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 development.

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.

Gender based differences, pharmacogenetics and adverse events in chronic pain management.

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.

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.

Genetic Contribution in Low Back Pain: A Prospective Genetic Association Study.

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.

Randomized, Controlled, Crossover Study of Self-administered Jacobson Relaxation in Chronic, Nonspecific, Low-back Pain.

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.

The relationship of salivary testosterone and male sexual dysfunction in opioid-associated androgen deficiency (OPIAD).

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.

Chronic Pain Features Relate to Quality of Life More than Physiopathology: A Cross-Sectional Evaluation in Pain Clinics.

OBJECTIVE: To compare the impact of chronic pain physiopathology on health-related quality of life (HR-QoL), considering the influence of pain features and psychosocial adjustment (intensity, interference, psychological comorbidities, and sleep quality). DESIGN: A cross-sectional study involving 1,025 noncancer patients with predominantly neuropathic, nociceptive, or mixed chronic pain conditions was conducted in 88 pain clinics within Spain. The EuroQol-5 Dimensions instrument (EQ-5D) was used to measure HR-QoL. The Brief Pain Inventory (BPI), Hospital Anxiety and Depression Scale (HADS), and sleep scale developed for the MOS study (MOS-SQ) were used to measure pain features and psychosocial adjustment. Multivariate analyses were used to model HR-QoL measures. RESULTS: All patients reported very low HR-QoL. The mean EQ-5D index scores were 0.33, 0.36, and 0.37 in the mixed, neuropathic, and nociceptive pain groups, respectively. The differences did not reach statistical significance (P = 0.057). Patients with nociceptive pain had less pain (least pain intensity score: 4.7 vs. 5.2 in the other groups; P = 0.006), less interference with daily activities (BPI average interference score: 6.3 vs. 6.6 and 6.7 in the neuropathic and mixed pain groups, respectively; P = 0.013), less anxiety (HADS score: 8.5 vs. 9.6 and 9.7 in the same respective groups; P = 0.001), and fewer sleep problems (MOS-SQ sleep problems index: 46.8 vs. 52.2 and 50.2 in the same respective groups; P = 0.005). In the adjusted analyses, HR-QoL measures were explained by pain intensity, anxiety, and sleep quality, but not by physiopathological pain type. CONCLUSIONS: Pain features, particularly intensity, have a greater impact than pain physiopathology on HR-QoL. Distinct physiopathological mechanisms give rise to different pain features that, in turn, may mediate the HR-QoL of patients with chronic pain. This could be used to improve pain management strategies.

Clinical prediction of opioid use disorder in chronic pain patients: a cohort-retrospective study with a pharmacogenetic approach.

BACKGROUND: Opioids are widely used in chronic non-cancer pain (CNCP) management. However, they remain controversial due to serious risk of causing opioid use disorder (OUD). Our main aim was to develop a predictive model for future clinical translation that include pharmacogenetic markers. METHODS: An observational study was conducted in 806 pre-screened Spanish CNCP patients, under long-term use of opioids, to compare cases (with OUD, N.=137) with controls (without OUD, N.=669). Mu-opioid receptor 1 (OPRM1, A118G, rs1799971) and catechol-O-methyltransferase (COMT, G472A, rs4680) genetic variants plus cytochrome P450 2D6 (CYP2D6) liver enzyme phenotypes were analyzed. Socio-demographic, clinical and pharmacological outcomes were also registered. A logistic regression model was performed. The model performance and diagnostic accuracy were calculated. RESULTS: OPRM1-AA genotype and CYP2D6 poor and ultrarapid metabolizers together with three other potential predictors: 1) age; 2) work disability; 3) oral morphine equivalent daily dose (MEDD), were selected with a satisfactory diagnostic accuracy (sensitivity: 0.82 and specificity: 0.85), goodness of fit (P=0.87) and discrimination (0.89). Cases were ten-year younger with lower incomes, more sleep disturbances, benzodiazepines use, and history of substance use disorder in front of controls. CONCLUSIONS: Functional polymorphisms related to OPRM1 variant and CYP2D6 phenotypes may predict a higher OUD risk. Established risk factors such as young age, elevated MEDD and lower incomes were identified. A predictive model is expected to be implemented in clinical setting among CNCP patients under long-term opioids use.

Predictive Model for Opioid Use Disorder in Chronic Pain: A Development and Validation Study.

BACKGROUND/OBJECTIVE: There are several questionnaires for the challenge of anticipating opioid use disorder (OUD). However, many are not specific for chronic non-cancer pain (CNCP) or have been developed in the American population, whose sociodemographic factors are very different from the Spanish population, leading to scarce translation into clinical practice. Thus, the aim of this study is to prospectively validate a predictive model for OUD in Spanish patients under long-term opioids. METHODS: An innovative two-stage predictive model was developed from retrospective (n = 129) and non-overlapping prospective (n = 100) cohorts of real-world CNCP outpatients. All subjects used prescribed opioids for 6 or more months. Sociodemographic, clinical and pharmacological covariates were registered. Mu-opioid receptor 1 (OPRM1, A118G, rs1799971) and catechol-O-methyltransferase (COMT, G472A, rs4680) genetic variants plus cytochrome P450 2D6 (CYP2D6) liver enzyme phenotypes were also analyzed. The model performance and diagnostic accuracy were calculated. RESULTS: The two-stage model comprised risk factors related to OUD (younger age, work disability and high daily opioid dose) and provided new useful information about other risk factors (low quality of life, OPRM-G allele and CYP2D6 extreme phenotypes). The validation showed a satisfactory accuracy (70% specificity and 75% sensitivity) for our predictive model with acceptable discrimination and goodness of fit. CONCLUSIONS: Our study presents the results of an innovative model for predicting OUD in our setting. After external validation, it could represent a change in the paradigm of opioid treatment, helping clinicians to better identify and manage the risks and reduce the side effects and complications.

Health-Related Quality of Life in Chronic Pain Treated With Tapentadol Versus Oxycodone/Naloxone and Its Determinants: A Real-World, Single-Center Retrospective Cohort Study in Spain.

OBJECTIVES: A substantial proportion of patients with chronic noncancer pain (CNCP) are treated with tapentadol (TAP) or oxycodone/naloxone (OXN) to improve their perceived physical and mental health over time. METHODS: A cross-sectional study was conducted in 135 CNCP outpatients with usual prescribing (TAP: n = 58, OXN: n = 77) at a tertiary-care Spanish Hospital to compare health-related quality-of-life (HRQoL) records. Health utility was derived from the EQ-5D-3L. Regression models were performed to search for other HRQoL determinants. Pain intensity, relief, analgesic prescription, adverse events, inpatient stays, emergency department visits, and change to painkiller prescriptions were registered from electronic records. RESULTS: Health utility (0.43 ± 0.24 scores, from -0.654 to 1) was similar for both opioids, although TAP showed a significantly low daily opioid dose requirement, neuromodulators use, and constipation side effect compared with OXN. After multivariable adjustment, the significant predictors of impaired HRQoL were pain intensity (ß = -0.227, 95% CI -0-035 to -0.005), number of adverse events (ß = -0.201, 95% CI -0.024 to -0.004), and opioid daily dose (ß = -0.175, 95% CI -0.097 to -0.012). Male sex (ß = -0.044) and pain relief (ß = 0.158) should be taken into account for future studies. CONCLUSIONS: HRQoL was similar for TAP and OXN in real-world patients with CNCP, albeit with a TAP opioid-sparing effect. More work is needed to explore HRQoL determinants in relation to long-term opioid use in CNCP.

Co-crystal of tramadol-celecoxib (CTC) for acute moderate-to-severe pain.

OBJECTIVE: This narrative review aims to provide a clinical perspective on the potential role of co-crystal of tramadol-celecoxib (CTC) in the management of acute moderate-to-severe pain by synthesizing the available preclinical and clinical data, with emphasis on phase 3 trials. METHODS: A non-systematic literature review was performed using a targeted PubMed search for articles published between January 1, 2000, and May 2, 2023; all publication types were permitted, and selected articles were limited to those published in English. Search results were manually reviewed to identify references based on their preclinical and clinical relevance to CTC and management of acute moderate-to-severe pain. RESULTS: The crystalline structure of CTC alters the physicochemical properties of tramadol and celecoxib, modifying their pharmacokinetics. If taken in a free combination, tramadol reduces absorption of celecoxib. Conversely, administration of CTC slows tramadol absorption and lowers its maximum plasma concentration, while increasing celecoxib plasma concentration through its enhanced release. In clinical studies across models of acute moderate-to-severe pain, CTC demonstrated an early onset of analgesia, with improved efficacy and lower rescue medication use, compared with either agent alone. CTC's safety profile was in line with that expected for the individual components; no additive effects were observed. CTC exhibited tramadol-sparing effects, with efficacy seen at lower daily/cumulative opioid doses vs. tramadol alone. CONCLUSIONS: Results from phase 3 trials suggest that the modified physicochemical properties of tramadol and celecoxib in CTC translate into an improved clinical benefit-risk profile, including fewer opioid-related adverse effects due to lower overall opioid dosing.

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.

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.

Sex Differences in Opioid Response Linked to OPRM1 and COMT genes DNA Methylation/Genotypes Changes in Patients with Chronic Pain.

Analgesic-response variability in chronic noncancer pain (CNCP) has been reported due to several biological and environmental factors. This study was undertaken to explore sex differences linked to OPRM1 and COMT DNA methylation changes and genetic variants in analgesic response. A retrospective study with 250 real-world CNCP outpatients was performed in which data from demographic, clinical, and pharmacological variables were collected. DNA methylation levels (CpG island) were evaluated by pyrosequencing, and their interaction with the OPRM1 (A118G) and COMT (G472A) gene polymorphisms was studied. A priori-planned statistical analyses were conducted to compare responses between females and males. Sex-differential OPRM1 DNA methylation was observed to be linked to lower opioid use disorder (OUD) cases for females (p = 0.006). Patients with lower OPRM1 DNA methylation and the presence of the mutant G-allele reduced opioid dose requirements (p = 0.001), equal for both sexes. Moreover, COMT DNA methylation levels were negatively related to pain relief (p = 0.020), quality of life (p = 0.046), and some adverse events (probability > 90%) such as constipation, insomnia, or nervousness. Females were, significantly, 5 years older with high anxiety levels and a different side-effects distribution than males. The analyses demonstrated significant differences between females and males related to OPRM1 signalling efficiency and OUD, with a genetic-epigenetic interaction in opioid requirements. These findings support the importance of sex as a biological variable to be factored into chronic pain-management studies.

Good practice recommendations to better coordinate the management of oncological pain: a Delphi survey.

Treatment of oncological pain is complex and requires a multidisciplinary management approach between oncology services and pain units. Although significant improvements have been achieved in the treatment and overall survival of cancer patients, the management of oncological pain has not followed the same directions. Many patients are not referred to pain units even though they could benefit from it. The purpose of this Delphi survey was to map the current situation in the management of cancer pain, identify barriers and propose recommendations to improve its management by emphasizing the importance of collaboration and coordination between oncology services and pain units. A survey among members with recognized experience in the management of oncology patients and oncological pain was held based on the Delphi method principles. The experts were asked to vote preselected statements on cancer pain management in two rounds and conclusions and recommendations were formulated based on the consensus reached for each statement. Barriers and areas for improvement were identified: need of multidisciplinary management approach, effective communication between oncology services and pain units, timely referral of cancer patients to pain units, training of health care professionals dealing with cancer aspects and identification of those patients that could benefit from a multidisciplinary management of their oncological disease. The experts issued recommendations targeting the identified barriers and areas for improvement by defining the service requirements of hospital and units treating cancer pain patients, establishing referral pathways necessities and adopted measures to improve the care of cancer patients.

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.

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' 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 health-care 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 Differences in Oxycodone/Naloxone vs. Tapentadol in Chronic Non-Cancer Pain: An Observational Real-World Study.

Despite the large body of research on sex differences in pain, there is a lack of translation to real-world pain management. Our aim was to analyse the sex differences in the analgesic response to oxycodone/naloxone (OXN) and tapentadol (TAP), in comparison with other opioids (OPO) commonly prescribed for chronic non-cancer pain (CNCP). An observational and cross-sectional study was conducted on ambulatory CNCP patients (n = 571). Sociodemographic, clinical (pain intensity, relief, and quality of life), safety (adverse events (AEs), adverse drug reactions), hospital frequentations and pharmacological (morphine equivalent daily dose (MEDD)) variables were collected. Multiple linear regressions were carried out to assess the association between sex and outcomes. Sex differences were observed, with lower female tolerability and higher hospital frequentation, especially in the OXN group (OR AEs report = 2.8 [1.8−4.4], p < 0.001). Here, females showed higher hospital use (23% hospital admission, 30% prescription change, p < 0.05), requiring a higher MEDD (127 ± 103 mg/day, p < 0.05), compared to OXN men. Regardless of the opioid group, CNCP women were significantly older than men (three years), with significantly higher benzodiazepine use (OR = 1.6 [1.1−2.3]), more constipation (OR = 1.34 [0.93−1.90]) and headache (OR = 1.45 [0.99−2.13]) AEs, than men who were more likely to refer sexual dysfunction (OR = 2.77 [1.53−5.01]), and loss of libido (OR = 1.93 [1.22−3.04]). Sex-differences were found related to poorer female drug tolerability and higher hospital resources, even worst in OXN female users. Other differences related to older female ages and benzodiazepine prescription, need to be further analysed from a gender perspective.

A Delphi Study on the Management of Neuropathic Cancer Pain in Spain: The DOLNEO Study.

Purpose: The objectives of this project were to assess the current situation and management of cancer-related neuropathic pain (CRNP) in Spain and to provide specific recommendations for the assessment, diagnosis and treatment of CRNP using a Delphi methodology. Methods: This was a qualitative study that followed a Delphi methodology using a questionnaire with 56 statements that were grouped into 5 areas related to CRNP: prevalence and impact, pathophysiology, assessment and diagnosis, specific syndromes, treatment, and multidisciplinary approach. Based on the responses, the scientific committee prepared an algorithm and a recommended pathway for the management of CRNP. Results: Seventy-nine physicians attended the meeting and completed the questionnaire. Consensus was reached for all statements relating to the prevalence and impact of CRNP. However, the perceptions of specialists from palliative care of the frequency and impact of CRNP differed from those of other specialists. A high degree of consensus was reached for all statements concerning the assessment and diagnosis of CRNP. Regarding specific syndromes, the only statement with a lack of consensus was that on the frequency of NP in patients undergoing radiotherapy. There were some disagreements regarding the multidisciplinary approach and referral criteria for the management of NP. Conclusion: Our results show a large degree of agreement on the assessment, diagnosis and treatment of cancer-related neuropathic pain among the specialists involved in its management. There were, however, some disagreements regarding the multidisciplinary approach and referral criteria for the management of neuropathic pain.