The rate of prescription opioid-related overdose death increased substantially in the United States over the past decade. Patterns of opioid prescribing may be related to risk of overdose mortality.
...To examine the association of maximum prescribed daily opioid dose and dosing schedule ("as needed," regularly scheduled, or both) with risk of opioid overdose death among patients with cancer, chronic pain, acute pain, and substance use disorders.
Case-cohort study.
Veterans Health Administration (VHA), 2004 through 2008.
All unintentional prescription opioid overdose decedents (n = 750) and a random sample of patients (n = 154,684) among those individuals who used medical services in 2004 or 2005 and received opioid therapy for pain. Main Outcome Measure Associations of opioid regimens (dose and schedule) with death by unintentional prescription opioid overdose in subgroups defined by clinical diagnoses, adjusting for age group, sex, race, ethnicity, and comorbid conditions.
The frequency of fatal overdose over the study period among individuals treated with opioids was estimated to be 0.04%.The risk of overdose death was directly related to the maximum prescribed daily dose of opioid medication. The adjusted hazard ratios (HRs) associated with a maximum prescribed dose of 100 mg/d or more, compared with the dose category 1 mg/d to less than 20 mg/d, were as follows: among those with substance use disorders, adjusted HR = 4.54 (95% confidence interval CI, 2.46-8.37; absolute risk difference approximation ARDA = 0.14%); among those with chronic pain, adjusted HR = 7.18 (95% CI, 4.85-10.65; ARDA = 0.25%); among those with acute pain, adjusted HR = 6.64 (95% CI, 3.31-13.31; ARDA = 0.23%); and among those with cancer, adjusted HR = 11.99 (95% CI, 4.42-32.56; ARDA = 0.45%). Receiving both as-needed and regularly scheduled doses was not associated with overdose risk after adjustment.
Among patients receiving opioid prescriptions for pain, higher opioid doses were associated with increased risk of opioid overdose death.
Despite increased focus on reducing opioid prescribing for long-term pain, little is known regarding the incidence and risk factors for persistent opioid use after surgery.
To determine the incidence ...of new persistent opioid use after minor and major surgical procedures.
Using a nationwide insurance claims data set from 2013 to 2014, we identified US adults aged 18 to 64 years without opioid use in the year prior to surgery (ie, no opioid prescription fulfillments from 12 months to 1 month prior to the procedure). For patients filling a perioperative opioid prescription, we calculated the incidence of persistent opioid use for more than 90 days among opioid-naive patients after both minor surgical procedures (ie, varicose vein removal, laparoscopic cholecystectomy, laparoscopic appendectomy, hemorrhoidectomy, thyroidectomy, transurethral prostate surgery, parathyroidectomy, and carpal tunnel) and major surgical procedures (ie, ventral incisional hernia repair, colectomy, reflux surgery, bariatric surgery, and hysterectomy). We then assessed data for patient-level predictors of persistent opioid use.
The primary outcome was defined a priori prior to data extraction. The primary outcome was new persistent opioid use, which was defined as an opioid prescription fulfillment between 90 and 180 days after the surgical procedure.
A total of 36 177 patients met the inclusion criteria, with 29 068 (80.3%) receiving minor surgical procedures and 7109 (19.7%) receiving major procedures. The cohort had a mean (SD) age of 44.6 (11.9) years and was predominately female (23 913 66.1%) and white (26 091 72.1%). The rates of new persistent opioid use were similar between the 2 groups, ranging from 5.9% to 6.5%. By comparison, the incidence in the nonoperative control cohort was only 0.4%. Risk factors independently associated with new persistent opioid use included preoperative tobacco use (adjusted odds ratio aOR, 1.35; 95% CI, 1.21-1.49), alcohol and substance abuse disorders (aOR, 1.34; 95% CI, 1.05-1.72), mood disorders (aOR, 1.15; 95% CI, 1.01-1.30), anxiety (aOR, 1.25; 95% CI, 1.10-1.42), and preoperative pain disorders (back pain: aOR, 1.57; 95% CI, 1.42-1.75; neck pain: aOR, 1.22; 95% CI, 1.07-1.39; arthritis: aOR, 1.56; 95% CI, 1.40-1.73; and centralized pain: aOR, 1.39; 95% CI, 1.26-1.54).
New persistent opioid use after surgery is common and is not significantly different between minor and major surgical procedures but rather associated with behavioral and pain disorders. This suggests its use is not due to surgical pain but addressable patient-level predictors. New persistent opioid use represents a common but previously underappreciated surgical complication that warrants increased awareness.
At least 2.3 million people in the U.S. have an opioid use disorder, less than 40% of whom receive evidence-based treatment. Buprenorphine used as part of medication-assisted treatment has high ...potential to address this gap because of its approval for use in non-specialty outpatient settings, effectiveness at promoting abstinence, and cost effectiveness. However, less than 4% of licensed physicians are approved to prescribe buprenorphine for opioid use disorder, and approximately 47% of counties lack a buprenorphine-waivered physician. Existing policies contribute to workforce barriers to buprenorphine provision and access. Providers are reticent to prescribe buprenorphine because of workforce barriers, such as (1) insufficient training and education on opioid use disorder treatment, (2) lack of institutional and clinician peer support, (3) poor care coordination, (4) provider stigma, (5) inadequate reimbursement from private and public insurers, and (6) regulatory hurdles to obtain the waiver needed to prescribe buprenorphine in non-addiction specialty treatment settings. Policy pathways to addressing these provider workforce barriers going forward include providing free and easy-to-access education for providers about opioid use disorders and medication-assisted treatment, eliminating buprenorphine waiver requirements for those licensed to prescribe controlled substances, enforcing insurance parity requirements, requiring coverage of evidence-based medication-assisted treatment as essential health benefits, and providing financial incentives for care coordination across healthcare professional types—including behavioral health counselors and other non-physicians in specialty and non-specialty settings.
This article is part of a supplement entitled The Behavioral Health Workforce: Planning, Practice, and Preparation, which is sponsored by the Substance Abuse and Mental Health Services Administration and the Health Resources and Services Administration of the U.S. Department of Health and Human Services.
In response to adverse outcomes from prescription opioids, the Centers for Disease Control and Prevention (CDC) released the Guideline for Prescribing Opioids for Chronic Pain in March 2016.
To test ...the hypothesis that the CDC guideline release corresponded to declines in specific opioid prescribing practices.
Interrupted time series analysis of monthly prescribing measures from the IQVIA transactional data warehouse and Real-World Data Longitudinal Prescriptions population-level estimates based on retail pharmacy data. Population size was determined by U.S. Census monthly estimates.
United States, 2012 to 2017.
Persons prescribed opioid analgesics.
Outcomes included opioid dosage, days supplied, overlapping benzodiazepine prescriptions, and the overall rate of prescribing.
The rate of high-dosage prescriptions (≥90 morphine equivalent milligrams per day) was 683 per 100 000 persons in January 2012 and declined by 3.56 (95% CI, -3.79 to -3.32) per month before March 2016 and by 8.00 (CI, -8.69 to -7.31) afterward. Likewise, the percentage of patients with overlapping opioid and benzodiazepine prescriptions was 21.04% in January 2012 and declined by 0.02% (CI, -0.04% to -0.01%) per month before the CDC guideline release and by 0.08% (CI, -0.08% to -0.07%) per month afterward. The overall opioid prescribing rate was 6577 per 100 000 persons in January 2012 and declined by 23.48 (CI, -26.18 to -20.78) each month before the guideline release and by 56.74 (CI, -65.96 to -47.53) per month afterward.
No control population; inability to determine the appropriateness of opioid prescribing.
Several opioid prescribing practices were decreasing before the CDC guideline, but the time of its release was associated with a greater decline. Guidelines may be effective in changing prescribing practices.
CDC.
Little is known about real-world COVID-19 vaccine effectiveness (VE) in racially and ethnically diverse, elderly populations with high comorbidity burden.
To determine the effectiveness of messenger ...RNA COVID-19 vaccines.
Target trial emulation study comparing newly vaccinated persons with matched unvaccinated controls.
U.S. Department of Veterans Affairs health care system.
Among persons receiving care in the Veterans Affairs health care system (
= 5 766 638), those who received at least 1 dose of the Moderna or Pfizer-BioNTech COVID-19 vaccine from 11 December 2020 to 25 March 2021 (
= 2 099 871) were matched to unvaccinated controls in a 1:1 ratio according to demographic, clinical, and geographic characteristics.
Follow-up for SARS-CoV-2 infection or SARS-CoV-2-related death, defined as death within 30 days of infection, began after the vaccination date or an identical index date for the matched unvaccinated controls and continued until up to 30 June 2021.
Vaccine effectiveness against SARS-CoV-2 infection or SARS-CoV-2-related death.
Vaccinated and unvaccinated groups were well matched; both were predominantly male (92.9% vs. 93.4%), had advanced age (mean, 68.7 years in both groups), had diverse racial and ethnic distribution (for example, Black: 17.3% vs. 17.0%, Hispanic: 6.5% vs. 6.1%), and had substantial comorbidity burden. Vaccine effectiveness 7 or more days after the second vaccine dose was 69% (95% CI, 67% to 70%) against SARS-CoV-2 infection and 86% (CI, 82% to 89%) against SARS-CoV-2-related death and was similar when follow-up was extended to 31 March versus 30 June. Vaccine effectiveness against infection decreased with increasing age and comorbidity burden.
Predominantly male population and lack of data on SARS-CoV-2 variants.
In an elderly, diverse, high-comorbidity population, COVID-19 VE against infection was substantially lower than previously reported, but VE against death was high. Complementary infection mitigation efforts remain important for pandemic control, even with vaccination.
U.S. Department of Veterans Affairs.
High placebo responses have been observed across a wide range of pathologies, severely impacting drug development.
To examine neurochemical mechanisms underlying the formation of placebo effects in ...patients with major depressive disorder (MDD).
In this study involving 2 placebo lead-in phases followed by an open antidepressant administration, we performed a single-blinded 2-week crossover randomized clinical trial of 2 identical oral placebos (described as having either active or inactive fast-acting antidepressant-like effects) followed by a 10-week open-label treatment with a selective serotonin reuptake inhibitor or, in some cases, another agent as clinically indicated. The volunteers (35 medication-free patients with MDD at a university health system) were studied with positron emission tomography and the µ-opioid receptor-selective radiotracer 11Ccarfentanil after each 1-week inactive and active oral placebo treatment. In addition, 1 mL of isotonic saline was administered intravenously within sight of the volunteer during positron emission tomographic scanning every 4 minutes over 20 minutes only after the 1-week active placebo treatment, with instructions that the compound may be associated with the activation of brain systems involved in mood improvement. This challenge stimulus was used to test the individual capacity to acutely activate endogenous opioid neurotransmision under expectations of antidepressant effect.
Changes in depressive symptoms in response to active placebo and antidepressant. Baseline and activation measures of µ-opioid receptor binding.
Higher baseline µ-opioid receptor binding in the nucleus accumbens was associated with better response to antidepressant treatment (r = 0.48; P = .02). Reductions in depressive symptoms after 1 week of active placebo treatment, compared with the inactive, were associated with increased placebo-induced µ-opioid neurotransmission in a network of regions implicated in emotion, stress regulation, and the pathophysiology of MDD, namely, the subgenual anterior cingulate cortex, nucleus accumbens, midline thalamus, and amygdala (nucleus accumbens: r = 0.6; P < .001). Placebo-induced endogenous opioid release in these regions was associated with better antidepressant treatment response, predicting 43% of the variance in symptom improvement at the end of the antidepressant trial.
These data demonstrate that placebo-induced activation of the µ-opioid system is implicated in the formation of placebo antidepressant effects in patients with MDD and also participate in antidepressant responses, conferring illness resiliency, during open administration.
clinicaltrials.gov Identifier:NCT02178696.
Murine models suggest that opioids alter the gut microbiota, which may impact opioid tolerance and psychopathology. We examined how gut microbiota characteristics related to use of opioid agonists ...and antagonists among people receiving outpatient addiction treatment. Patients (n = 46) collected stool samples and were grouped by use of opioid agonists (heroin, prescription opioids), antagonists (naltrexone), agonist-antagonist combinations (buprenorphine-naloxone), or neither agonists nor antagonists within the month before enrollment. We sequenced the V4 region of the 16S rRNA gene using Illumina MiSeq to examine how alpha diversity, enterotypes, and relative abundance of bacterial genera varied by opioid agonist and antagonist exposures. Compared to 31 participants who used neither agonists nor antagonists, 5 participants who used opioid agonists (without antagonists) had lower microbiota diversity, Bacteroides enterotypes, and lower relative abundance of Roseburia, a butyrate producing genus, and Bilophila, a bile acid metabolizing genus. There were no differences in gut microbiota features between those using agonist + antagonists (n = 4), antagonists only (n = 6), and neither agonists nor antagonists. Similar to murine morphine exposure models, opioid agonist use was associated with lower microbiota diversity. Lower abundance of Roseburia and Bilophila may relate to the gut inflammation/permeability and dysregulated bile acid metabolism observed in opioid-exposed mice.
Objective To study the association between benzodiazepine prescribing patterns including dose, type, and dosing schedule and the risk of death from drug overdose among US veterans receiving opioid ...analgesics.Design Case-cohort study.Setting Veterans Health Administration (VHA), 2004-09.Participants US veterans, primarily male, who received opioid analgesics in 2004-09. All veterans who died from a drug overdose (n=2400) while receiving opioid analgesics and a random sample of veterans (n=420 386) who received VHA medical services and opioid analgesics.Main outcome measure Death from drug overdose, defined as any intentional, unintentional, or indeterminate death from poisoning caused by any drug, determined by information on cause of death from the National Death Index.Results During the study period 27% (n=112 069) of veterans who received opioid analgesics also received benzodiazepines. About half of the deaths from drug overdose (n=1185) occurred when veterans were concurrently prescribed benzodiazepines and opioids. Risk of death from drug overdose increased with history of benzodiazepine prescription: adjusted hazard ratios were 2.33 (95% confidence interval 2.05 to 2.64) for former prescriptions versus no prescription and 3.86 (3.49 to 4.26) for current prescriptions versus no prescription. Risk of death from drug overdose increased as daily benzodiazepine dose increased. Compared with clonazepam, temazepam was associated with a decreased risk of death from drug overdose (0.63, 0.48 to 0.82). Benzodiazepine dosing schedule was not associated with risk of death from drug overdose.Conclusions Among veterans receiving opioid analgesics, receipt of benzodiazepines was associated with an increased risk of death from drug overdose in a dose-response fashion.
Since 1999, more than 600 000 people have died from opioid overdoses in the USA and Canada, and the current rate of mortality in each country exceeds even that of the worst year of the HIV/AIDS ...epidemic. The Commission's analysis of the crisis focused on seven domains: (1) the North American opioid crisis as a case study in multi-system regulatory failure, (2) opioids' dual nature as both a benefit and a risk to health, (3) building integrated, well supported, and enduring systems of care for people with substance use disorders, (4) maximising the benefits and minimising the adverse effects of the involvement of the criminal justice system with people who are addicted to opioids, (5) creating healthy environments that can yield long-term declines in the incidence of addiction, (6) stimulating greater innovation in the response to the opioid crisis, and (7) preventing the North American opioid crisis from spreading globally. The Commission therefore recommends curtailing pharmaceutical product promotion, insulating medical education from pharmaceutical industry influence, closing the so-called revolving door between regulators and industry, making post-approval drug monitoring and risk mitigation a function of government, and firewalling bodies with formal power over prescribing from industry influence. ...a major investment in
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