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.

Prescription opioid use among people with opioid dependence and concurrent benzodiazepine and gabapentinoid exposure: An analysis of overdose and all-cause mortality.

BACKGROUND: Studies investigating mortality risk associated with use of opioid analgesics, benzodiazepines, gabapentinoids, and opioid agonist treatment (OAT) among people with opioid dependence (PWOD) are lacking. This study addresses this gap using a cohort of 37,994 PWOD initiating opioid analgesics between July 2003 and July 2018 in New South Wales, Australia. METHODS: Linked administrative records provided data on dispensings, sociodemographics, clinical characteristics, OAT, and mortality. Cox proportional hazards models assessed associations between time-varying measures of individual and concurrent medicine use and OAT with all-cause mortality, accidental opioid overdose, non-drug induced accidents, and non-drug-induced suicide. Opioid analgesic dose effects, expressed as oral morphine equivalents (OMEs) per day, were also examined. OUTCOMES: During the study period, 3167 individuals died. Compared with no use, all medicines of interest were associated with increased accidental opioid overdose risk; hazard ratios (HR) ranged from 1.33 (95 % CI: 1.05-1.68) for opioid analgesic use to 6.10 (95 % CI: 4.11-9.06) for opioid analgesic, benzodiazepine and gabapentinoid use. Benzodiazepine use was associated with increased non-drug-induced accidents and non-drug-induced suicides. For all-cause mortality, all combinations of benzodiazepines and gabapentinoids with opioid analgesics were associated with increased risk (aHRs ranged from 1.35 to 2.73). For most medicines/medicine combinations, all-cause mortality risk was reduced when in OAT compared to out of OAT. Higher opioid analgesic doses were associated with increased all-cause mortality (e.g., 90-199 mg vs 1-49 mg OME per day: HR 1.90 [95 % CI: 1.52-2.40]). INTERPRETATION: The increased mortality risk associated with benzodiazepines and gabapentinoids among PWOD appear to be reduced when engaged in OAT. A greater focus on encouraging OAT engagement, providing overdose prevention education, and access and coverage of overdose antidotes is necessary to minimise the unintended consequences of medicines use in this population.

Predictors of fatal and nonfatal overdose after prescription of opioids for chronic pain: a systematic review and meta-analysis of observational studies.

BACKGROUND: Higher doses of opioids, mental health comorbidities, co-prescription of sedatives, lower socioeconomic status and a history of opioid overdose have been reported as risk factors for opioid overdose; however, the magnitude of these associations and their credibility are unclear. We sought to identify predictors of fatal and nonfatal overdose from prescription opioids. METHODS: We systematically searched MEDLINE, Embase, CINAHL, PsycINFO and Web of Science up to Oct. 30, 2022, for observational studies that explored predictors of opioid overdose after their prescription for chronic pain. We performed random-effects meta-analyses for all predictors reported by 2 or more studies using odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Twenty-eight studies (23 963 716 patients) reported the association of 103 predictors with fatal or nonfatal opioid overdose. Moderate- to high-certainty evidence supported large relative associations with history of overdose (OR 5.85, 95% CI 3.78-9.04), higher opioid dose (OR 2.57, 95% CI 2.08-3.18 per 90-mg increment), 3 or more prescribers (OR 4.68, 95% CI 3.57-6.12), 4 or more dispensing pharmacies (OR 4.92, 95% CI 4.35-5.57), prescription of fentanyl (OR 2.80, 95% CI 2.30-3.41), current substance use disorder (OR 2.62, 95% CI 2.09-3.27), any mental health diagnosis (OR 2.12, 95% CI 1.73-2.61), depression (OR 2.22, 95% CI 1.57-3.14), bipolar disorder (OR 2.07, 95% CI 1.77-2.41) or pancreatitis (OR 2.00, 95% CI 1.52-2.64), with absolute risks among patients with the predictor ranging from 2-6 per 1000 for fatal overdose and 4-12 per 1000 for nonfatal overdose. INTERPRETATION: We identified 10 predictors that were strongly associated with opioid overdose. Awareness of these predictors may facilitate shared decision-making regarding prescribing opioids for chronic pain and inform harm-reduction strategies SYSTEMATIC REVIEW REGISTRATION: Open Science Framework (https://osf.io/vznxj/).

A multimorbidity model for estimating health outcomes from the syndemic of injection drug use and associated infections in the United States.

BACKGROUND: Fatal drug overdoses and serious injection-related infections are rising in the US. Multiple concurrent infections in people who inject drugs (PWID) exacerbate poor health outcomes, but little is known about how the synergy among infections compounds clinical outcomes and costs. Injection drug use (IDU) converges multiple epidemics into a syndemic in the US, including opioid use and HIV. Estimated rates of new injection-related infections in the US are limited due to widely varying estimates of the number of PWID in the US, and in the absence of clinical trials and nationally representative longitudinal observational studies of PWID, simulation models provide important insights to policymakers for informed decisions. METHODS: We developed and validated a MultimorbiditY model to Reduce Infections Associated with Drug use (MYRIAD). This microsimulation model of drug use and associated infections (HIV, hepatitis C virus [HCV], and severe bacterial infections) uses inputs derived from published data to estimate national level trends in the US. We used Latin hypercube sampling to calibrate model output against published data from 2015 to 2019 for fatal opioid overdose rates. We internally validated the model for HIV and HCV incidence and bacterial infection hospitalization rates among PWID. We identified best fitting parameter sets that met pre-established goodness-of-fit targets using the Pearson's chi-square test. We externally validated the model by comparing model output to published fatal opioid overdose rates from 2020. RESULTS: Out of 100 sample parameter sets for opioid use, the model produced 3 sets with well-fitting results to key calibration targets for fatal opioid overdose rates with Pearson's chi-square test ranging from 1.56E-5 to 2.65E-5, and 2 sets that met validation targets. The model produced well-fitting results within validation targets for HIV and HCV incidence and serious bacterial infection hospitalization rates. From 2015 to 2019, the model estimated 120,000 injection-related overdose deaths, 17,000 new HIV infections, and 144,000 new HCV infections among PWID. CONCLUSIONS: This multimorbidity microsimulation model, populated with data from national surveillance data and published literature, accurately replicated fatal opioid overdose, incidence of HIV and HCV, and serious bacterial infections hospitalization rates. The MYRIAD model of IDU could be an important tool to assess clinical and economic outcomes related to IDU behavior and infections with serious morbidity and mortality for PWID.

Considerations for the design of overdose education and naloxone distribution interventions: results of a multi-stakeholder workshop.

INTRODUCTION: Opioid overdose epidemic is a public health crisis that is impacting communities around the world. Overdose education and naloxone distribution programs equip and train lay people to respond in the event of an overdose. We aimed to understand factors to consider for the design of naloxone distribution programs in point-of-care settings from the point of view of community stakeholders. METHODS: We hosted a multi-stakeholder co-design workshop to elicit suggestions for a naloxone distribution program. We recruited people with lived experience of opioid overdose, community representatives, and other stakeholders from family practice, emergency medicine, addictions medicine, and public health to participate in a full-day facilitated co-design discussion wherein large and small group discussions were audio-recorded, transcribed and analysed using thematic approaches. RESULTS: A total of twenty-four participants participated in the multi-stakeholder workshop from five stakeholder groups including geographic and setting diversity. Collaborative dialogue and shared storytelling revealed seven considerations for the design of naloxone distribution programs specific to training needs and the provision of naloxone, these are: recognizing overdose, how much naloxone, impact of stigma, legal risk of responding, position as conventional first aid, friends and family as responders, support to call 911. CONCLUSION: To create an naloxone distribution program in emergency departments, family practice and substance use treatment services, stigma is a central design consideration for training and naloxone kits. Design choices that reference the iconography, type, and form of materials associated with first aid have the potential to satisfy the need to de-stigmatize overdose response.

Opioid Overdose Risk Following Hospital Discharge Among Individuals Prescribed Long-Term Opioid Therapy: a Risk Interval Analysis.

BACKGROUND: Individuals prescribed long-term opioid therapy (LTOT) have increased risk of readmission and death after hospital discharge. The risk of opioid overdose during the immediate post-discharge time period is unknown. OBJECTIVE: To examine the association between time since hospital discharge and opioid overdose among individuals prescribed LTOT. DESIGN: Self-controlled risk interval analysis. PARTICIPANTS: Adults prescribed LTOT with at least one hospital discharge at a safety-net health system and a non-profit healthcare organization in Colorado. MAIN MEASURES: We identified individuals prescribed LTOT who were discharged from January 2006 through June 2019. The outcome was a composite of fatal and non-fatal opioid overdoses during a 90-day post-discharge observation period, identified using electronic health record (EHR) and vital statistics data. Risk intervals included days 0-6 after index and subsequent hospital discharges. Control intervals ranged from days 7 to 89 after index discharge and included all other time during the observation period that did not fall within a risk interval or time readmitted during a subsequent hospitalization, which was excluded. Poisson regression was used to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI) for overdose events during risk in comparison to control intervals. KEY RESULTS: We identified 7695 adults (63.3% over 55 years, 59.4% female, 20.3% Hispanic) who experienced 9499 total discharges during the study period. Twenty-one overdoses occurred during their observation periods (1174 per 100,000 person-years [9 in risk, 12 in control]). Overdose risk was significantly higher during the risk interval in comparison to the control interval (IRR 6.92; 95% CI 2.92-16.43). CONCLUSION: During the first 7 days after hospital discharge, individuals prescribed LTOT appear to be at elevated risk for opioid overdose. Clarifying mechanisms of overdose risk may help inform in-hospital and post-discharge prevention strategies.

Individuals Dying of Overdoses Related to Pharmaceutical Opioids Differ from Individuals Dying of Overdoses Related to Other Substances: A Population-Based Register Study.

BACKGROUND: Pharmaceutical opioid (PO) overdose deaths have increased in many Western countries. There are indications that those dying from a PO overdose differ from those dying from other types of overdoses. These differences might pose a challenge as the majority of current preventive measures are tailored toward those with the characteristics of "conventional" overdose deaths. OBJECTIVE: We investigated differences in the characteristics of persons who died from PO overdoses compared to all other overdoses. MATERIAL AND METHODS: Using the Norwegian Cause of Death Registry, we retrieved information on overdoses classified according to ICD-10 and identified PO overdoses (T40.2; T40.4) and all other overdoses (T40.X; T43.6) in 2010-2019. By linking data from nationwide registers, we analyzed data on opioid dispensations and the history of mental and behavioral disorders. 1,224 persons were registered with PO overdoses and 1,432 persons with other overdoses. RESULTS: Persons in the PO overdose group were older and were more frequently women (35.0% vs. 20.5%) than persons with other overdoses. They had a higher prevalence of chronic pain (35.8% vs. 13.2%), history of cancer (8.1% vs. 1.8%), filled prescriptions of analgetic opioids more frequently the month before death (38.8% vs. 12.0%), and used threefold higher doses of prescribed opioids compared to individuals in all other overdose group (66 vs. 26 oral morphine equivalents/day). In the PO overdose group, oxycodone and fentanyl were more frequently dispensed, while codeine was more frequently dispensed in the other overdose groups. A lower proportion of those in the PO overdose group had recorded diagnoses of substance use disorders, schizophrenia, and hyperkinetic disorder compared to the other overdose groups. CONCLUSION: Persons dying from overdoses on POs often differ from the population targeted by existing prevention strategies, as they are more frequently older women with chronic pain and using high doses of prescription opioids.

Epidemiology, Outcomes, and Trends of Patients With Sepsis and Opioid-Related Hospitalizations in U.S. Hospitals.

OBJECTIVES: Widespread use and misuse of prescription and illicit opioids have exposed millions to health risks including serious infectious complications. Little is known, however, about the association between opioid use and sepsis. DESIGN: Retrospective cohort study. SETTING: About 373 U.S. hospitals. PATIENTS: Adults hospitalized between January 2009 and September 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sepsis was identified by clinical indicators of concurrent infection and organ dysfunction. Opioid-related hospitalizations were identified by the International Classification of Diseases, 9th Revision, Clinical Modification codes and/or inpatient orders for buprenorphine. Clinical characteristics and outcomes were compared by sepsis and opioid-related hospitalization status. The association between opioid-related hospitalization and all-cause, in-hospital mortality in patients with sepsis was assessed using mixed-effects logistic models to adjust for baseline characteristics and severity of illness.The cohort included 6,715,286 hospitalizations; 375,479 (5.6%) had sepsis, 130,399 (1.9%) had opioid-related hospitalizations, and 8,764 (0.1%) had both. Compared with sepsis patients without opioid-related hospitalizations (n = 366,715), sepsis patients with opioid-related hospitalizations (n = 8,764) were younger (mean 52.3 vs 66.9 yr) and healthier (mean Elixhauser score 5.4 vs 10.5), had more bloodstream infections from Gram-positive and fungal pathogens (68.9% vs 47.0% and 10.6% vs 6.4%, respectively), and had lower in-hospital mortality rates (10.6% vs 16.2%; adjusted odds ratio, 0.73; 95% CI, 0.60-0.79; p < 0.001 for all comparisons). Of 1,803 patients with opioid-related hospitalizations who died in-hospital, 928 (51.5%) had sepsis. Opioid-related hospitalizations accounted for 1.5% of all sepsis-associated deaths, including 5.7% of sepsis deaths among patients less than 50 years old. From 2009 to 2015, the proportion of sepsis hospitalizations that were opioid-related increased by 77% (95% CI, 40.7-123.5%). CONCLUSIONS: Sepsis is an important cause of morbidity and mortality in patients with opioid-related hospitalizations, and opioid-related hospitalizations contribute disproportionately to sepsis-associated deaths among younger patients. In addition to ongoing efforts to combat the opioid crisis, public health agencies should focus on raising awareness about sepsis among patients who use opioids and their providers.

Ingenuity and resiliency of syringe service programs on the front lines of the opioid overdose and COVID-19 crises.

As COVID-19 accelerated throughout 2020, syringe service programs (SSPs) faced challenges necessitating programmatic adaptations to prevent overdose deaths while simultaneously keeping workers and participants safe from COVID-19. We used qualitative methods to gain an understanding of the social context within which SSPs are operating during the COVID-19 pandemic. We conducted 36 in-depth interviews with program representatives from 18 programs and used the Exploration, Preparation, Implementation, Sustainment (EPIS) implementation framework to guide data analysis. We focused on 3 of the 4 EPIS constructs: Outer context, inner context, and innovation factors. Our data indicate that responding to the pandemic led to innovations in service delivery such as secondary and mail-based distribution, adoption of telemedicine for enrolling participants in medications for opioid use disorder (MOUD) and use of virtual training platforms for overdose prevention. We found high levels of staff and volunteer commitment, which was a cornerstone to the success of these innovations. We observed that many SSPs were short-staffed because of their commitment to safety, and some lost current funding as well as opportunities for future funding. Despite minimal staffing and diminished funding, SSPs innovated at an accelerated pace. To ensure the sustainability of these new approaches, a supportive external context (federal, state, and local policies and funding) is needed to support the development of SSPs' inner contexts (organizational characteristics, characteristics of individuals) and sustainment of the innovations achieved regarding delivery of naloxone and MOUD.

Opioids are not a major cause of death of patients with sickle cell disease.

According to the Center of Disease Control and Prevention (CDC) database, the total number of deaths due to opioid overdose from 1999 through 2018 was 840,629. Given the alarming nature of these statistics, patients who requested prescription for opioids became targets of suspicion and possible accusation of maladaptive behavior. Patients with sickle cell disease (SCD) were often not exempt from such accusations and became guilty by association. In order to clarify the effect of opioids on the mortality of patients with SCD, the mortality rates for children and adults with SCD were investigated using the CDC Wide-ranging Online Data for Epidemiologic Research (WONDER) Multiple Cause of Death database which is based on all the death certificates issued in the USA from 1999 to 2018. The data showed that 15,765 patients with SCD died from 1999 to 2018. Only 348 patients with SCD died due to opioids. The CDC database contains 27 categories of death based on ICD-10 codes in patients with SCD, and opioids were the 19th ranking cause of death. Surprisingly the most common causes of death of patients with SCD included circulatory, infection, respiratory, genitourinary, and vaso-occlusive crises/acute chest syndrome disorders in decreasing frequency. The mean age of death of females was 41.9 years and of males 39.3 years (p < 0.0001). Death due to SCD and death due to SCD and opioids were highest in the Southern Region of the USA.

Restoration of breathing after opioid overdose and spinal cord injury using temporal interference stimulation.

Respiratory insufficiency is a leading cause of death due to drug overdose or neuromuscular disease. We hypothesized that a stimulation paradigm using temporal interference (TI) could restore breathing in such conditions. Following opioid overdose in rats, two high frequency (5000 Hz and 5001 Hz), low amplitude waveforms delivered via intramuscular wires in the neck immediately activated the diaphragm and restored ventilation in phase with waveform offset (1 Hz or 60 breaths/min). Following cervical spinal cord injury (SCI), TI stimulation via dorsally placed epidural electrodes uni- or bilaterally activated the diaphragm depending on current and electrode position. In silico modeling indicated that an interferential signal in the ventral spinal cord predicted the evoked response (left versus right diaphragm) and current-ratio-based steering. We conclude that TI stimulation can activate spinal motor neurons after SCI and prevent fatal apnea during drug overdose by restoring ventilation with minimally invasive electrodes.

The Geography of Opioid Use Disorder: A Data Triangulation Approach.

Opioid use disorder is complex and not easily quantified among US populations because there are no dedicated reporting systems in place. We review indicators of opioid use disorder available at the state and county (human immunodeficiency virus diagnoses among people who inject drugs, hepatitis C diagnosis in people <50 years, opioid overdose death rates, and opioid prescription rate). The interpretation of the ecological results and the visualization of indicators at the local level will provide actionable insights for clinicians and public health officials seeking to mitigate the consequences of opioid use disorder at the patient and community levels.

Prehospital Laryngeal Tube Airway Device Placement Resulting in Hypopharyngeal Perforation: A Case Report.

A 26-year-old female patient presented in cardiac arrest from presumed opioid overdose. An Ambu King LTS-D laryngeal device was placed by EMS providers for airway management during the resuscitation. There was no documented difficulty with placement and breath sounds and waveform capnography were consistent with appropriate placement. The resuscitation was terminated on scene after extensive resuscitative efforts by the EMS crew. Upon autopsy of the patient, it was discovered that the laryngeal tube device had caused a deep 5 cm perforation to the left piriform recess. The laryngeal tube had bent and was pushed into the perforation in the piriform recess; had the patient had regain of spontaneous circulation this could have caused significant morbidity. Laryngeal tube airway devices have shown increased usage in healthcare settings, in particular in the prehospital arena. Studies of these airway devices have shown they have quick insertion times, high success rates, and low complications. Tongue swelling and minor trauma are common complications of laryngeal tube airway devices. The case report describes a rare, yet potentially life-threatening, complication of laryngeal tube airway device placement- hypopharyngeal injury. If unrecognized, this injury could lead to serious complications. Providers should be aware of the common and uncommon injuries that are associated with prehospital laryngeal tube airway device placement.

Emergency Department Visits for Opioid Overdoses Among Patients With Cancer.

BACKGROUND: Patients with cancer may be at risk of high opioid use due to physical and psychosocial factors, although little data exist to inform providers and policymakers. Our aim is to examine overdoses from opioids leading to emergency department (ED) visits among patients with cancer in the United States. METHODS: The Healthcare Cost and Utilization Project Nationwide Emergency Department Sample was queried for all adult cancer-related patient visits with a primary diagnosis of opioid overdose between 2006 and 2015. Temporal trends and baseline differences between patients with and without opioid-related ED visits were evaluated. Multivariable logistic regression analysis was used to identify risk factors associated with opioid overdose. All statistical tests were two-sided. RESULTS: Between 2006 and 2015, there were a weighted total of 35 339 opioid-related ED visits among patients with cancer. During this time frame, the incidence of opioid-related ED visits for overdose increased twofold (P < .001). On multivariable regression (P < .001), comorbid diagnoses of chronic pain (odds ratio [OR] 4.51, 95% confidence interval [CI] = 4.13 to 4.93), substance use disorder (OR = 3.54, 95% CI = 3.28 to 3.82), and mood disorder (OR = 3.40, 95% CI = 3.16 to 3.65) were strongly associated with an opioid-related visit. Patients with head and neck cancer (OR = 2.04, 95% CI = 1.82 to 2.28) and multiple myeloma (OR = 1.73, 95% CI = 1.32 to 2.26) were also at risk for overdose. CONCLUSIONS: Over the study period, the incidence of opioid-related ED visits in patients with cancer increased approximately twofold. Comorbid diagnoses and primary disease site may predict risk for opioid overdose.