Epigenetic and sex differences in opioid use disorder in chronic pain: A real-world study linked with OPRM1 DNA methylation

Opioid use disorder (OUD) is a multifaceted condition influenced by sex, genetic and environmental factors that could be linked with epigenetic changes. Understanding how these factors interact is crucial to understand and address the development and progression of this disorder. Our aim was to elucidate different potential epigenetic and genetic mechanisms between women and men that correlate with OUD under real-world pain unit conditions. Associations between analgesic response and the DNA methylation level of the opioid mu receptor (OPRM1) gene (CpG sites 1–5 selected in the promoter region) were evaluated in 345 long opioid-treated chronic non cancer pain: cases with OUD (n = 67) and controls (without OUD, n = 278). Cases showed younger ages, low employment status and quality of life, but higher morphine equivalent daily dose and psychotropic use, compared to the controls. The patients with OUD showed a significant decrease in OPRM1 DNA methylation, which correlated with clinical outcomes like pain relief, depression and different adverse events. Significant differences were found at the five CpG sites studied for men, and exclusively in women for CpG site 3, in relation to OUD diagnosis. These findings support the importance of epigenetics and sex as biological variables to be considered toward efficient OUD understanding and therapy developmen

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

Bone fractures in patients using tapentadol or oxycodone: an exploratory US claims database study

Aim: To explore fracture outcomes with tapentadol or oxycodone, two opioids with differing mechanisms of action. Materials &amp; methods: Retrospective cohort pilot study, using MarketScan® Commercial and Medicare Supplemental claims databases, on patients with postoperative pain, back pain, or osteoarthritis and ≥1 claim for tapentadol (n = 16,457), oxycodone (n = 1,356,920), or both (n = 15,893) between June 2009 and December 2015. Results: During 266,826 and 9,007,889 days of tapentadol and oxycodone treatment, patients evidenced 1080 and 72,275 fractures, respectively. Fracture rates per treatment-year were 1.512 for tapentadol and 3.013 for oxycodone. Conclusion: Examination of administrative claims has inherent limitations, but this exploratory analysis indicates a lower fracture rate with tapentadol than oxycodone in the analyzed dataset, which needs confirmation by further clinical trials

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

Sex Bias and Genotype Influence on Opioid Safety Profile in Chronic Low Back Pain

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±16mm), 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

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

Health benefits of an adverse events reporting system for chronic pain patients using long-term opioids

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

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

OPRM1 Gene Interaction with Sleep in Chronic Pain Patients Treated with Opioids

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