Initiation Patterns and Transitions Among Adults Using Stimulant Drugs: Latent Transition Analysis.

BACKGROUND: The fourth wave of the drug overdose epidemic in the United States includes increasing rates of stimulant-involved overdose. Recent studies of transitions leading to stimulant misuse have shown complex patterns that are not universally applicable because they have isolated individual populations or individual behaviors. A comprehensive analysis of transitions between behaviors and the associations with present-day problematic drug use has not been conducted. OBJECTIVE: This study aims to determine whether adults from the general population who use stimulants initiate use through a heterogeneous combination of behaviors and quantify the association between these typologies with present-day problematic drug use. METHODS: Individuals who have reported use of any stimulant in their lifetime were recruited from the 2021 Survey of Nonmedical Use of Prescription Drugs Program, a nationally representative web-based survey on drug use, to participate in a rapid follow-up survey about their past stimulant use. Individuals were asked which stimulants they used, the reasons for use, the routes of administration, and the sources of the stimulant. For each stimulant-related behavior, they were asked at what age, between 6 and 30 years, they initiated each behavior in a 6-year time window. A latent transition analysis was used to characterize heterogeneity in initiation typologies. Mutually exclusive pathways of initiation were identified manually by the researchers. The association of these pathways with present-day problematic drug use was calculated using logistic regression adjusted by the current age of the respondent. RESULTS: From a total of 1329 participants, 740 (55.7%) reported lifetime prescription stimulant use and 1077 (81%) reported lifetime illicit stimulant use. Three typologies were identified. The first typology was characterized by illicit stimulant initiation to get high, usually via oral or snorting routes and acquisition from friends or family or a dealer (illicit experimentation). The second typology was characterized by low, but approximately equal probabilities of initiating 1-2 new behaviors in a time window, but no singular set of behaviors characterized the typology (conservative initiation). The third was characterized by a high probability of initiating many diverse combinations of behaviors (nondiscriminatory experimentation). The choice of drug initiated was not a strong differentiator. Categorization of pathways showed those who were only in an illicit experimentation status (reference) had the lowest odds of having severe present-day problematic drug use. Odds were higher for a conservative initiation-only status (odds ratio [OR] 1.84, 95% CI 1.14-2.94), which is higher still for those moving from illicit experimentation to conservative initiation (OR 3.50, 95% CI 2.13-5.74), and highest for a nondiscriminatory experimentation status (OR 5.45, 95% CI 3.39-8.77). CONCLUSIONS: Initiation of stimulant-related use behaviors occurred across many time windows, indicating that multiple intervention opportunities are presented. Screening should be continued throughout adulthood to address unhealthy drug use before developing into full substance use disorders.

Differing Behaviors Around Adult Nonmedical Use of Prescription Stimulants and Opioids: Latent Class Analysis.

BACKGROUND: The availability of central nervous system stimulants has risen in recent years, along with increased dispensing of stimulants for treatment of, for example, parent-reported attention-deficit/hyperactivity disorder in children and new diagnoses during adulthood. Typologies of drug use, as has been done with opioids, fail to include a sufficient range of behavioral factors to contextualize person-centric circumstances surrounding drug use. Understanding these patterns across drug classes would bring public health and regulatory practices toward precision public health. OBJECTIVE: The objective of this study was to quantitatively delineate the unique behavioral profiles of adults who currently nonmedically use stimulants and opioids using a latent class analysis and to contrast the differences in findings by class. We further evaluated whether the subgroups identified were associated with an increased Drug Abuse Screening Test-10 (DAST-10) score, which is an indicator of average problematic drug use. METHODS: This study used a national cross-sectional web-based survey, using 3 survey launches from 2019 to 2020 (before the COVID-19 pandemic). Data from adults who reported nonmedical use of prescription stimulants (n=2083) or prescription opioids (n=6127) in the last 12 months were analyzed. A weighted latent class analysis was used to identify the patterns of use. Drug types, motivations, and behaviors were factors in the model, which characterized unique classes of behavior. RESULTS: Five stimulant nonmedical use classes were identified: amphetamine self-medication, network-sourced stimulant for alertness, nonamphetamine performance use, recreational use, and nondiscriminatory behaviors. The drug used nonmedically, acquisition through a friend or family member, and use to get high were strong differentiators among the stimulant classes. The latter 4 classes had significantly higher DAST-10 scores than amphetamine self-medication (P<.001). In addition, 4 opioid nonmedical use classes were identified: moderate pain with low mental health burden, high pain with higher mental health burden, risky behaviors with diverse motivations, and nondiscriminatory behaviors. There was a progressive and significant increase in DAST-10 scores across classes (P<.001). The potency of the opioid, pain history, the routes of administration, and psychoactive effect behaviors were strong differentiators among the opioid classes. CONCLUSIONS: A more precise understanding of how behaviors tend to co-occur would improve efficacy and efficiency in developing interventions and supporting the overall health of those who use drugs, and it would improve communication with, and connection to, those at risk for severe drug outcomes.

The association between the availability of over the counter codeine and the prevalence of non-medical use.

PURPOSE: To investigate the prevalence of non-medical use (NMU) of codeine in Germany, Italy, Spain and the UK and whether availability of OTC codeine has any association with NMU of the drug. METHODS: Data collected in the online Survey of Non-Medical Use of Prescription Drugs, in surveys launched in the second half of 2018 from (Germany (n = 14,969), Italy, (n = 9974), Spain (n = 9912) and the UK (n = 9819) were analysed. For each survey, the estimated prevalence and 95% confidence interval (CI) of respondents reporting NMU of prescription and/or OTC codeine within the last 12 months were calculated and compared. RESULTS: The prevalence of last 12-month NMU in Spain was 12.6% (95% CI 11.7-13.6) for prescription codeine, 6.3% (5.6-7.0) for OTC codeine and 16.1% (15.1-17.3) for any codeine (prescription and/or OTC). The prevalence of last 12-month NMU in the UK was 5.4% (4.9-5.8) for prescription codeine, 4.5% (4.1-5.0) for OTC codeine and 8.3% (7.8-8.9) for any codeine (prescription and/or OTC). The prevalence of last 12-month NMU for prescription codeine was 2.1% (1.9-2.4) in Germany and 1.9% (1.7-2.2) in Italy. CONCLUSION: The prevalence of last 12-month NMU of any codeine product is approximately eight times greater in Spain and four times greater in the UK compared to Germany and Italy where the drug is only available by prescription. While other factors may contribute, these findings suggest that availability of codeine OTC is associated with greater NMU.

Comparison of hospital claims and poison center data to evaluate health impact of opioids, cannabis and synthetic cannabinoids.

INTRODUCTION: Over the past 10 years, opioids and cannabis have garnered significant attention due to misuse and legalization trends. Different datasets and surveillance mechanisms can lead to different conclusions the due to a variety of factors. The primary objective of this study was to compare and describe trends of opioid, cannabis, and synthetic cannabinoid-related healthcare encounters and poison center (PC) cases in Colorado, a state that has legalized cannabis. METHODS: This was a retrospective study comparing hospital claims data (Colorado Hospital Association (CHA)) and poison center cases to describe opioid, cannabis and synthetic cannabinoid-related healthcare encounters and exposures in Colorado from 2013 to 2017 using related genetic codes and International Statistical Classification of Disease codes. RESULTS: Both datasets observed increases in cannabis related encounters and exposures after recreational cannabis legalization in 2014. CHA reported an increase for cannabis-related ER visits from 14,109 in 2013 to 18,118 in 2017 while PC noted a 74.4% increase in cannabis-related cases (125 to 218). CHA inpatient visits associated with cannabis also increased (8311 in 2013 to 14,659 in 2017). On the other hand, Opioid-related exposures to the PC fell (1092 in 2013 to 971 in 2017) while both Opioid-related ER visits (8580 in 2013 to 12,928 in 2017) and inpatient visits in CHA increased (9084 in 2013 to 13,205). CONCLUSIONS: This study demonstrates the differences in surveillance methodology for concurrent drug abuse epidemics using hospital claims and PC data. Both systems provide incomplete reports, but in combination can provide a more complete picture.

Changes in Hydrocodone Misuse Exposures Reported to U.S. Poison Centers Following Rescheduling in 2014.

BACKGROUND: In 2014, the Drug Enforcement Administration rescheduled hydrocodone combination products to Schedule II to reduce nonmedical use and diversion. METHODS: The impact of rescheduling was assessed using quarterly data from 2011 through 2019 from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System Poison Center Program and IQVIATM Longitudinal Prescription Data. Trends and immediate changes in prescriptions dispensed and misuse exposures before and after rescheduling involving hydrocodone, oxycodone, and other Schedule II opioid analgesics were calculated using segmented regression. RESULTS: Hydrocodone prescriptions were stable pre-rescheduling, decreased by 2.7% (95% CI: -3.6%, -1.8%, p < 0.0001) per quarter post-rescheduling. Misuse exposures involving hydrocodone were decreasing by 3.2% (95% CI: -3.9%, -2.4%, p < 0.0001) per quarter pre-rescheduling and decreased by 4.9% (95% CI: -5.5%, -4.2%, p < 0.0001) post-rescheduling. Immediate decreases in hydrocodone prescriptions and misuse exposure rates in 2014Q4 compared to 2014Q3 were significant and different from oxycodone or other Schedule II opioids. Schedule II opioid analgesics prescriptions in aggregate were stable prior to rescheduling, decreased by 10.8% (95%CI: -14.0%, -7.6%, p < 0.0001) immediately after the rescheduling, and decreased by 2.3% per quarter (95% CI: -3.1%, -1.5%, p < 0.0001) subsequently. Misuse exposures involving these opioids were decreasing by 3.3% (95% CI: -4.1%, -2.5%, p < 0.0001) prior to rescheduling then by 2.8%, (95% CI: -3.4%, -2.2%, p < 0.0001) after rescheduling. The immediate change in misuse was not significant. CONCLUSIONS: Rescheduling corresponded with changes in hydrocodone prescribing and misuse not offset by increases in other Schedule II opioid analgesics. Misuse exposures for hydrocodone and comparators were decreasing prior to rescheduling with little change post-intervention.

Adverse Events Related to Accidental Unintentional Ingestions From Cough and Cold Medications in Children.

OBJECTIVES: Previous research has demonstrated that accidental unsupervised ingestions (AUIs) were responsible for the majority of cough and cold medication (CCM) ingestions leading to significant adverse events (AEs) in children. The objective of this analysis was to characterize the role of AUIs in the morbidity associated with CCM exposure in children. METHODS: This surveillance study collected data from 5 United States data sources from 2009 to 2016, in children younger than 6 years with an AE from an AUI involving at least 1 CCM over-the-counter pharmaceutical ingredient. An expert panel reviewed each case to determine causality. RESULTS: From 4756 total cases reviewed, 3134 (65.9%) had an AE from an AUI determined to be at least potentially related to a CCM ingredient. The majority (61.3%) of cases occurred in children aged 2 to younger than 4 years. Most exposures occurred in the child's own residence (94.9%), and 43.8% were admitted to a health care facility (22.0% to a critical care unit). Dextromethorphan and diphenhydramine, when packaged alone or in combination products, contributed to 96.0% of AUIs. The most common specific products involved were single-ingredient pediatric liquid diphenhydramine (30.1%) and single-ingredient pediatric liquid dextromethorphan (21.4%). There were 3 deaths from solid diphenhydramine formulations. CONCLUSIONS: There continues to be opportunities for the implementation of interventions to prevent AUIs of CCM in children. Additional emphasis on engineering controls, such as flow restrictors for liquid formulations targeting diphenhydramine and dextromethorphan products, represent additional opportunities to further reduce AEs from AUIs of CCM.

Measuring prescription opioid misuse and its consequences.

AIMS: Prescription drug misuse in the USA increased during the 1990s to 2010. The epidemic stimulated the need new analytical strategies and techniques to understand the medications involved, user characteristics and other factors needed to address the epidemic. METHODS: A strategy of mosaic surveillance has evolved. Using real world evidence, the goal is to paint a more complete profile of a drug's real world misuse using triangulation-integrating results from multiple sources, where each approach has unrelated sources of bias. RESULTS: Research findings have been remarkably consistent across multiple data sources. The most commonly misused opioid medications: hydrocodone = oxycodone > methadone = buprenorphine = tramadol = fentanyl (prescription form) > morphine > hydromorphone = oxymorphone > tapentadol. This rank order is similar to the number of prescriptions dispensed for each product in the USA. In the USA, prescription opioid misuse started to decrease about 2011. Typically, multiple drugs are misused together, particularly in lethal cases. Immediate release formulations are more commonly misused than extended release formulations. The introduction of tamper resistant formulations to resist crushing were followed by a decrease in misuse of those products. CONCLUSIONS: The rapid expansion of opioid prescribing was accompanied by increasing misuse and mortality. Interventions such as prescription drug monitoring programmes, increased law enforcement and abuse deterrent formulations have been followed by decreases in misuse of most opioid analgesics.

An evaluation of online discussion relating to nonmedical use of prescription opioids within the UK.

AIM: To identify and describe the nature of online discussion relating to prescription opioids within the UK. METHODS: We performed analysis of posts originating in the UK related to buprenorphine, hydrocodone, oxycodone and tramadol using Social Studio, a web-monitoring platform. The study included posts published between January 2014 and December 2016. The data were cleaned to produce a final dataset consisting only of substantive mentions, which were then categorised by defined themes. RESULTS: The final dataset included a total of 17 361 substantive mentions (2936 buprenorphine, 2894 hydrocodone, 3826 oxycodone and 7705 tramadol). The most common theme for all 4 drugs was sharing experience or opinion comprising over 90% of mentions for each drug, while discussion related to polysubstance use was present in >1/4 of mentions across drug substances. Mentions related to diversion were more common for hydrocodone and oxycodone (8.1% [6.3-10.1 95% confidence interval] and 7.8% [6.5-9.2], respectively) than buprenorphine or tramadol (4.1 and 3.9% [3.5-4.3], respectively). CONCLUSION: This investigation shows that there is substantial online discussion relating to a variety of nonmedical use (NMU) behaviours of prescription opioids within the UK, including for hydrocodone, which is not medically available. Web monitoring provides useful data and merits future investigation; this could include expansion to other categories of drugs and a more in-depth analysis of motivations behind NMU, both of which could add timely evidence regarding the current situation in the UK and help inform public health interventions for NMU of prescription drugs.

Nonmedical use of benzodiazepines and Z-drugs in the UK.

AIMS: To estimate prevalence of last 12-month nonmedical use (NMU) of benzodiazepines and Z-drugs (the nonbenzodiazepine hypnotics zaleplon, zolpidem and zopiclone) in the UK. METHODS: Data were collected using the Non-Medical Use of Prescription Drugs survey with poststratification weighting applied to be representative of the UK population (≥16 years). Participants were questioned about whether they had nonmedically used benzodiazepines and/or Z-drugs in the last 12-months and from where they had obtained the drug (including via a prescription, or illicitly from a friend/family member, a dealer or via the internet). Additional questions were asked about last 12-month use of illicit drugs (cannabis, cocaine, 3,4-methylenedioxymethylamphetamine [MDMA], non-pharmaceutical amphetamine, crack cocaine and/or heroin). RESULTS: The study included 10 006 eligible participants representing approximately 52 927 000 UK adults. The estimated prevalence of past 12-month NMU of any benzodiazepine and/or Z-drug was 1.2% (95% confidence interval: 1.0-1.5) corresponding to approximately 635 000 adults; amongst this group only an estimated 4.6% (1.2-8.0) had NMU of both a benzodiazepine and a Z-drug. The highest prevalence of NMU for only Z-drugs was among those who had used heroin in the last 12-months (5.4%, 2.7-10.5), whilst the highest prevalence of NMU for only benzodiazepines was among those who had used illicit stimulants in the last 12-months: cocaine (5.9%, 3.8-8.9), amphetamine (5.6%, 3.1-10.0) and MDMA (5.2%, 3.1-8.8). The drug non-medically used was more commonly acquired without than with a prescription for both only benzodiazepines (70.2%, 59.4-81.1 compared to 51.3%, 41.5-64.6) and only Z-drugs (75.6%, 61.6-89.7 compared to 33.9%, 16.9-51.0). CONCLUSION: There is little overlap between benzodiazepine and Z-drug NMU suggesting distinct nonmedical use of the drugs; future studies need to explore whether this relates to personal preference, drug availability or other factors. A significant proportion are acquiring these drugs for NMU without a prescription, so without guidance and monitoring from a medical practitioner. While the dangers of mixing benzodiazepines and heroin/other opioids are well documented, there is a paucity of data regarding concomitant NMU of benzodiazepines and stimulant drugs, or NMU of Z-drugs and opioids, and, given the prevalence of these combinations, this requires further investigation.

Non-medical use of benzodiazepines and GABA analogues in Europe.

AIMS: We investigated the prevalence of non-medical use (NMU) of benzodiazepines and GABA analogues in Europe. METHODS: Data were collected using the online Non-Medical Use of Prescription Drugs (NMURx) survey from France, Germany, Italy, Spain and the UK. RESULTS: The study included 55 223 eligible surveys which, after post-stratification weights were applied, represented approximately 260 million European adults. Lifetime NMU of benzodiazepines was highest in Spain (6.5%, 95% CI: 6.0-7.0) and lowest in Germany (1.7%, 1.5-2.0). Lifetime NMU of GABA analogues was highest in Germany (5.4%, 5.0-5.7) and lowest in France (2.2%, 1.9-2.5) and the UK (2.2%, 1.9-2.6) While no notable difference was observed for France or the UK, there was a higher prevalence of last 12-month NMU of benzodiazepines compared to GABA analogues in Italy (2.4 times higher) and Spain (3.0 times higher) and a higher prevalence of NMU of GABA analogues compared to benzodiazepines in Germany (2.6 times higher). CONCLUSION: This study shows that there is variation in NMU of benzodiazepines and GABA analogues among countries. Of particular interest is the high incidence of GABA analogue NMU in Germany and benzodiazepine NMU in Spain. Further research to identify factors and motivations responsible for the higher prevalence observed are essential to inform public health policies in those countries.

Drug product dispensing and estimates of use in a general population survey as a signal detection problem.

PURPOSE: Understanding potential bias due to rarity of the outcome is important when monitoring newly approved drugs and drugs with low availability to the general public. Although there is an increasing use of online surveys to investigate health outcomes, the limits of inference due to drug availability have not been studied. The goal of this study was to quantify the relationship between dispensing of prescription drugs and estimates of use in an online general population survey. METHODS: An online repeated, cross-sectional survey from 2018 to 2020 was used to estimate the number of adults in the United States who used prescription drugs in the general population and compared to estimated number of prescriptions dispensed over an equivalent time period. Joinpoint regression was used to quantify thresholds. A sample of respondents was retested to estimate reliability statistics. RESULTS: A model with a single threshold was the best fit, with the estimated threshold of 565 000 (95% CI: 9500-11 600 000) prescriptions dispensed per year. Above the threshold, there was a significant association between dispensing and estimates (p < 0.001); below the threshold, the relationship was not significant (p = 0.912). Above the threshold, responses were more reliable than random chance, and reliability steadily increased with increased dispensing. CONCLUSIONS: These results suggest the threshold demarcates two distinct pharmacoepidemiological paradigms when investigating drug use in general population surveys. Dispensing can be used as a guide to determine the epidemiological paradigm that is best suited.

Postmarketing Analysis of Misuse, Abuse, and Diversion of Xtampza ER.

OBJECTIVE: To evaluate abuse, misuse, and diversion of Xtampza ER, an extended-release (ER) abuse-deterrent formulation (ADF) of oxycodone. METHODS: Abuse, misuse, and diversion of Xtampza ER were assessed using Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System data sources. Xtampza ER was compared with immediate-release (IR) oxycodone, other ADF ER products combined, and non-ADF ER products combined. RESULTS: Xtampza ER prescriptions increased 50-fold during the study period. In contrast, cases from poison centers, substance abuse treatment centers, and diversion were infrequent and did not increase. Adjusted for prescriptions dispensed, poison center exposures were greater for IR oxycodone (rate ratio [RR] = 2.3, P = 0.008), other ADF ER opioids (RR = 5.2, P < 0.001), and non-ADF ER opioids (RR = 2.5, P = 0.004) than for Xtampza ER. In Treatment Center Programs Combined, past-month abuse prevalence for other ADF ER opioids (odds ratio [OR] = 7.4, P < 0.001) and non-ADF ER opioids (OR = 2.0, P = 0.002) was greater than Xtampza ER; IR oxycodone was not significantly different (OR = 1.2, P = 0.349). In the Drug Diversion Program, rates for IR oxycodone (RR = 3.7, P = 0.003), other ADF ER opioids (RR = 4.2, P = 0.002), and non-ADF ER opioids (RR = 3.4, P = 0.007) were greater than Xtampza ER. Adjustment using morphine equivalents provided similar results, except that IR oxycodone in Treatment Center Programs Combined became higher than Xtampza ER. Nonoral abuse cases involving Xtampza ER were infrequent; Web monitoring data support findings that Xtampza ER is difficult to abuse nonorally. CONCLUSION: Xtampza ER abuse, misuse, and diversion and tampering are low relative to other prescription opioid analgesics. Abuse and diversion did not increase over the study period.

Changes in Mortality Involving Extended-Release and Long-Acting Opioids After Implementation of a Risk Evaluation and Mitigation Strategy.

OBJECTIVE: To assess changes in mortality rates in extended-release and long-acting (ER/LA) opioid analgesics after the implementation of the Risk Evaluation and Mitigation Strategy (REMS). SETTING: All drug poisoning deaths in three states: Florida, Oregon, and Washington. Data were obtained through state vital records offices and the Researched Abuse, Diversion and Addiction-Related Surveillance System Medical Examiner Program. METHODS: Using cause-of-death literal text from death certificates, individual opioid active pharmaceutical ingredients (APIs) involved in each death were identified using rules-based natural language processing. Population-adjusted and prescriptions dispensed-adjusted mortality rates were calculated for all ER/LA opioid analgesic and individual opioid APIs. Rates before and after implementation of the REMS were compared. Rate changes were compared with rates from two APIs with little or no inclusion in the REMS: benzodiazepines and hydrocodone. RESULTS: The mean ER/LA opioid analgesic population-adjusted mortality rate significantly decreased in all three states (FL: P = 0.003; OR: P = 0.003; WA: P < 0.001). Mortality rates for benzodiazepines and hydrocodone also decreased and were not statistically different. Significant heterogeneity in mortality rates of individual opioids was observed between the three states. When adjusted for prescription volume, the ER/LA opioid analgesic mortality rate decreased in all three states, but was significant only for Washington (P < 0.001). CONCLUSIONS: The population-adjusted mortality rate of ER/LA opioid analgesics has decreased in three states. Notably, the contributions to mortality rates by individual opioid analgesics were not uniform across the three states in this study. However, these changes were not generally distinct from changes in mortality rates where comparator substances were involved.

Nonmedical use of alprazolam in the UK: Results from a nationally representative survey.

There is concern in the UK about nonmedical use (NMU) of alprazolam (Xanax). We investigated the epidemiology of alprazolam NMU compared with diazepam using data from the Survey of Non-Medical Use of Prescription Drugs (NMURx) programme (collected 28 September-1 December 2017). The survey included 10 019 respondents and was weighted by age, sex and region to represent 52 927 659 UK adults. The estimated national prevalence of lifetime NMU of alprazolam was 0.32% (95% confidence interval: 0.19-0.46), and 1.30% (1.06-1.54) for diazepam. The prevalence of NMU in the last 90 days was significantly different when split by age category for alprazolam (P < .001), but not for diazepam (P = .262) with alprazolam NMU being more common among younger adults (age 16-24 years: 0.37%; age 25-34 years: 0.14%; 35 years or older: 0.01%). Further research is needed to fully understand the motivations of alprazolam NMU and to monitor whether the popularity of alprazolam will rise.

The Efficacy of Antivenin Latrodectus (Black Widow) Equine Immune F(ab')2 Versus Placebo in the Treatment of Latrodectism: A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial.

STUDY OBJECTIVE: The antivenom currently available for treatment of systemic black widow envenomation (latrodectism) is composed of equine whole immunoglobin. Although considered effective, it has been associated with anaphylaxis and 2 reported fatalities. We test the efficacy and safety of new equine antivenom composed of purified F(ab')2 antibody fragments. METHODS: A randomized, double-blind, placebo-controlled trial was conducted at 16 sites across the United States. Subjects aged 10 years or older with moderate to severe pain because of black widow spider envenomation received F(ab')2 antivenom or placebo. The primary outcome measure was treatment failure, which was defined as failure to achieve and maintain clinically significant reduction in pain for 48 hours posttreatment. Secondary measures of pain intensity differences and summed pain intensity difference were computed. Adverse events were recorded. RESULTS: Sixty patients were treated (29 antivenom and 31 placebo). The mean age was 39 years and 68% were male. There were 15 treatment failures in the antivenom group and 24 in the placebo group (P=.019). Differences in pain intensity difference between groups were lower at each postbaseline point, and the mean summed pain intensity difference was greater for the antivenom group (difference 2,133; 95% confidence interval 177 to 4,090). No deaths or serious drug-related adverse events were detected. CONCLUSION: The F(ab')2 antivenom met the predefined primary outcome of reduced treatment failures. Secondary outcomes of pain intensity difference and summed pain intensity difference also supported efficacy. The rate of symptom improvement in the placebo group was higher than expected, which may be related to enrollment criteria or placebo effect.

Causal inference for evaluating prescription opioid abuse using trend-in-trend design.

PURPOSE: One response to the opioid crisis in the United States has been the development of opioid analgesics with properties intended to reduce non-oral use. Previous evaluations of abuse in the community have relied on population averaged interrupted time series Poisson models with utilization offsets. However, competing interventions and secular trends complicate interpretation of time-series analyses. An alternative research design, trend-in-trend, accounts for heterogeneity in per capita opioid dispensing and unmeasured time-varying confounding, which provides a causal evaluation, provided that underlying assumptions are met. METHODS: Trend-in-trend can be modeled using a logistic regression framework. In logistic regression, exposure was any product-specific outpatient dispensing by three-digit ZIP code and calendar quarter, for 22 opioids. The outcome was any product-specific abuse case ascertained from poison centers and drug treatment programs, covering 94% of the US population, between July 2009 and December 2016. Product-specific odds ratios compared places without dispensing with places with any dispensing; the causal contrast represents the odds of product-specific abuse in the community given exposure. RESULTS: Dispensing of new and low-volume opioids varied considerably across the country, with no region showing high of all products. Of 22 opioids analyzed, the three with approved labeling as intended to deter abuse ranked near the lowest in both absolute (population-adjusted rates: 1.7, 0.9, and 8.2 per million people per quarter, respectively) and relative measures (trend-in-trend ORs: 1.96, 1.79, 1.69, respectively). CONCLUSIONS: Postmarketing studies of prescription opioid abuse may benefit by evolving from unadjusted surveillance rates to a causal inference approach.

Understanding multi-pill ingestion of prescription opioids: Prevalence, characteristics, and motivation.

PURPOSE: Oral use is the primary route of administration among non-medical prescription opioid users. While progression to non-oral routes and shifts to stronger opioids have been previously studied as ways to cope with tolerance, the prevalence and patterns of those who cope by increasing the number of pills/tablets ingested at one time (ie, multi-pill use) has not been assessed. METHODS: A subset (N = 231) of treatment-seeking opioid users from a national opioid surveillance system, participating in the Researchers and Participants Interacting Directly (RAPID) Program, completed an online survey centered on multi-pill use. RESULTS: Over two-thirds of non-medical prescription opioid users had a history of multi-pill use (67.7%), defined as ingesting four or more of the same pill, intact and at the same time. Among these (n = 154), the median maximum number of pills taken at one time was eight, with over 20% ingesting 11 or more pills in a single instance. Nearly half engaged in multi-pill ingestion more than once a day in the past month (43.8%), with accessibility to lower dose pills being the primary motivator (85.4%). Hydrocodone immediate-release (IR) compounds were by far the most frequently endorsed (90.3%), followed by oxycodone IR tablets with acetaminophen (76.0%) and oxycodone IR tablets containing no acetaminophen/ibuprofen (56.5%). CONCLUSIONS: These results indicate that the ingestion of multiple opioid pills/tablets is extremely common among treatment-seeking opioid users. This, and other forms of non-medical oral use of prescription opioids, should be taken under consideration when developing prevention and intervention efforts targeting the opioid epidemic.

Scoring the best deal: Quantity discounts and street price variation of diverted oxycodone and oxymorphone.

PURPOSE: Diverted prescription opioids are significant contributors to drug overdose mortality. Street price has been suggested as an economic metric of the diverted prescription opioid black market. This study examined variables that may influence the street price of diverted oxycodone and oxymorphone. METHODS: A cross-sectional study was conducted utilizing data from the previously validated, crowdsourcing website StreetRx. Street price reports of selected oxycodone and oxymorphone products, between August 22, 2014 and June 30, 2016, were considered for analysis. Geometric means and 95% confidence intervals were calculated comparing prices per milligram of drug in US dollars. Univariate and multivariable regressions were used to examine the influence of dosage strength, drug formulation, and bulk purchasing on street price. RESULTS: A total of 5611 oxycodone and 1420 oxymorphone reports were analyzed. Across various dosages and formulations, geometric mean prices per milligram ranged between $0.12 and $1.07 for oxycodone and $0.73 and $2.90 for oxymorphone. For a 2-fold increase in dosage strength, there is a 24.0% (95% CI: -28.1%, -19.6%, P < 0.001) and a 22.5% (95% CI: -24.2%, -20.8%, P < 0.001) decrease on average in price per milligram for oxycodone and oxymorphone, respectively. Lower potency, high dosage strength, crush-resistant opioids, and those purchased in bulk were significantly cheaper. CONCLUSION: Street prices for diverted oxycodone and oxymorphone are influenced by multiple factors including potency, dosage, formulation, and bulk purchasing. Buyers who purchase large quantities of low potency, large dosage, crush-resistant formulation prescription opioids can expect to achieve the lowest price.

Brief report: Characterization of marijuana use in us college students by state marijuana legalization status as reported to an online survey.

BACKGROUND AND OBJECTIVE: US college student marijuana use is the highest since 1980. The objective was to investigate use characteristics among college students. METHODS: The RADARS® System College Survey Program surveyed individuals in a university, technical or online school. This was a secondary analysis of existing data. RESULTS: Seven thousand one hundred five students were enrolled, <30% of students' perceived marijuana use a health risk. Students in medical states were more likely to use marijuana compared to non-legal states. (p < .001) Smoking and edibles were common methods of use. CONCLUSIONS: Higher reports of college student use were observed in medical states without differences in risk perception. SCIENTIFIC SIGNIFICANCE: This study further demonstrates the public health impact of marijuana legalization by comparing college study use of marijuana by state legalization status, and demonstrating high rates of use of concentrated products. These findings should be factored when determining regulations and preventative measures when legalizing marijuana. (Am J Addict 2019;28:266-269).