Opioid analgesics for nociceptive cancer pain: A comprehensive review.

Pain is one of the most burdensome symptoms in people with cancer, and opioid analgesics are considered the mainstay of cancer pain management. For this review, the authors evaluated the efficacy and toxicities of opioid analgesics compared with placebo, other opioids, nonopioid analgesics, and nonpharmacologic treatments for background cancer pain (continuous and relatively constant pain present at rest), and breakthrough cancer pain (transient exacerbation of pain despite stable and adequately controlled background pain). They found a paucity of placebo-controlled trials for background cancer pain, although tapentadol or codeine may be more efficacious than placebo (moderate-certainty to low-certainty evidence). Nonsteroidal anti-inflammatory drugs including aspirin, piroxicam, diclofenac, ketorolac, and the antidepressant medicine imipramine, may be at least as efficacious as opioids for moderate-to-severe background cancer pain. For breakthrough cancer pain, oral transmucosal, buccal, sublingual, or intranasal fentanyl preparations were identified as more efficacious than placebo but were more commonly associated with toxicities, including constipation and nausea. Despite being recommended worldwide for the treatment of cancer pain, morphine was generally not superior to other opioids, nor did it have a more favorable toxicity profile. The interpretation of study results, however, was complicated by the heterogeneity in the study populations evaluated. Given the limited quality and quantity of research, there is a need to reappraise the clinical utility of opioids in people with cancer pain, particularly those who are not at the end of life, and to further explore the effects of opioids on immune system function and quality of life in these individuals.

Outcomes After a Statewide Policy to Improve Evidence-Based Treatment of Back Pain Among Medicaid Enrollees in Oregon.

BACKGROUND: A novel Oregon Medicaid policy guiding back pain management combined opioid restrictions with emphasis on non-opioid and non-pharmacologic therapies. OBJECTIVE: To examine the effect of the policy on prescribing, health outcomes, and health service utilization. DESIGN: Using Medicaid enrollment, medical and prescription claims, prescription drug monitoring program, and vital statistics files, we analyzed the policy's association with selected outcomes using interrupted time series models. SUBJECTS: Adult Medicaid patients with back pain enrolled between 2014 and 2018. INTERVENTION: The Oregon Medicaid back pain policy. MAIN MEASURES: Opioid and non-opioid medication prescribing, procedural care, substance use and mental health conditions, and outpatient and inpatient healthcare utilization. KEY RESULTS: The policy was associated with decreases in the percentage of Medicaid enrollees with back pain receiving any opioids (- 2.68 percentage points [95% CI - 3.14, - 2.23] level, - 1.01 pp [95% CI - 1.1, - 0.92] slope), days of short-acting opioid use (- 0.4 days [95% CI - 0.53, - 0.26] slope), receipt of more than 7 days of short-acting opioids (- 2.36 pp [95% CI - 2.76, - 1.95] level, - 0.91 pp [95% CI - 1, - 0.83] slope), chronic opioid use (- 1.27 pp [95% CI - 1.59, - 0.94] level, - 0.46 [95% CI - 0.53, - 0.39 slope), and spinal surgeries and procedures. Among secondary outcomes, we found no increase in opioid overdose and a small, statistically significant trend decrease in opioid use disorders. There were small increases in non-opioid substance use and mental health diagnoses and visits but no increase in self-harm. CONCLUSIONS: A state Medicaid policy emphasizing evidence-based back pain management was associated with decreases in opioid prescribing, spinal surgeries, and opioid use disorder trends, but also short-term increases in mental health encounters and an increase in non-opioid substance use disorder trends. Such policies may help reinforce evidence-based care, but must be designed with consideration of potential harms.

Impact of 30-day prescribed opioid dose trajectory on fatal overdose risk: A population-based, statewide cohort study.

BACKGROUND: Both increases and decreases in patients' prescribed daily opioid dose have been linked to increased overdose risk, but associations between 30-day dose trajectories and subsequent overdose risk have not been systematically examined. OBJECTIVE: To examine the associations between 30-day prescribed opioid dose trajectories and fatal opioid overdose risk during the subsequent 15 days. DESIGN: Statewide cohort study using linked prescription drug monitoring program and death certificate data. We constructed a multivariable Cox proportional hazards model that accounted for time-varying prescription-, prescriber-, and pharmacy-level factors. PARTICIPANTS: All patients prescribed an opioid analgesic in California from March to December, 2013 (5,326,392 patients). MAIN MEASURES: Dependent variable: fatal drug overdose involving opioids. Primary independent variable: a 16-level variable denoting all possible opioid dose trajectories using the following categories for current and 30-day previously prescribed daily dose: 0-29, 30-59, 60-89, or ≥90 milligram morphine equivalents (MME). KEY RESULTS: Relative to patients prescribed a stable daily dose of 0-29 MME, large (≥2 categories) dose increases and having a previous or current dose ≥60 MME per day were associated with significantly greater 15-day overdose risk. Patients whose dose decreased from ≥90 to 0-29 MME per day had significantly greater overdose risk compared to both patients prescribed a stable daily dose of ≥90 MME (aHR 3.56, 95%CI 2.24-5.67) and to patients prescribed a stable daily dose of 0-29 MME (aHR 7.87, 95%CI 5.49-11.28). Patients prescribed benzodiazepines also had significantly greater overdose risk; being prescribed Z-drugs, carisoprodol, or psychostimulants was not associated with overdose risk. CONCLUSIONS: Large (≥2 categories) 30-day dose increases and decreases were both associated with increased risk of fatal opioid overdose, particularly for patients taking ≥90 MME whose opioids were abruptly stopped. Results align with 2022 CDC guidelines that urge caution when reducing opioid doses for patients taking long-term opioid for chronic pain.

Factors associated with unplanned clinical encounters for ureteral stent-related symptoms.

BACKGROUND, INTRODUCTION AND AIM: Ureteral stent-related symptoms (USRS) often result in unplanned phone calls and ER visits. We hypothesize that patient factors can be identified to predict these unplanned encounters. METHODS AND MATERIALS: Retrospective analysis of indwelling ureteral stent placements from 2014 to 2019 at a single institution by CPT code was performed. Patient demographics, discharge medications, and clinical factors were evaluated using multiple logistic regression with respect to postoperative telephone and emergency room (ER) encounters for USRS. RESULTS: Of 374 patients, 75 (20.1%) had one or more encounters for USRS: 48 (12.8%) called the clinic and 39 (10.4%) returned to the ER. Chronic opioid use was predictive of calls to clinic and ER visits (OR 3.21 [CI 1.42-6.97], p < 0.01 and OR 3.64 [CI 1.45-8.98], p < 0.01). Survival analysis stratified by history of chronic opioid use and discharge opioid prescriptions demonstrated that opioid naïve patients receiving opioids at discharge had unplanned encounters sooner and more often [Calls p = 0.025, ER p = 0.041]), whereas patients with chronic opioid use returned to the ER sooner and more frequently when prescribed additional opioids (Calls p = 0.4, ER p = 0.002). CONCLUSION: Patients with a history of chronic opioid use may experience more intense USRS or have a lower threshold to seek medical care than opioid naïve patients and tend to bypass calling the clinic for the ER. Given that none of the studied medications reduced unplanned patient contact for USRS, urologists should consider upfront definitive management of urinary obstruction when appropriate.

Transdermal Opioids and the Quality of Life of the Cancer Patient: A Systematic Literature Review.

OBJECTIVE: This systematic literature review aims to evaluate the effectiveness of transdermal opioids in managing cancer pain and their impact on the quality of life (QoL) of patients. DATA SOURCES: A systematic literature review conducted following the PRISMA protocol, focusing on randomized clinical trials found in the Lilacs, Embase, PubMed, and SciELO databases over the last 20 years. STUDY SELECTION AND DATA EXTRACTION: We included randomized clinical trials, published in English, Portuguese, or Spanish, which assessed the impact of transdermal opioids on the QoL. Data extraction was facilitated using the Rayyan app. DATA SYNTHESIS: Six articles meeting the inclusion and exclusion criteria were analyzed. These studies covered a population ranging from 24 to 422 cancer patients experiencing moderate to severe pain. The risk of bias was assessed in each study, generally being categorized as uncertain or high. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The findings indicate that the analgesic effectiveness and side effects of transdermal formulations (specifically buprenorphine and fentanyl) for managing moderate to severe cancer pain are comparable to, or in some cases superior to, those of oral opioids traditionally employed. CONCLUSIONS: Transdermal therapy was suggested to have several advantages over oral opioid therapy in enhancing cancer patients' QoL. These benefits span various dimensions, including pain management, physical functioning, mental health, vitality, overall patient improvement, anger/aversion, strength/activity, general QoL, cognitive and emotional functions, fatigue, and insomnia.

Matching study design to prescribing intention: The prevalent new-user design for studying abuse-deterrent formulations of opioids.

PURPOSE: In drug studies, research designs requiring no prior exposure to certain drug classes may restrict important populations. Since abuse-deterrent formulations (ADF) of opioids are routinely prescribed after other opioids, choice of study design, identification of appropriate comparators, and addressing confounding by "indication" are important considerations in ADF post-marketing studies. METHODS: In a retrospective cohort study using claims data (2006-2018) from a North Carolina private insurer [NC claims] and Merative MarketScan [MarketScan], we identified patients (18-64 years old) initiating ADF or non-ADF extended-release/long-acting (ER/LA) opioids. We compared patient characteristics and described opioid treatment history between treatment groups, classifying patients as traditional (no opioid claims during prior six-month washout period) or prevalent new users. RESULTS: We identified 8415 (NC claims) and 147 978 (MarketScan) ADF, and 10 114 (NC claims) and 232 028 (MarketScan) non-ADF ER/LA opioid initiators. Most had prior opioid exposure (ranging 64%-74%), and key clinical differences included higher prevalence of recent acute or chronic pain and surgery among patients initiating ADFs compared to non-ADF ER/LA initiators. Concurrent immediate-release opioid prescriptions at initiation were more common in prevalent new users than traditional new users. CONCLUSIONS: Careful consideration of the study design, comparator choice, and confounding by "indication" is crucial when examining ADF opioid use-related outcomes.

Patterns of filled prescriptions and the association with risk of drug-induced death. A population-based nested case-control register study.

PURPOSE: Opioid analgesics (OA) and other pharmaceuticals have been associated with drug-induced deaths. However, there is a lack of knowledge regarding patterns of use of these pharmaceuticals in the population and regarding such associations. We identify and describe subgroups of people with different patterns of filled prescriptions of OA and other relevant pharmaceuticals and examine associations with drug-induced deaths. In addition, we estimate the proportion of drug-induced deaths with a filled OA prescription and OA as cause of death. METHODS: A Norwegian population-based nested case-control register study with cases (drug-induced deaths 2010-2018, N = 2388) and population controls matched for age, gender and year of inclusion (N = 21 465). Patterns of filled prescriptions for opioid analgesics (OA), benzodiazepines and benzodiazepine-related drugs, gabapentinoids, ADHD medication and antidepressants/antipsychotics were explored by k-means cluster analysis. Associations with drug-induced deaths were estimated by conditional logistic regression adjusted for sociodemographic characteristics. Overlap of filled OA prescriptions and OA as cause of death was estimated. RESULTS: Five clusters were identified: 'few prescriptions', 'weak OA', 'ADHD medication', 'sedative/psychiatric morbidity' and 'strong OA'. The 'strong OA' cluster had higher socioeconomic status compared to the other groupings. The risk of drug-induced death was also highest in this cluster (OR = 35.5; CI 25.6-49.3) and, for 68% (CI 64-73) of cases, filled prescriptions for OA was indicated as the underlying cause of death. CONCLUSIONS: The cluster analysis identified a subgroup with filled prescriptions of OA and other pharmaceuticals and a higher socioeconomic status than other subgroups. This subgroup had a high risk of drug-induced death that needs to be addressed.

Impact of opioid analgesics on survival in cancer patients receiving immune checkpoint inhibitors.

PURPOSE: This study aimed to assess the effects of concurrent opioid analgesic (OA) use with immune checkpoint inhibitors (ICIs) on progression-free survival (PFS) and overall survival (OS). METHODS: In this observational retrospective study, we included advanced cancer patients who received ICIs at Hacettepe University Hospital's Department of Medical Oncology between June 2018 and January 2023. RESULTS: Our study included 375 recurrent or metastatic cancer patients treated with ICIs in the first, second line, or beyond. There were no significant differences between the OA-treated and OA-untreated groups regarding median age, age group, gender, primary tumor location, ICI type, or the presence of baseline liver and lung metastases. However, the OA-treated group exhibited a significantly higher proportion of patients who had received three or more prior treatments before initiating ICIs (p = 0.015). OA-Untreatment was significantly correlated with prolonged mPFS (6.83 vs. 4.30 months, HR 0.59, 95% CI 0.44-0.79, p < 0.001) and mOS (17.05 vs. 7.68 months, HR 0.60, 95% CI 0.45-0.80, p < 0.001). CONCLUSIONS: Our study demonstrates an association between the concurrent use of OAs and reduced OS and PFS in patients treated with ICIs. While OA treatment serves as a surrogate marker for higher disease burden, it may also suggest a potential biological relationship between opioids and immunotherapy efficacy.

A secondary analysis: the impact of pre-existing chronic pain among patients with cancer presenting to the emergency department with acute pain.

PURPOSE: Patients with cancer may experience pain from cancer itself or its treatment. Additionally, chronic pain (CP) predating a patient's cancer diagnosis may make the etiology of pain less clear and the management of pain more complex. In this brief report, we investigated differences in biopsychosocial characteristics, pain severity, and opioid consumption, comparing groups of cancer patients with and without a history of CP who presented to the emergency department (ED) with a complaint of cancer-related pain. METHODS: This secondary analysis of a prospective cohort study included patients with cancer who presented to the ED with a complaint of pain (≥ 4/10). Sociodemographic, clinical, psychological, and pain characteristics were assessed in the ED and subsequent hospitalization. Mann-Whitney U-, T-, and Chi-square tests were used to compare differences between patients with and without pre-existing CP before cancer. RESULTS: Patients with pre-existing CP had lower income (p = 0.21) and less formal education (p = 0.25) and were more likely to have a diagnosis of depression or substance use disorder (p < 0.01). Patients with pre-existing CP reported significantly greater pain severity in the ED and during hospitalization compared to those without pre-existing CP (p < 0.05), despite receiving greater amounts of opioid analgesics (p = 0.036). CONCLUSION: Identifying a history of pre-existing CP during intake may help identify patients with cancer with difficult to manage pain, who may particularly benefit from multimodal interventions and supportive care. In addition, referral of these patients for the management of co-occurring pain disorders may help decrease the usage of the ED for undertreated pain.

Predictors of persistent opioid use in Australian primary care: A retrospective cohort study, 2018-2022.

OBJECTIVE: To examine the predictors of persistent opioid use ('persistence') in people initiating opioids for non-cancer pain in Australian primary care. DESIGN: A retrospective cohort study. SETTING: Australian primary care. SUBJECTS: People prescribed opioid analgesics between 2018-2022, identified through the Population Level Analysis and Reporting (POLAR) database. METHODS: Persistence was defined as receiving opioid prescriptions for at least 90 days with a gap of less than 60 days between subsequent prescriptions. Multivariable logistic regression was used to examine the predictors of persistent opioid use. RESULTS: The sample consisted of 343,023 people initiating opioids for non-cancer pain; of these, 16,527 (4.8%) developed persistent opioid use. Predictors of persistence included older age (≥75 vs 15-44 years: Adjusted odds ratio: 1.67, 95% CI: 1.58-1.78), concessional beneficiary status (1.78, 1.71-1.86), diagnosis of substance use disorder (1.44, 1.22-1.71) and chronic pain (2.05, 1.85-2.27), initiation of opioid therapy with buprenorphine (1.95, 1.73-2.20) and long-acting opioids (2.07, 1.90-2.25), provision of higher quantity of opioids prescribed at initiation (total OME of ≥ 750mg vs < 100mg: 7.75, 6.89-8.72), provision of repeat/refill opioid prescriptions at initiation (2.94, 2.77-3.12), and prescription of gabapentinoids (1.59, 1.50-1.68), benzodiazepines (1.43, 1.38-1.50) and z-drugs (e.g., zopiclone, zolpidem; 1.61, 1.46-1.78). CONCLUSIONS: These findings add to the limited evidence of individual-level factors associated with persistent opioid use. Further research is needed to understand the clinical outcomes of persistent opioid use in people with these risk factors to support the safe and effective prescribing of opioids.