesta a largo plazo se mantuvo en el 51% de los pacientes incluidos, persistiendo un descenso en la prescripción de opioides (24%, p-valor<0.001) desde la visita final del PTI. Esta disminución fue mayor en las mujeres, que lograron reducir su DDEM un 57% más que los hombres. Todo ello sin cambios significativos en la situación clínica, con un 34% con dolor leve (29 ± 33 mm) y un 16% dado de alta. De los pacientes que siguen acudiendo a la UDO, se observó un incremento en el número de EA (2, p-valor<0.001) pero con un menor número de RAM (8%, p-valor=0.049), sobre todo en los hombres. El genotipo OPRM1- AG se asoció a un mayor uso de tramadol (29%, p-valor=0.017) y mayores sospechas RAM (12%, p-valor=0.036), a largo plazo. Por otro lado, el fenotipo CYP2D6 metabolizador ultrarrápido (MU) mostró una mayor DDEM (123 ± 172 mg/día, p-valor<0.001), y, el lento (ML) una peor calidad de vida (32 ± 8 mm, p-valor=0.040). Conclusiones: Se observa que el PTI mantiene su efectividad a largo plazo en la mitad de los casos con un menor uso de opioides, especialmente en las mujeres. Asimismo, el genotipo AG del gen OPRM1 y el fenotipo CYP2D6 influyeron, sobre todo, en el perfil de seguridad y dosis total de opioides en pacientes con DCNO y DOP.Introduction: Patients with chronic non-cancer pain (CNCP) with iatrogenic induced opioid dependence (IOD) in the Pain Unit (PU) are subjected to an individual therapeutic protocol (ITP) more than 5 years ago. This program counted with an average of 70% of responders in the short-term. Additionally, the OPRM1 genotype influenced the effectiveness and safety of the analgesic response, suggesting a possible influence of sex. However, the long-term effectiveness and safety of ITP is still unknown. Objectives: To characterize the patterns of response to ITP in the long-term (≥24 months) in patients with IOD, analyzing possible associations with the genetic variants involved in the pharmacological response of opioid analgesics. Methodology: Observational, cross-sectional study in patients with IOD who went through the ITP and were characterized as responders (yes/no). Sociodemographic data (age, sex) as well as clinical (pain intensity and relief, quality of life, functionality, adverse events (AEs) and suspected adverse drug reactions (ADRs)) and pharmacological data (opioid prescription (yes/no), equivalent daily dose of morphine (DDEM), type of analgesic or concomitant medication, among others) were collected. Likewise, a pharmacogenetic study of the variants of the OPRM1 gene (rs1799971, A118G) and CYP2D6 phenotype was performed; and also sex differences were analyzed. Results: The long-term response persisted in the 51% of the included patients, with a decrease in the opioid prescription (24%, p-value<0.001) since the final visit of ITP. This reduction was greater in women, who reduced their DDEM by 57% more than men. This was achieved without significant changes in the clinical situation, where 34% have mild pain (29 ± 33 mm) and 16% are discharged from the hospital. Among patients who continue in the PU, there was an increase in the number of AEs (2, p-value<0.001) but a lower number of reported ADRs (8%, p-value=0.049), especially in men. The OPRM1-AG genotype was associated with a larger use of tramadol (29%, p-value=0.017) and suspicions of ADRs (12%, p-value=0.036), in the long-term. On the other hand, CYP2D6 ultra-fast metabolizers (UM) phenotype showed a higher DDEM (123 ± 172 mg/day, p-value<0.001), and the poor phenotype (PM) was associated with a worse quality of life (32 ± 8 mm, p-value=0.040). Conclusions: The ITP maintains its effectiveness in the long-term in half of the cases with a lower opioid consumption, especially in women. Likewise, the OPRM1-AG genotype and the CYP2D6 phenotype influenced the safety profile and the total dose of opioids in patients with CNCP and IOD

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

(1) 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

Long-term deprescription in chronic pain and opioid use disorder patients: Pharmacogenetic and sex differences

More than half of patients with opioid use disorder for chronic non-cancer pain (CNCP) reduced their dose through a progressive opioid withdrawal supported by a rotation to buprenorphine and/or tramadol. The aim of this research is to analyse the long-term effectiveness of opioid deprescription taking into account the impact of sex and pharmacogenetics on the inter-individual variability. A cross-sectional study was carried out from October 2019 to June 2020 on CNCP patients who had previously undergone an opioid deprescription (n = 119 patients). Demographic, clinical (pain, relief and adverse events) and therapeutic (analgesic use) outcomes were collected. Effectiveness (< 50 mg per day of morphine equivalent daily dose without any aberrant opioid use behaviour) and safety (number of side-effects) were analysed in relation to sex differences and pharmacogenetic markers impact [OPRM1 genotype (rs1799971) and CYP2D6 phenotypes]. Long-term opioid deprescription was achieved in 49 % of the patients with an increase in pain relief and a reduction of adverse events. CYP2D6 poor metabolizers showed the lowest long-term opioid doses. Here, women showed a higher degree of opioid deprescription, but increased use of tramadol and neuromodulators, as well as an increased number of adverse events. Long-term deprescription was successful in half of the cases. Understanding sex and gender interaction plus a genetic impact could help to design more individualized strategies for opioid deprescription