Abuse-deterrent formulations and opioid-related harms in North Carolina, 2010-2018.

Abuse-deterrent formulations of opioid analgesics (ADFs) were introduced to reduce opioid-related harms among pain patients, but post-marketing study results have been mixed. However, these studies may be subject to bias from selection criteria, comparator choice, and potential confounding by "indication," highlighting the need for thorough study design considerations. In a sample of privately insured patients prescribed ADF or non-ADF extended-release/long-acting (ER/LA) opioids in North Carolina, we implemented a version of the prevalent new-user design to evaluate the relationship between ADFs and opioid use disorder (OUD, n=235) and opioid overdose (n=18) through six months of follow-up using inverse probability-weighted cumulative incidence functions and Fine-Gray models. The weighted hazard [HRw] of opioid overdose among patients initiating ADFs was 0.87 (95% CI: 0.23, 3.24) times as high as among patients who initiated, restarted, or continued non-ADF ER/LA opioids. We observed a short-term benefit of ADFs for incident OUD (HRw=0.58; 95% CI: 0.35, 0.93) compared to non-ADF ER/LA opioids in the first six weeks of follow-up, but this benefit disappeared later in follow-up (HRw=1.30; 0.86, 1.95). In summary, our findings add to the expanding body of evidence that there is no clear long-term reduction in harm from ADF opioids among patients in outpatient use.

Evidence-based treatment for opioid use disorder is widely unavailable and often discouraged by providers of residential substance use services in North Carolina.

INTRODUCTION: Opioid agonist treatment (OAT) is the only treatment for opioid use disorder (OUD) proven to reduce overdose mortality, yet access to this evidence-based treatment remains poor. The purpose of this cross-sectional audit study was to assess OAT availability at residential substance use services in North Carolina. METHODS: We conducted a state-wide inventory of residential substance use service providers in North Carolina and subsequently called all providers identified, posing as uninsured persons who use heroin, seeking treatment services. Program characteristics, as reported in phone calls, were systematically recorded. We used Fisher's exact tests to assess what program characteristics were associated with OAT availability and with staff making discouraging comments about OAT. We used unsupervised agglomerative clustering to identify facilities with similar characteristics. RESULTS: Of the 94 treatment providers identified, we successfully contacted and collected data from 66. Of those, only 7 (10.6 %) provide OAT on site; an additional 9 (13.6 %) allow OAT through an outside or community-based prescriber. Only 8 (12.1 %) providers were licensed to provide residential substance use treatment. Staff from 33 (50.0 %) providers made negative, discouraging, or stigmatizing remarks about OAT-for example, that OAT substitutes one addiction for another or does not constitute "true recovery." OAT availability was positively associated with a provider holding a state license for any substance use-related service (41.9 % vs 8.6 %, p = 0.002) and offering 12-step programming (36.1 % vs. 10/0 %, p = 0.020). OAT availability was negatively associated with faith-based programming (6.1 % vs 42.4 %, p = 0.001), dress codes (5.3 % vs 50.0 %, p < 0.001), and mandates that residents work in a provider-owned and -operated commercial enterprise (5.0 % vs 32.6 %, p = 0.026). Cluster analysis revealed that the most common (n = 21) type of service provider in North Carolina is an unlicensed, faith-based organization that prohibits OAT, imposes a dress code, and mandates that residents work, often in provider-owned and -operated commercial enterprises. CONCLUSION: Evidence-based treatments for OUD are largely unavailable at providers of residential substance use services in North Carolina. The prohibition of OAT occurs most often among providers who are unlicensed and impose labor and/or 12-step mandates on residents. Changes to state licensure requirements and exemptions may help improve OAT availability.

Xylazine is an agonist at kappa opioid receptors and exhibits sex-specific responses to opioid antagonism.

Xylazine is in the unregulated drug supply at increasing rates, usually combined with fentanyl, necessitating understanding of its pharmacology. Despite commentary from politicians, and public health officials, it is unknown how xylazine impacts naloxone efficacy, and. few studies have examined it alone. Here, we examine the impact of xylazine alone and in combination with fentanyl on several behaviors in mice. Surprisingly, naloxone precipitates withdrawal from xylazine and fentanyl/xylazine coadministration, with enhanced sensitivity in females. Further, xylazine is a full agonist at kappa opioid receptors, a potential mechanism for its naloxone sensitivity. Finally, we demonstrate surprising effects of xylazine to kappa opioid antagonism, which are relevant for public health considerations. These data address an ongoing health crisis and will help inform critical policy and healthcare decisions.

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.

Higher First 30-Day Dose of Buprenorphine for Opioid Use Disorder Treatment Is Associated With Decreased Mortality.

OBJECTIVE: Buprenorphine is a medication for opioid use disorder that reduces mortality. This study aims to investigate the less well-understood relationship between the dose in the early stages of treatment and the subsequent risk of death. METHODS: We used Kentucky prescription monitoring data to identify adult Kentucky residents initiating transmucosal buprenorphine medication for opioid use disorder (January 2017 to November 2019). Average daily buprenorphine dose for days covered in the first 30 days of treatment was categorized as ≤8 mg, >8 to ≤16 mg, and >16 mg. Patients were followed for 365 days after the first 30 days of buprenorphine treatment. Endpoints were opioid-involved overdose death and death from other causes. Causes and dates of death were obtained using Kentucky death certificate records. Associations were evaluated using multivariable Fine and Gray models adjusting for patient baseline characteristics. RESULTS: In the cohort of 49,857 patients, there were 227 opioid-involved overdose deaths and 459 deaths from other causes. Compared with ≤8 mg, the adjusted subdistribution hazard ratio (aSHR) of opioid-involved overdose death decreased by 55% (aSHR, 0.45; 95% confidence interval [CI], 0.34-0.60) and 64% (aSHR, 0.36; 95% CI, 0.25-0.52) for patients receiving doses of >8 to ≤16 mg and >16 mg, respectively. The incidence of death from other causes was lower in patients receiving >8 to ≤16 mg (aSHR, 0.78; 95% CI, 0.62-0.98) and >16 mg (aSHR, 0.62; 95% CI, 0.47-0.80) versus ≤8 mg dose. CONCLUSIONS: Higher first 30-day buprenorphine doses were associated with reduced opioid-involved overdose death and death from other causes, supporting benefit of higher dosing in reducing mortality.

Naloxone Accessibility by Standing Order in North Carolina Community Pharmacies.

BACKGROUND: According to a standing order in North Carolina (NC), naloxone can be purchased without a provider prescription. OBJECTIVE: The objective of this study is to examine whether same-day naloxone accessibility and cost vary by pharmacy type and rurality in NC. METHODS: A cross-sectional telephone audit of 202 NC community pharmacies stratified by pharmacy type and county of origin was conducted in March and April 2023. Trained "secret shoppers" enacted a standardized script and recorded whether naloxone was available and its cost. We examined the relationship between out-of-pocket naloxone cost, pharmacy type, and rurality. RESULTS: Naloxone could be purchased in 53% of the pharmacies contacted; 26% incorrectly noting that naloxone could be filled only with a provider prescription and 21% did not sell naloxone. Naloxone availability by standing order was statistically different by pharmacy type (chain/independent) (χ2 = 20.58, df = 4, P value < 0.001), with a higher frequency of willingness to dispense according to the standing order by chain pharmacies in comparison to independent pharmacies. The average quoted cost for naloxone nasal spray at chain pharmacies was $84.69; the cost was significantly more ($113.54; P < 0.001) at independent pharmacies. Naloxone cost did not significantly differ by pharmacy rurality (F2,136 = 2.38, P = 0.10). CONCLUSION: Approximately half of NC community pharmacies audited dispense naloxone according to the statewide standing order, limiting same-day access to this life-saving medication. Costs were higher at independent pharmacies, which could be due to store-level policies. Future studies should further investigate these cost differences, especially as intranasal naloxone transitions from a prescription only to over-the-counter product.

Medications for Opioid Use Disorder and Mortality and Hospitalization Among People With Opioid Use-related Infections.

BACKGROUND: Severe skin and soft tissue infections related to injection drug use have increased in concordance with a shift to heroin and illicitly manufactured fentanyl. Opioid agonist therapy medications (methadone and buprenorphine) may improve long-term outcomes by reducing injection drug use. We aimed to examine the association of medication use with mortality among people with opioid use-related skin or soft tissue infections. METHODS: An observational cohort study of Medicaid enrollees aged 18 years or older following their first documented medical encounters for opioid use-related skin or soft tissue infections during 2007-2018 in North Carolina. The exposure was documented medication use (methadone or buprenorphine claim) in the first 30 days following initial infection compared with no medication claim. Using Kaplan-Meier estimators, we examined the difference in 3-year incidence of mortality by medication use, weighted for year, age, comorbidities, and length of hospital stay. RESULTS: In this sample, there were 13,286 people with opioid use-related skin or soft tissue infections. The median age was 37 years, 68% were women, and 78% were white. In Kaplan-Meier curves for the total study population, 12 of every 100 patients died during the first 3 years. In weighted models, for every 100 people who used medications, there were four fewer deaths over 3 years (95% confidence interval = 2, 6). CONCLUSION: In this study, people with opioid use-related skin and soft tissue infections had a high risk of mortality following their initial healthcare visit for infections. Methadone or buprenorphine use was associated with reductions in mortality.

Prevalence of fentanyl in methamphetamine and cocaine samples collected by community-based drug checking services.

BACKGROUND: Overdose deaths involving stimulants and opioids simultaneously have raised the specter of widespread contamination of the stimulant supply with fentanyl. METHODS: We quantified prevalence of fentanyl in street methamphetamine and cocaine, stratified by crystalline texture, analyzing samples sent voluntarily to a public mail-in drug checking service (May 2021-June 2023). Samples from 77 harm reduction programs and clinics originated in 25 US states. Sample donors reported expected drug and physical descriptions. Substances were identified by gas chromatography-mass spectrometry. Negative binomial models were used to calculate fentanyl prevalence, adjusting for potential confounders related to sample selection. We also examined if xylazine changed donors' accuracy of detecting fentanyl. RESULTS: We analyzed 718 lab-confirmed samples of methamphetamine (64%) and cocaine (36%). The adjusted prevalence of fentanyl was 12.5% (95% CI: 2.2%, 22.9%) in powder methamphetamine and 14.8% (2.3%, 27.2%) in powder cocaine, with notable geographic variation. Crystalline forms of both methamphetamine (Chisq=57, p<0.001) and cocaine (Chisq=18, p<0.001) were less likely to contain fentanyl: less than 1% of crystal methamphetamine (2/276) and no crack cocaine (0/53). Heroin was present in 6.6% of powder cocaine samples. Xylazine reduced donors' ability to detect fentanyl, with correct classification dropping from 92% to 42%. CONCLUSIONS: Fentanyl was detected primarily in powder forms of methamphetamine and cocaine. Recommended interventions include expanding community-based drug checking, naloxone and fentanyl test strip distribution for people who use stimulants , and supervised drug consumption sites. New strategies to dampen variability in street drug composition are needed to reduce inadvertent fentanyl exposure.

Mortality associated with bacterial and fungal infections and overdose among people with drug use diagnoses.

PURPOSE: Hospital visits for drug use-related bacterial and fungal infections have increased alongside overdose deaths. The incidence of mortality from these infections and the comparison to overdose mortality is not established. METHODS: This cohort study examined mortality outcomes among adults with drug use diagnoses who were insured by public and private plans during 2007 through 2018 in North Carolina. We examined bacterial- and fungal infection-related mortality and overdose mortality using cumulative incidence functions. RESULTS: Among 131,522 people with drug use diagnoses, the median age was 45 years (interquartile range: 31-57), 58% were women and 65% had an opioid use disorder diagnosis. The 1-year incidence of bacterial and fungal infection-associated mortality was progressively higher as age increased (35-49 years: 9 per 10,000 people, 50-64 years: 23 per 10,000, 65+ years: 50 per 10,000 people). Conversely, the 1-year incidence of overdose mortality was markedly lower among older adults compared to those under the age of 65 (18-34 years: 34 deaths per 10,000 people; 35-49 years: 47 per 10,000; 50-64 years: 41 per 10,000; 65+ years: 9 per 10,000). CONCLUSIONS: Bacterial and fungal infections and overdose were notable causes of death among adults with drug use diagnoses, and varied by age group.

Reducing the harms of xylazine: clinical approaches, research deficits, and public health context.

OBJECTIVES: Xylazine has emerged as a consistent part of the unregulated drug supply in recent months. We discuss major domains of xylazine's harm, current knowledge deficits, clinical and harm reduction strategies for minimizing harm, and xylazine's public health and policy context. As an interdisciplinary team from across the USA, we have pooled our knowledge to provide an overview of xylazine's current and emerging contexts. METHODS: To inform this essay, the pertinent literature was reviewed, clinical knowledge and protocols were shared by multiple clinicians with direct expertise, and policy and public health context were added by expert authors. RESULTS: We describe xylazine's major harm domains-acute poisoning, extended sedation, and wounds, along with anemia and hyperglycemia, which have been reported anecdotally but lack as clear of a connection to xylazine. Current successful practices for xylazine wound care are detailed. Understanding xylazine's epidemiology will also require greater investment in drug checking and surveillance. Finally, approaches to community-based wound care are discussed, along with an orientation to the larger policy and public health context. CONCLUSIONS: Addressing the harms of xylazine requires interdisciplinary participation, investment in community-based harm reduction strategies, and improved drug supply surveillance. The relatively unique context of xylazine demands buy-in from public health professionals, harm reduction professionals, clinicians, basic science researchers, policymakers and more.

Drugs involved in Kentucky drug poisoning deaths and relation with antecedent controlled substance prescription dispensing.

BACKGROUND: The shift from prescription to illicit drugs involved in drug poisoning deaths raises questions about the current utility of prescription drug monitoring program (PDMP) data to inform drug poisoning (overdose) prevention efforts. In this study, we describe relations between specific drugs involved in Kentucky drug poisoning deaths and antecedent controlled substance (CS) dispensing. METHODS: The study used linked death certificates and PDMP data for 2,248 Kentucky resident drug poisoning deaths in 2021. Death certificate literal text analysis identified drugs mentioned with involvement (DMI) in drug poisoning deaths. We characterized the concordance between each DMI and the CS dispensing history for this drug at varying timepoints since 2008. RESULTS: Overall, 25.5% of all decedents had dispensed CS in the month before fatal drug poisoning. Over 80% of decedents were dispensed opioid(s) since 2008; the percentage was similar regardless of opioid involvement in the poisoning death. One-third of decedents had dispensed buprenorphine for treatment of opioid use disorder since 2008, but only 6.1% had dispensed buprenorphine in the month preceding death. Fentanyl/fentanyl analogs were DMI in 1,568 (69.8%) deaths, yet only 3% had received a fentanyl prescription since 2008. The highest concordance in the month preceding death was observed for clonazepam (43.6%). CONCLUSION: Overall, concordance between CS dispensing history and the drugs involved in poisoning deaths was low, suggesting a need to reevaluate the complex relationships between prescription medication exposure and overdose death and to expand harm reduction interventions both within and outside the healthcare system to reduce drug poisoning mortality.

Exposure and Reactions to Cancer Treatment Misinformation and Advice: Survey Study.

BACKGROUND: Cancer treatment misinformation, or false claims about alternative cures, often spreads faster and farther than true information on social media. Cancer treatment misinformation can harm the psychosocial and physical health of individuals with cancer and their cancer care networks by causing distress and encouraging people to abandon support, potentially leading to deviations from evidence-based care. There is a pressing need to understand how cancer treatment misinformation is shared and uncover ways to reduce misinformation. OBJECTIVE: We aimed to better understand exposure and reactions to cancer treatment misinformation, including the willingness of study participants to prosocially intervene and their intentions to share Instagram posts with cancer treatment misinformation. METHODS: We conducted a survey on cancer treatment misinformation among US adults in December 2021. Participants reported their exposure and reactions to cancer treatment misinformation generally (saw or heard, source, type of advice, and curiosity) and specifically on social media (platform, believability). Participants were then randomly assigned to view 1 of 3 cancer treatment misinformation posts or an information post and asked to report their willingness to prosocially intervene and their intentions to share. RESULTS: Among US adult participants (N=603; mean age 46, SD 18.83 years), including those with cancer and cancer caregivers, almost 1 in 4 (142/603, 23.5%) received advice about alternative ways to treat or cure cancer. Advice was primarily shared through family (39.4%) and friends (37.3%) for digestive (30.3%) and natural (14.1%) alternative cancer treatments, which generated curiosity among most recipients (106/142, 74.6%). More than half of participants (337/603, 55.9%) saw any cancer treatment misinformation on social media, with significantly higher exposure for those with cancer (53/109, 70.6%) than for those without cancer (89/494, 52.6%; P<.001). Participants saw cancer misinformation on Facebook (39.8%), YouTube (27%), Instagram (22.1%), and TikTok (14.1%), among other platforms. Participants (429/603, 71.1%) thought cancer treatment misinformation was true, at least sometimes, on social media. More than half (357/603, 59.2%) were likely to share any cancer misinformation posts shown. Many participants (412/603, 68.3%) were willing to prosocially intervene for any cancer misinformation posts, including flagging the cancer treatment misinformation posts as false (49.7%-51.4%) or reporting them to the platform (48.1%-51.4%). Among the participants, individuals with cancer and those who identified as Black or Hispanic reported greater willingness to intervene to reduce cancer misinformation but also higher intentions to share misinformation. CONCLUSIONS: Cancer treatment misinformation reaches US adults through social media, including on widely used platforms for support. Many believe that social media posts about alternative cancer treatment are true at least some of the time. The willingness of US adults, including those with cancer and members of susceptible populations, to prosocially intervene could initiate the necessary community action to reduce cancer treatment misinformation if coupled with strategies to help individuals discern false claims.

Identifying barriers and facilitators to COVID-19 vaccination uptake among People Who Use Drugs in Canada: a National Qualitative Study.

BACKGROUND: People Who Use Drugs (PWUD) have lower vaccination uptake than the general population, and disproportionately experience the burden of harms from vaccine-preventable diseases. We conducted a national qualitative study to: (1) identify the barriers and facilitators to receiving COVID-19 vaccinations among PWUD; and (2) identify interventions to support PWUD in their decision-making. METHODS: Between March and October 2022, semi-structured interviews with PWUD across Canada were conducted. Fully vaccinated (2 or more doses) and partially or unvaccinated (1 dose or less) participants were recruited from a convenience sample to participate in telephone interviews to discuss facilitators, barriers, and concerns about receiving COVID-19 vaccines and subsequent boosters, and ways to address concerns. A total of 78 PWUD participated in the study, with 50 participants being fully vaccinated and 28 participants partially or unvaccinated. Using thematic analysis, interviews were coded based on the capability, opportunity, and motivation-behavior (COM-B) framework. RESULTS: Many partially or unvaccinated participants reported lacking knowledge about the COVID-19 vaccine, particularly in terms of its usefulness and benefits. Some participants reported lacking knowledge around potential long-term side effects of the vaccine, and the differences of the various vaccine brands. Distrust toward government and healthcare agencies, the unprecedented rapidity of vaccine development and skepticism of vaccine effectiveness were also noted as barriers. Facilitators for vaccination included a desire to protect oneself or others and compliance with government mandates which required individuals to get vaccinated in order to access services, attend work or travel. To improve vaccination uptake, the most trusted and appropriate avenues for vaccination information sharing were identified by participants to be people with lived and living experience with drug use (PWLLE), harm reduction workers, or healthcare providers working within settings commonly visited by PWUD. CONCLUSION: PWLLE should be supported to design tailored information to reduce barriers and address mistrust. Resources addressing knowledge gaps should be disseminated in areas and through organizations where PWUD frequently access, such as harm reduction services and social media platforms.

All Hands on Deck: We Need Multiple Approaches To Uncover the Neuroscience behind the Opioid Overdose Crisis.

Opioid use disorder (OUD) affects millions of people throughout the United States, yet there are only three Food and Drug Administration-approved pharmacological treatments. Though these treatments have been shown to be effective, the number of overdose deaths continues to rise. The increase of fentanyl, fentanyl analogs, and adulterants in the illicit drug supply has further complicated treatment strategies. Preclinical researchers strive to model OUD to better understand this complicated disorder, and this research is a critical enabler for the development of novel treatments. As a result, there are many different preclinical models of OUD. Often, researchers form strong opinions on what they believe to be the "best" model to mimic the human condition. Here, we argue that researchers should be supportive of multiple models to promote new perspectives and discoveries and always consider the trends in human opioid use when designing preclinical studies. We describe the benefits of contingent and noncontingent models as well as models of opioid withdrawal and how each of these can help illuminate different components of OUD.

Intended and unintended consequences: Changes in opioid prescribing practices for postsurgical, acute, and chronic pain indications following two policies in North Carolina, 2012-2018 - Controlled and single-series interrupted time series analyses.

BACKGROUND: The potential misapplication of current opioid prescribing policies remains understudied and may have substantial adverse implications for patient safety. METHODS: We used autoregressive integrated moving average models to assess level and trend changes in monthly 1) prescribing rates, 2) days' supply, and 3) daily morphine milligram equivalents (MME) of incident opioid prescriptions relative to 1) a state medical board initiative to reduce high-dose and -volume opioid prescribing and 2) legislation to limit initial opioid prescriptions for acute and postsurgical pain. We examined outcomes by pain indication overall and by cancer history, using prescribing patterns for benzodiazepines to control for temporal trends. We used large private health insurance claims data to include North Carolina residents, aged 18-64, insured at any point between January 2012 and August 2018. RESULTS: After the medical board initiative, prescribing patterns for chronic pain patients did not change; conversely, acute and postsurgical pain patients experienced immediate declines in daily MME. Post-legislation prescription rates did not decline for those with acute, postsurgical, and non-cancer pain, but instead declined among cancer patients with chronic pain. Chronic pain patients experienced the largest days' supply declines post-legislation, instead of acute and postsurgical pain patients. CONCLUSIONS: We found mixed evidence on the potential impact of two opioid prescribing policies, with some observed declines in a group not intended to be impacted by the policy. This study provides evidence of the need for clearer opioid prescribing policies to ensure impacts on intended populations and avoid unintended consequences.