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.

Evidence-Based Guidelines for Prehospital Pain Management: Recommendations.

This project sought to develop evidence-based guidelines for the administration of analgesics for moderate to severe pain by Emergency Medical Services (EMS) clinicians based on a separate, previously published, systematic review of the comparative effectiveness of analgesics in the prehospital setting prepared by the University of Connecticut Evidence-Based Practice Center for the Agency for Healthcare Research and Quality (AHRQ). A technical expert panel (TEP) was assembled consisting of subject matter experts in prehospital and emergency care, and the development of evidence-based guidelines and patient care guidelines. A series of nine "patient/population-intervention-comparison-outcome" (PICO) questions were developed based on the Key Questions identified in the AHRQ systematic review, and an additional PICO question was developed to specifically address analgesia in pediatric patients. The panel made a strong recommendation for the use of intranasal fentanyl over intravenous (IV) opioids for pediatric patients without intravenous access given the supporting evidence, its effectiveness, ease of administration, and acceptance by patients and providers. The panel made a conditional recommendation for the use of IV non-steroidal anti-inflammatory drugs (NSAIDs) over IV acetaminophen (APAP). The panel made conditional recommendations for the use of either IV ketamine or IV opioids; for either IV NSAIDs or IV opioids; for either IV fentanyl or IV morphine; and for either IV ketamine or IV NSAIDs. A conditional recommendation was made for IV APAP over IV opioids. The panel made a conditional recommendation against the use of weight-based IV ketamine in combination with weight-based IV opioids versus weight-based IV opioids alone. The panel considered the use of oral analgesics and a conditional recommendation was made for either oral APAP or oral NSAIDs when the oral route of administration was preferred. Given the lack of a supporting evidence base, the panel was unable to make recommendations for the use of nitrous oxide versus IV opioids, or for IV ketamine in combination with IV opioids versus IV ketamine alone. Taken together, the recommendations emphasize that EMS medical directors and EMS clinicians have a variety of effective options for the management of moderate to severe pain in addition to opioids when designing patient care guidelines and caring for patients suffering from acute pain.

Extended-release naltrexone for people with alcohol use disorder on therapeutic anticoagulation: A case series.

WHAT IS KNOWN AND OBJECTIVE: Individuals with medication adherence challenges or a preference for long-acting medications may benefit from extended-release naltrexone (XR-NTX) for treatment of alcohol use disorder (AUD). Individuals on therapeutic anticoagulation were excluded from XR-NTX studies and its safety in this population has not been reported. CASE SUMMARY: We conducted structured retrospective chart review of six individuals who received XR-NTX for AUD while on therapeutic anticoagulation between November 2019 and Deccember 2020. We found no documented complications among six individuals who received up to 11 doses of XR-NTX while on therapeutic anticoagulation. WHAT IS NEW AND CONCLUSION: XR-NTX may be safely tolerated by patients on therapeutic anticoagulation. We need larger studies evaluating XR-NTX administration in patients on therapeutic anticoagulation and those with coagulopathies, including individuals with alcohol-related liver disease, to better quantify risks and benefits for shared decision-making.

The impact of California wildfires on patient access to prescription opioids.

BACKGROUND: Patients on long-term opioid therapy are particularly vulnerable to disruptions in medication access, especially during traumatic and chaotic events such as wildfires and other natural disasters. OBJECTIVES: To determine whether past highly destructive California wildfires were associated with disrupted access to prescription opioids for patients receiving long-term, and therefore physically dependent on, opioid medications. METHODS: Using California prescription drug monitoring program data, this retrospective study selected patients with long-term prescription opioid use episodes residing in ZIP code tabulation areas impacted by either the Camp Fire or Tubbs Fire. Autoregressive integrated moving average time series models were fit to pre-fire data to forecast post-fire expected values and then compared with observed post-fire data, specifically for weekly proportions of long-term episodes with early fills, late fills, changes in patients' prescriber and pharmacy, and fills within a different ZIP code tabulation area than the patient's residence. RESULTS: After the Camp Fire, there were significant spikes in the proportions of early fills (peak at 56% of total, week 1 after fire), late fills (peak at 29%, week 6), and immediate significant increases in prescriber (peak at 37%, week 3) and pharmacy changes (peak at 71%, week 1) in high-impact ZIP code tabulation areas. Low-impact ZIP code tabulation areas experienced no similar disruptions. Disruptions due to the Tubbs Fire were far less severe. CONCLUSION: Access to prescription opioids was greatly disrupted for patients living in areas most impacted by the Camp Fire. Future research should explore effectiveness of current state and federal controlled substance prescribing policies to determine what improvements are needed to minimize disruptions in medication access due to wildfires and other natural disasters.

A Risk Prediction Model for Long-term Prescription Opioid Use.

BACKGROUND: Tools are needed to aid clinicians in estimating their patients' risk of transitioning to long-term opioid use and to inform prescribing decisions. OBJECTIVE: The objective of this study was to develop and validate a model that predicts previously opioid-naive patients' risk of transitioning to long-term use. RESEARCH DESIGN: This was a statewide population-based prognostic study. SUBJECTS: Opioid-naive (no prescriptions in previous 2 y) patients aged 12 years old and above who received a pill-form opioid analgesic in 2016-2018 and whose prescriptions were registered in the California Prescription Drug Monitoring Program (PDMP). MEASURES: A multiple logistic regression approach was used to construct a prediction model with long-term (ie, >90 d) opioid use as the outcome. Models were developed using 2016-2017 data and validated using 2018 data. Discrimination (c-statistic), calibration (calibration slope, intercept, and visual inspection of calibration plots), and clinical utility (decision curve analysis) were evaluated to assess performance. RESULTS: Development and validation cohorts included 7,175,885 and 2,788,837 opioid-naive patients with outcome rates of 5.0% and 4.7%, respectively. The model showed high discrimination (c-statistic: 0.904 for development, 0.913 for validation), was well-calibrated after intercept adjustment (intercept, -0.006; 95% confidence interval, -0.016 to 0.004; slope, 1.049; 95% confidence interval, 1.045-1.053), and had a net benefit over a wide range of probability thresholds. CONCLUSIONS: A model for the transition from opioid-naive status to long-term use had high discrimination and was well-calibrated. Given its high predictive performance, this model shows promise for future integration into PDMPs to aid clinicians in formulating opioid prescribing decisions at the point of care.

Pharmacist furnishing of naloxone in California: A follow-up analysis.

BACKGROUND: Increasing naloxone access in communities has been a priority to mitigate the increasing rate of opioid-related overdose deaths. OBJECTIVES: The aims of this telephone survey were to estimate the availability of naloxone furnishing (provided without a prescription) by community pharmacists in California and examine the changes that occurred between 2018 and 2020. METHODS: A telephone audit of a random representative sample of 1271 California licensed community pharmacies was conducted from January 22, 2020, to February 24, 2020. The results were compared with those of a survey of 1147 California licensed community pharmacies that was conducted from January 23, 2018, to February 28, 2018. The primary outcomes measured were naloxone availability without a prescription, information on formulations, cost, insurance billing, and stocking status. RESULTS: There was a statistically significant increase in the furnishing of naloxone, as well as stocking and billing, in California from 2018 to 2020. Although fewer than half of the pharmacies were willing to provide naloxone without a prescription in 2020 (n = 487, 42.4%), this was an 80% increase from 2018 (P < 0.001). Of the pharmacies furnishing naloxone, many (n = 399, 81.9%) had nasal naloxone in stock, a large and statistically significant increase from 2018 when only 50.6% reported having it in stock (P < 0.001). In 2020, 90% of the pharmacies reported correctly that pharmacist-furnished naloxone could be billed to insurance compared with 56.9% in 2018 (P < 0.001). The median cash price of nasal naloxone (pack of 2) at chain pharmacies in 2020 was $131 (interquartile range [IQR] $129-$138) compared with $153 (IQR, $141-$163; P = 0.001) at independent pharmacies. CONCLUSION: Community pharmacy-based access to naloxone increased in a statistically significant manner in California, although more than half of the pharmacies still do not provide such access. This study demonstrates the need for further efforts to expand community pharmacy-based access to naloxone.

Using Prescription Drug Monitoring Program Data to Assess Likelihood of Incident Long-Term Opioid Use: a Statewide Cohort Study.

BACKGROUND: Limiting the incidence of opioid-naïve patients who transition to long-term opioid use (i.e., continual use for > 90 days) is a key strategy for reducing opioid-related harms. OBJECTIVE: To identify variables constructed from data routinely collected by prescription drug monitoring programs that are associated with opioid-naïve patients' likelihood of transitioning to long-term use after an initial opioid prescription. DESIGN: Statewide cohort study using prescription drug monitoring program data PARTICIPANTS: All opioid-naïve patients in California (no opioid prescriptions within the prior 2 years) age ≥ 12 years prescribed an initial oral opioid analgesic from 2010 to 2017. METHODS AND MAIN MEASURES: Multiple logistic regression models using variables constructed from prescription drug monitoring program data through the day of each patient's initial opioid prescription, and, alternatively, data available up to 30 and 60 days after the initial prescription were constructed to identify probability of transition to long-term use. Model fit was determined by the area under the receiver operating characteristic curve (C-statistic). KEY RESULTS: Among 30,569,125 episodes of patients receiving new opioid prescriptions, 1,809,750 (5.9%) resulted in long-term use. Variables with the highest adjusted odds ratios included concurrent benzodiazepine use, ≥ 2 unique prescribers, and receipt of non-pill, non-liquid formulations. C-statistics for the day 0, day 30, and day 60 models were 0.81, 0.88, and 0.94, respectively. Models assessing opioid dose using the number of pills prescribed had greater discriminative capacity than those using milligram morphine equivalents. CONCLUSIONS: Data routinely collected by prescription drug monitoring programs can be used to identify patients who are likely to develop long-term use. Guidelines for new opioid prescriptions based on pill counts may be simpler and more clinically useful than guidelines based on days' supply or milligram morphine equivalents.

Trends in Buprenorphine to Treat Opioid Use Disorder in California, 2012 to 2018: Medicaid Outpaces the Rest of the State.

OBJECTIVES: Opioid use disorder remains undertreated in the United States. One of the primary mechanisms for expanding access to treatment has been the use of buprenorphine. In this study, we compare prescribing trends of buprenorphine paid through Medicaid versus other payer sources. METHODS: Combined data from California's prescription drug monitoring program and California's Department of Health Care Services was used to obtain statewide quarterly prescription rates for buprenorphine, indicated for the treatment of opioid use disorder, from 2012 to 2018. RESULTS: From 2012 to 2018, the rate of individuals treated with buprenorphine in Medicaid increased by 657% (1.39-10.5 Medicaid beneficiaries per 10,000) with increases beginning in 2014 and continuing through 2018. Rate of individual prescribing among non-Medicaid sources increased by 93.7% (6.54-12.7 non-Medicaid individuals per 10,000) with most increases occurring before 2014. CONCLUSIONS: California Medicaid has made considerable gains in buprenorphine access, with access growing steadily even after expansions through the Affordable Care Act plateaued. In contrast, recent gains in buprenorphine access for individuals without Medicaid are uninspiring, indicating that initiatives to improve buprenorphine access to patients without Medicaid are urgently needed.

Evidence-Based Guidelines for EMS Administration of Naloxone.

The opioid crisis is a growing concern for Americans, and it has become the leading cause of injury-related death in the United States. An adjunct to respiratory support that can reduce this high mortality rate is the administration of naloxone by Emergency Medical Services (EMS) practitioners for patients with suspected opioid overdose. However, clear evidence-based guidelines to direct EMS use of naloxone for opioid overdose have not been developed. Leveraging the recent Agency for Healthcare Research and Quality (AHRQ) systematic review on the EMS administration of naloxone for opioid poisonings, federal partners determined the need for a clinical practice guideline for EMS practitioners faced with suspected opioid poisoning. Project funding was provided by the National Highway Traffic Safety Administration, Office of EMS, (NHTSA OEMS), and the Health Resources and Services Administration, Maternal and Child Health Bureau's EMS for Children Program (EMSC). The objectives of this project were to develop and disseminate an evidence-based guideline and model protocol for administration of naloxone by EMS practitioners to persons with suspected opioid overdose. We have four recommendations relating to route of administration, all conditional, and all supported by low or very low certainty of evidence. We recommend the intravenous route of administration to facilitate titration of dose, and disfavor the intramuscular route due to difficulty with titration, slower time to clinical effect, and potential exposure to needles. We equally recommend the intranasal and intravenous routes of administration, while noting there are variables which will determine which route is best for each patient. Where we are unable to make recommendations due to evidence limitations (dosing, titration, timing, and transport) we offer technical remarks. Limitations of our work include the introduction of novel synthetic opioids after many of the reviewed papers were produced, which may affect the dose of naloxone required for effect, high risk of bias and imprecision in the reviewed papers, and the introduction of new naloxone administration devices since many of the reviewed papers were published. Future research should be conducted to evaluate new devices and address the introduction of synthetic opioids.

Cigarette Smoking Cessation Intervention for Buprenorphine Treatment Patients.

Introduction: Patients receiving medication assisted therapy (MAT) for opioid use disorder have high cigarette smoking rates. Cigarette smoking interventions have had limited success. We evaluated an intervention to increase cigarette abstinence rates in patients receiving buprenorphine-assisted therapy. Methods: Cigarette smokers (N = 175; 78% male; 69% Caucasian; 20% Hispanic), recruited from a buprenorphine clinic were randomly assigned to either an extended innovative system intervention (E-ISI) or to Standard Treatment Control (STC). The E-ISI combined motivational intervention with extended treatment (long-term nicotine replacement therapy , varenicline, and extended cognitive behavioral therapy). STC received written information about quit-lines, medication, and resources. Assessments were held at baseline and 3, 6, 12, and 18 months. Seven-day biochemically verified point-prevalence cigarette abstinence was the primary outcome measure. Results: Fifty-four percent of E-ISI participants entered the extended treatment intervention; E-ISI and STC differed at 3 months on abstinence status but not at months 6, 12, and 18. E-ISI participants were more likely to attempt to quit, to have a goal of complete abstinence, and to be in a more advanced stage of change than STC participants. A higher number of cigarettes smoked and the use of cannabis in the previous 30 days predicted continued smoking. Conclusions: The E-ISI was successful in increasing motivation to quit smoking but did not result in long-term abstinence. The failure of treatments that have been efficacious in the general population to produce abstinence in patients receiving MAT of opioid use disorder suggests that harm reduction and other innovative interventions should be explored. Implications: This study demonstrates that an intervention combining motivational interviewing with an extended treatment protocol can increase cigarette quit attempts, enhance cigarette abstinence goals, and further movement through stages of change about quitting smoking in patients receiving MAT for opioid use disorder who smoke cigarettes. The intervention did not increase abstinence rates over those observed in a standard treatment control, however. The latter finding supports those of earlier investigators who also failed to find efficacy for smoking cessation in this population and who also used interventions effective in the general population. This pattern of findings suggests that patients with opioid use disorder can be motivated to change smoking behavior, but alternative and innovative approaches to cigarette smoking treatment should be studied.

Aripiprazole for the treatment of methamphetamine dependence: a randomized, double-blind, placebo-controlled trial.

AIMS: To test aripiprazole for efficacy in decreasing use in methamphetamine-dependent adults, compared to placebo. DESIGN: Participants were randomized to receive 12 weeks of aripiprazole or placebo, with a 3-month follow-up and a platform of weekly 30-minute substance abuse counseling. SETTING: The trial was conducted from January 2009 to March 2012 at the San Francisco Department of Public Health. PARTICIPANTS: Ninety actively using, methamphetamine-dependent, sexually active adults were recruited from community venues. MEASUREMENTS: The primary outcome was regression estimated reductions in weekly methamphetamine-positive urines. Secondary outcomes were study medication adherence [by self-report and medication event monitoring systems (MEMS)], sexual risk behavior and abstinence from methamphetamine. FINDINGS: Participant mean age was 38.7 years, 87.8% were male, 50.0% white, 18.9% African American, and 16.7% Latino. Eighty-three per cent of follow-up visits and final visits were completed. By intent-to-treat, participants assigned to aripiprazole had similar reductions in methamphetamine-positive urines as participants assigned to placebo [risk ratio (RR) 0.88, 95% confidence interval (CI): 0.66-1.19, P = 0.41]. Urine positivity declined from 73% (33 of 45 participants) to 45% (18 of 40) in the placebo arm and from 77% (34 of 44) to 44% (20 of 35) in the aripiprazole arm. Adherence by MEMS and self-report was 42 and 74%, respectively, with no significant difference between arms (MEMS P = 0.31; self-report P = 0.17). Most sexual risk behaviors declined similarly among participants in both arms (all P > 0.05). There were no serious adverse events related to study drug, although participants randomized to aripiprazole reported more akathisia, fatigue and drowsiness (P < 0.05). CONCLUSION: Compared with placebo, aripiprazole did not reduce methamphetamine use significantly among actively using, dependent adults.

Mirtazapine to reduce methamphetamine use: a randomized controlled trial.

CONTEXT: No approved pharmacologic treatments for methamphetamine dependence exist. Methamphetamine use is associated with high morbidity and is a major cofactor in the human immunodeficiency virus epidemic among men who have sex with men (MSM). OBJECTIVE: To determine whether mirtazapine would reduce methamphetamine use among MSM who are actively using methamphetamine. DESIGN: Double-blind, randomized, controlled, 12-week trial of mirtazapine vs placebo conducted from September 5, 2007, to March 4, 2010. SETTING: San Francisco Department of Public Health. PARTICIPANTS: Participants were actively using, methamphetamine-dependent, sexually active MSM seen weekly for urine sample collection and substance use counseling. INTERVENTIONS: Random assignment to daily oral mirtazapine (30 mg) or placebo; both arms included 30-minute weekly substance use counseling. MAIN OUTCOME MEASURES: The primary study outcome was reduction in methamphetamine-positive urine test results. Secondary outcomes were study medication adherence (by self-report and medication event monitoring systems) and sexual risk behavior. RESULTS: Sixty MSM were randomized, 85% of follow-up visits were completed, and 56 participants (93%) completed the final visit. In the primary intent-to-treat analysis, participants assigned to the mirtazapine group had fewer methamphetamine-positive urine test results compared with participants assigned to the placebo group (relative risk, 0.57; 95% CI, 0.35-0.93, P = .02). Urine positivity decreased from 67% (20 of 30 participants) to 63% (17 of 27) in the placebo arm and from 73% (22 of 30) to 44% (12 of 27) in the mirtazapine arm. The number needed to treat to achieve a negative weekly urine test result was 3.1. Adherence was 48.5% by medication event monitoring systems and 74.7% by self-report; adherence measures were not significantly different between arms (medication event monitoring systems, P = .82; self-report, P = .92). Most sexual risk behaviors decreased significantly more among participants taking mirtazapine compared with those taking placebo (number of male partners with whom methamphetamine was used, P = .009; number of male partners, P = .04; episodes of anal sex with serodiscordant partners, P = .003; episodes of unprotected anal sex with serodiscordant partners, P = .003; episodes of insertive anal sex with serodiscordant partners, P = .001). There were no serious adverse events related to study drug or significant differences in adverse events by arm (P ≥ .99). CONCLUSION: The addition of mirtazapine to substance use counseling decreased methamphetamine use among active users and was associated with decreases in sexual risk despite low to moderate medication adherence. Trial Registration  clinicalTrials.gov Identifier NCT00497081.