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Background: Despite significant geographical heterogeneity of sociodemographic and clinical characteristics, little is known about potential differences in cannabis use behaviors in U.S. geographic areas. In this study, we examined cannabis use behaviors in large metropolitan, small metropolitan, and nonmetropolitan areas. We focused on interactions between geographic areas and health insurance status and medical cannabis laws (MCL)., Methods: Data came from the 2015-2018 National Survey on Drug Use and Health (NSDUH; N = 171,766 adults; N = 36,175 cannabis users). Weighted chi-squares tests of independence and multivariable Poisson regression models were used to examine study questions., Results: Past-year use was highest in large metropolitan areas (16.08 %). Frequent use was highest among nonmetropolitan area users (48.67 %). Uninsured adults had a higher likelihood of past-year use (RRR = 1.21, 95 % CI = 1.14, 1.29) and frequent use (RRR = 1.27, 95 % CI = 1.14, 1.41), but a lower likelihood of cannabis use disorder (RRR = 0.77, 95 % CI = 0.66, 0.89). Uninsured adults in nonmetropolitan areas had a higher likelihood (RRR = 1.62, 95 % CI = 1.39, 1.88) of past-year use than insured nonmetropolitan area adults. MCL state residency was associated with a higher likelihood of frequent use among nonmetropolitan (RRR = 1.39, 95 % CI = 1.11, 1.74) and small metropolitan users (RRR = 1.30, 95 % CI = 1.15, 1.47). Cannabis use disorder likelihood did not vary by geographic area., Conclusions: Lack of health insurance and MCL state residency are significant variables affecting cannabis use behaviors in small metropolitan and/or nonmetropolitan areas., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: With the recent legalization of recreational cannabis in Canada, cannabis-impaired driving is an important public safety concern. Our aim was to examine the association between recreational cannabis legalization and fatal motor vehicle collisions using data from the United States, which present a timely natural experiment of cannabis legalization., Methods: We conducted an ecologic study using the number of fatal motor vehicle collisions and the associated number of deaths for US jurisdictions with legalized recreational cannabis (2007-2018) retrieved from the US Fatality Analysis Reporting System. We examined jurisdiction-specific rates of fatal motor vehicle collisions and associated deaths before and after recreational cannabis legalization using Poisson regression and meta-analyzed estimates across jurisdictions using DerSimonian and Laird random-effects models., Results: After adjustment for calendar year, legalization was associated with increases in rates of fatal motor vehicle collisions (incidence rate ratio [IRR] 1.15, 95% confidence interval [CI] 1.06-1.26) and associated deaths (IRR 1.16, 95% CI 1.06-1.27). Differences between the first 12 months after legalization relative to subsequent months were inconclusive for rates of fatal motor vehicle collisions (IRR 0.92, 95% CI 0.84-1.02) and associated deaths (IRR 0.92, 95% CI 0.84-1.01)., Interpretation: Recreational cannabis legalization in the US was associated with a relative increased risk of fatal motor vehicle collisions of 15% and a relative increase in associated deaths of 16%, with no conclusive difference between the first and subsequent years after legalization. These findings raise concern that there could be a similar increase in fatal motor vehicle collisions and associated deaths in Canada following recreational cannabis legalization., Competing Interests: Competing interests: None declared., (© 2021 Joule Inc. or its licensors.)

Importance: The majority of US states have passed mandates requiring the use of electronic prescribing of controlled substances (EPCS) as a tool to reduce rates of opioid prescribing. It is not known whether increasing use of EPCS will have the intended effect., Objective: To assess the association between use of EPCS and trends in opioid prescribing., Design, Setting, and Participants: In this retrospective, longitudinal cohort study of all patients and prescribers in the 50 US states and the District of Columbia from 2010 to 2018, changes in state-level use of EPCS and concurrent changes in opioid prescribing in each state are described. Then the association between changes in the use of EPCS and opioid prescribing are estimated using state and year fixed-effects models that include covariates for policy change and state demographic change. Data Analysis was performed on May 5, 2020., Main Outcomes and Measures: The proportion of controlled substances in each state prescribed using EPCS based on opioid prescriptions per 100 persons and morphine milligram equivalents (MME) of opioids., Results: In 2018, the population-weighted percent of opioids prescribed using EPCS was 27%, up from 0% as of 2013. National rates of opioid prescriptions decreased from 78 prescriptions per 100 persons in 2013 to 53 in 2018. Over the same period, there was a decrease from 64 071 MME per 100 persons in 2013 to 40 906 MME per 100 persons in 2018, representing 36% of the 2013 level. By 2018, EPCS increased to 69.4% in states with mandates for its use and 23.6% in states without mandates. In multivariable models, a 10 percentage-point increase in the use of EPCS was associated with an additional 2 prescriptions per 100 persons (95% CI, 1.3-2.8) and a 0.8% (95% CI, 0.06%-1.5%) increase in MME per 100 persons., Conclusions and Relevance: These data suggest that an increased use of EPCS was not associated with decreased opioid prescribing or a decrease in the amount prescribed and may have been associated with a small increase in opioid prescribing. Opioid prescribing is associated with a variety of social and public health factors, and thus, despite the appeal, EPCS adoption alone may be insufficient to reduce opioid prescribing. Policy makers should consider levers to ensure that EPCS is integrated with outside data and that information is actively used to inform prescribing decisions.

Background: Research demonstrates an association between state-level medical marijuana laws (MMLs) and increased marijuana use (MU) and MU disorder (MUD) among adults, but has yet to explore this association among lesbian, gay and bisexual (LGB) individuals, including gender differences., Methods: We pooled the 2015-2017 National Survey on Drug Use and Health data for adults (n = 126,463) and used gender-stratified adjusted multivariable logistic regression to model the odds of past-year MU, past-year medical MU, daily/near-daily MU, and MUD; we also tested the interaction between MML state residence and sexual identity., Results: Bisexual women had higher past-year MU (40% versus 10.3%; aOR = 2.9[2.4-3.4]), daily/near-daily MU (9.8% versus 1.5%; aOR = 4.6[3.3-6.2]), and medical MU ((5.5% versus 1.2%) aOR = 5.5[3.8-8.1]) than heterosexual women. Gay/lesbian women also had higher past-year MU (26.1% versus 10.3%; aOR = 2.8[2.2-3.7]), daily/near-daily MU (5.6% versus 1.5%; aOR = 2.9[1.8-4.6]), and medical MU (4.7% versus 1.2%; aOR = 3.0(1.4-6.6]) than heterosexual women. Bisexual women in MML states had higher past-year MU ((44.4% vs. 34.1%); aOR = 1.8[1.5-2.1]) and medical use (7.1% vs. 3.3% (aOR = 2.5[1.5-3.9]) than bisexual women in non-MML states. The odds of any past-year medical MU for bisexual versus heterosexual women was different in MML versus non-MML states (Exponentiated β = 0.53, p = 0.01). Gay men in MML states had higher past year MU (31.2% versus 25.7%; aOR = 1.6[1.1-2.5] and medical MU (6.4% vs 1.7%; aOR = 5.0[4.2-6.1]) than gay men in non-MML states., Conclusions: Results suggest that MMLs may differentially impact MU for sexual minority individuals-particularly bisexual women. Findings demonstrate the need for states enacting MMLs to consider potential differential impacts on LGB populations., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: In January 2012, the Drug Enforcement Agency (DEA) classified carisoprodol as a Schedule IV controlled substance at the US federal level. We aimed to examine the effect of this policy on the use of carisoprodol in a commercially-insured population., Methods: This interrupted time series study included individuals with musculoskeletal disorders in the IBM MarketScan Commercial Database between December 2009 and February 2014. We used comparative segmented linear regression to assess changes in the proportions of patients who filled/newly filled carisoprodol each month., Results: A total of 13.3 million patients were included. 29 states with no scheduling prior to the DEA classification had lower baseline prevalence of carisoprodol use compared to 17 states that had scheduled carisoprodol individually before 2010 (11.0 vs. 21.1 patients with fills per 1000 patients). The federal scheduling was associated with an immediate decline (-1.12 per 1000 patients, p < 0.01) and decreasing trend in prevalence (-0.07 per 1000 patients per month, p = 0.02). This effect was not modified by existing state-level scheduling status. During the first, second, third, and fourth 6-month periods after federal scheduling, the relative difference between observed and predicted prevalence was 7.8%, 10.5%, 13.4%, and 19.8%. Similar patterns were observed for carisoprodol initiation. Overall, declining use was more pronounced among younger age groups and patients with injury., Conclusions: Schedule IV controlled substance classification at the federal level was associated with a moderate reduction in the dispensing of carisoprodol regardless of whether scheduling was already present at the state level., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: "Lock-in" programs (LIPs) are used by health insurers to address potential substance (eg, opioid) misuse among beneficiaries. We sought to (1) examine heterogeneity in trajectories of dispensed opioids (in average daily morphine milligram equivalents (MMEs)) over time: prior to, during, and following release from a LIP, and (2) assess associations between trajectory patterns and beneficiary characteristics., Methods: Medicaid claims were linked to Prescription Drug Monitoring Program records for a cohort of beneficiaries enrolled in the North Carolina Medicaid LIP (n = 2701). Using latent class growth analyses, we estimated trajectories of average daily MMEs of opioids dispensed to beneficiaries across specific time periods of interest., Results: Five trajectory patterns appeared to sufficiently describe underlying heterogeneity. Starting values and slopes varied across the 5 trajectory groups, which followed these overall patterns: (1) start at a high level of MMEs, end at a high level of MMEs (13.1% of cohort); (2) start medium, end medium (13.2%); (3) start medium, end low (21.5%); (4) start low, end medium (22.6%); and (5) start low, end low (29.6%). We observed strong associations between patterns and beneficiaries' demographics, substance use-related characteristics, comorbid conditions, and healthcare utilization., Conclusions: In its current form, the Medicaid LIP appeared to have limited impact on beneficiaries' opioid trajectories. However, strong associations between trajectory patterns and beneficiary characteristics provide insight into potential LIP design modifications that might improve program impact (eg, LIP integration of substance use disorder assessment and referral to treatment, assessment and support for alternate pain therapies)., (© 2018 John Wiley & Sons, Ltd.)

Background: This study assessed whether the Nationwide Emergency Department Sample (NEDS) could reliably fill the national drug surveillance gap caused by the discontinuation of the Drug Abuse Warning Network (DAWN)., Methods: Estimates of the drug-related emergency department (ED) visits derived from DAWN (2004-2011) and NEDS (2006-2013). Estimates of the underlying reason for the drug-related ED visit, patient characteristics, and the specific drugs involved were compared for 2011, the most recent overlapping data year in DAWN and NEDS. Trends in ED visits for major drugs of abuse were then compared over the period 2004-2013., Results: In 2011, DAWN and NEDS produced statistically similar estimates of the overall number of drug-related ED visits (5.1 vs. 4.9 million) and those involving drug misuse or abuse (2.65 vs. 2.77 million). Among the latter, estimates by gender, age group, and patient disposition were generally consistent across data systems, suggesting that NEDS and DAWN samples draw from a similar population. Main analyses reveal statistically similar estimates across data systems in both levels and trends for cocaine, amphetamines, and narcotic pain relievers. In contrast, the number of ED visits for sedatives and heroin was significantly undercounted in NEDS, whereas marijuana-related ED visits were undercounted in DAWN., Conclusions: This study demonstrates the utility of NEDS for conducting post-DAWN drug surveillance. Because NEDS cannot provide targeted surveillance of certain established (e.g., heroin) and emerging (e.g., fentanyl) drugs, however, it is critical that a data system that employs medical record-based reviews be implemented to augment the known weaknesses of NEDS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: In the United States, per-capita opioid dispensing has increased concurrently with analgesic-related mortality and morbidity since the 1990s. To deter diversion and abuse of controlled substances, most states have implemented electronic prescription drug monitoring programs (PDMPs). We evaluated the impact of state PDMPs on opioid dispensing., Methods: We acquired data on opioids dispensed in a given quarter of the year for each state and the District of Columbia from 1999 to 2008 from the Automation of Reports and Consolidated Orders System and converted them to morphine milligram equivalents (MMEs). We used multivariable linear regression modeling with generalized estimating equations to assess the effect of state PDMPs on per-capita dispensing of MMEs., Results: The annual MMEs dispensed per capita increased progressively until 2007 before stabilizing. Adjusting for temporal trends and demographic characteristics, implementation of state PDMPs was associated with a 3% decrease in MMEs dispensed per capita (p=0.68). The impact of PDMPs on MMEs dispensed per capita varied markedly by state, from a 66% decrease in Colorado to a 61% increase in Connecticut., Conclusions: Implementation of state PDMPs up to 2008 did not show a significant impact on per-capita opioids dispensed. To control the diversion and abuse of prescription drugs, state PDMPs may need to improve their usability, implement requirements for committee oversight of the PDMP, and increase data sharing with neighboring states.

Background: In August 2010, a tamper-resistant formulation of controlled-release oxycodone (OxyContin-OP) was introduced in the United States but not in Canada. Our objective was to determine whether introduction of OxyContin-OP in the United States influenced prescription volumes for the original controlled-release oxycodone formulation (OxyContin) at Canadian pharmacies near the international border., Methods: We conducted a population-based, serial, cross-sectional study of prescriptions dispensed from pharmacies in the 3 cities with the highest volume of US-Canada border crossings in Ontario: Niagara Falls, Windsor and Sarnia. We analyzed data on all outpatient prescriptions for OxyContin dispensed by Canadian pharmacies near each border crossing between 2010 Apr. 1 and 2012 Feb. 29. We calculated and compared monthly prescription rates, adjusted per 1000 population and stratified by tablet strength., Results: The number of tablets dispensed near 4 border crossings in the 3 Canadian cities remained stable over the study period. However, the rate of dispensing at pharmacies near the Detroit-Windsor Tunnel increased roughly 4-fold between August 2010 and February 2011, from 505 to 1969 tablets per 1000 population. By April 2011, following warnings to prescribers and pharmacies regarding drug-seeking behaviour, the dispensing rate declined to 1683 tablets per 1000 population in this area. By November 2011, the rate had returned to levels observed in early 2010. Our analyses suggest that 242 075 excess OxyContin tablets were dispensed near the Detroit-Windsor Tunnel between August 2010 and October 2011., Conclusions: Prescribing of the original formulation of controlled-release oxycodone rose substantially near a major international border crossing following the introduction of a tamper-resistant formulation in the United States. It is possible that the restriction of this finding to the area surrounding the Detroit-Windsor Tunnel reflects specific characteristics of this border crossing, including its high traffic volume, direct access to the downtown core and drug-trafficking patterns in the Detroit area. Our findings highlight the potential impact of cross-border differences in medication availability on drug-seeking behaviour.

Objective: This article examines the relationship between drug price and drug quality and how it varies across two of the most common regulatory regimes in the pharmaceutical market: minimum efficacy standards (MES) and a mix of MES and price control mechanisms (MES + PC)., Data Sources: Our primary data source is the Tufts-New England Medical Center-Cost Effectiveness Analysis Registry which have been merged with price data taken from MEPS (for the United States) and AIFA (for Italy)., Study Design: Through a simple model of adverse selection we model the interaction between firms, heterogeneous buyers, and the regulator., Principal Findings: The theoretical analysis provides two results. First, an MES regime provides greater incentives to produce high-quality drugs. Second, an MES + PC mix reduces the difference in price between the highest and lowest quality drugs on the market., Conclusion: The empirical analysis based on United States and Italian data corroborates these results., (© Health Research and Educational Trust.)

The European Federation of Statisticians in the Pharmaceutical Industry (EFSPI) engages more than 2000 statisticians through its ten national organizations. Amongst other things, EFSPI is involved in reviewing regulatory guidelines under development, including the draft FDA guideline on non-inferiority clinical trials. This review resulted in several critical comments relating to as follows: (i) the lack of one single standard for proving efficacy of new drugs implied by the guideline; (ii) the problems with the suggested 'fraction of effect to be preserved'; (iii) the formulation of the primary hypothesis in a non-inferiority trial aiming at indirectly demonstrating a new drug is superior to placebo; and (iv) the preference in the guideline for the fixed-margin method over the synthesis method in the analysis. The presumed implications of this guideline, if implemented as is, are (i) increased confusion of how efficacy could be demonstrated when placebo control is not available, (ii) more complicated communication between pharmaceutical industry and FDA because of the apparent disagreements on fundamental statistical matters, and (iii) illogical consequences in the approval process because of which order drugs are approved rather than how they fulfill the regulatory requirements. We believe that the area is not yet ready for such a prescriptive regulatory guidance and that further research and experience are required until the methodology can be finally agreed. A strategy needs to be developed by regulatory agencies together with drug industry and academia for a long term solution for this topic., (Copyright © 2011 John Wiley & Sons, Ltd.)

Adjusting for covariates makes efficient use of data and can improve the precision of study results or even reduce sample sizes. There is no easy way to adjust for covariates in a non-inferiority study for which the margin is defined as a risk difference. Adjustment is straightforward on the logit scale, but reviews of clinical studies suggest that the analysis is more often conducted on the more interpretable risk-difference scale. We examined four methods that allow for adjustment on the risk-difference scale: stratified analysis with Cochran-Mantel-Haenszel (CMH) weights, binomial regression with an identity link, the use of a Taylor approximation to convert results from the logit to the risk-difference scale and converting the risk-difference margin to the odds-ratio scale. These methods were compared using simulated data based on trials in HIV. We found that the CMH had the best trade-off between increased efficiency in the presence of predictive covariates and problems in analysis at extreme response rates. These results were shared with regulatory agencies in Europe and the USA, and the advice received is described., (Copyright © 2011 John Wiley & Sons, Ltd.)

Background: There has been tremendous progress over the last decade in the development of health products--drugs, vaccines, and diagnostics--for neglected diseases. There are now dozens of candidate products in the pipeline., Purpose: Our purpose is to assess challenges that will arise in later-stage clinical development of these candidate health products and propose a strategy that would help bring the costs, risks, and finances for their clinical trials into a better, more sustainable balance., Methods: We conducted a literature review of clinical trial-related publications, interviewed individuals sponsoring and conducting interventional clinical trials for neglected diseases, and analyzed data from Clinicaltrials.gov, a clinical trials registry, on neglected disease clinical trials initiating subject recruitment between January 1, 2003 and December 31, 2009. We quantified Clinicaltrials.gov data into country-specific participation in clinical trials and aggregated them into geographic regions. We employed bioinformatics and keyword methods to classify trials by type of intervention, sponsor, study phase, and therapeutic area., Results: Two substantial bottlenecks threaten our capacity to bring these candidate neglected disease therapies to those in need. First, the research and regulatory capacity in many neglected disease-endemic settings is not adequate to support the clinical trials that need to occur there in order to complete the development of these products. Second, even with expected attrition in the pipeline, current levels of financing are insufficient to support the clinical development of these products under current cost assumptions., Limitations: The proportion of trials of relevant studies not registered on Clinicaltrials.gov is not known, but is thought to be smaller post-2005, after the International Committee of Medical Journal Editors initiated a policy requiring investigators to deposit information about trial design into an accepted clinical trials registry before beginning patient enrollment., Conclusions: Realizing the promise of the neglected disease product pipeline will require not only increased funding for large-scale clinical trials and capacity building, but also greater attention to how these trials and their regulatory pathways can be improved to reduce unnecessary costs, delays, and risks to trial subjects. We propose a two-prong strategy: (1) adaptation and adoption of emerging research on 'sensible guidelines' for reducing large-scale, randomized clinical trial costs to the demands of the neglected disease product pipeline and (2) regional approaches to regulation and ethical review of clinical trials for health products for neglected diseases.

Aims: Although illicit drug purity is a widely discussed health risk, research explaining its geographic variation within a country is rare. This study examines whether proximity to the US-Mexico border, the United States' primary drug import portal, is associated with geographic variation in US methamphetamine, heroin and cocaine purity., Design: Distances (proximity) between the US-Mexico border and locations of methamphetamine, cocaine and heroin seizures/acquisitions (n = 239,070) recorded in STRIDE (System to Retrieve Information from Drug Evidence) were calculated for the period of 1990-2004. The association of drug purity with these distances and other variables, including time and seizure/acquisition size, was examined using hierarchical multivariate linear modeling (HMLM)., Setting: Coterminous United States., Findings: Methamphetamine, cocaine and heroin purity generally decreased with distance from the US-Mexico border. Heroin purity, however, after initially declining with distance, turned upwards-a U-shaped association. During 2000-04, methamphetamine purity also had a U-shaped association with distance. For each of the three drugs, temporal changes in the purity of small acquisitions (<10 g) were typically more dynamic in areas closer to the US-Mexico border., Conclusions: Geographic variance in methamphetamine, cocaine and heroin purity throughout the coterminous United States was associated with US-Mexico border proximity. The U-shaped associations between border-distance and purity for heroin and methamphetamine may be due to imports of those drugs via the eastern United States and southeast Canada, respectively. That said, areas closer to the US-Mexico border generally had relatively high illicit drug purity, as well as more dynamic change in the purity of small ('retail level') drug amounts., (© 2010 The Authors, Addiction © 2010 Society for the Study of Addiction.)

Background: Heroin coming into the United States historically comes from three widely dispersed geographical regions: Southwest Asia, Southeast Asia and Mexico. A fourth source of US-bound heroin, from Colombia, originated in the early 1990s. The fact that the four heroin sources produce differing morphologies and qualities of heroin has not been critically examined. In addition, it is not well established how the contemporary competing dynamics of interdiction, or restriction of heroin flows across international boundaries, and neoliberal, e.g., global expansion of free trade, policies are affecting heroin markets. This paper will highlight changes in the US heroin market, including source trends, the political economy of the now dominant source and the resultant effects on the heroin risk environment by US region., Methods: Using a structural and historical framework this paper examines two decades of secondary data sources, including government and drug control agency documents, on heroin flows together with published work on the political and economic dynamics in Latin America., Results: Co-occurring neoliberal economic reforms may have contributed to paradoxical effects of US/Colombian interdiction efforts. Since entering the US market, heroin from Colombia has been distributed at a much higher quality and lower retail price. An increasingly exclusive market has developed with Mexican and Colombian heroin gaining market share and displacing Asian heroin. These trends have had dramatic effects on the risk environment for heroin consumers. An intriguing factor is that different global sources of heroin produce substantially different products. Plausible associations exist between heroin source/form and drug use behaviours and harms. For example, cold water-soluble powdered heroin (sources: Asia, Colombia) may be associated with higher HIV prevalence in the US, while low-solubility "black tar" heroin (BTH; source: Mexico) is historically used in areas with reduced HIV prevalence. BTH is associated with soft tissue infections caused by Clostridium bacteria., Conclusion: Source and type of heroin are structural factors in the risk environment of heroin users: source dictates distribution and type predicts practice. How specific types of heroin are used and with what risk is therefore distributed geographically. Continued flux in the heroin market and its effects on the risk environment for drug users deserves further attention.

In mid-1995, a government effort to reduce the supply of methamphetamine precursors successfully disrupted the methamphetamine market and interrupted a trajectory of increasing usage. The price of methamphetamine tripled and purity declined from 90 percent to 20 percent. Simultaneously, amphetaminerelated hospital and treatment admissions dropped 50 percent and 35 percent, respectively. Methamphetamine use among arrestees declined 55 percent. Although felony methamphetamine arrests fell 50 percent, there is no evidence of substantial reductions in property or violent crime. The impact was largely temporary. The price returned to its original level within four months; purity, hospital admissions, treatment admissions, and arrests approached preintervention levels within eighteen months. (JEL I12, K42).

Background: The Prescription Drug User Fee Act (PDUFA) imposes deadlines for the completion of drug reviews by the Food and Drug Administration (FDA). Critics have suggested that these deadlines may result in rushed approvals and the emergence of unanticipated safety problems once a product is in clinical use., Methods: We assessed the association between the PDUFA deadlines and the timing of FDA drug approval by constructing dynamic Cox proportional-hazards models of review times for all new molecular entities approved between 1950 and 2005. To determine whether the deadlines were associated with postmarketing safety problems, we focused on drugs submitted since January 1993, when the deadlines were first imposed. We used exact logistic regression to determine whether drugs approved immediately before the deadlines were associated with a higher rate of postmarketing safety problems (e.g., withdrawals and black-box warnings) than drugs approved at other times., Results: Initiation of the PDUFA requirements concentrated the number of approval decisions made in the weeks immediately preceding the deadlines. As compared with drugs approved at other times, drugs approved in the 2 months before their PDUFA deadlines were more likely to be withdrawn for safety reasons (odds ratio, 5.5; 95% confidence interval [CI], 1.3 to 27.8), more likely to carry a subsequent black-box warning (odds ratio, 4.4; 95% CI, 1.2 to 20.5), and more likely to have one or more dosage forms voluntarily discontinued by the manufacturer (odds ratio, 3.3; 95% CI, 1.5 to 7.5)., Conclusions: PDUFA deadlines have appreciably changed the approval decisions of the FDA. Once medications are in clinical use, the discovery of safety problems is more likely for drugs approved immediately before a deadline than for those approved at other times., (Copyright 2008 Massachusetts Medical Society.)

Buprenorphine was approved in late 2004 for the treatment of opioid abuse and dependence in specially trained and certified physicians' offices. At the time of the approval, there was a regulatory concern that given the anticipated wide exposure there would be unexpectedly high levels of abuse in the high-risk population for which it was intended. To assess its abuse potential, the authors recruited more than 1000 individuals seeking treatment for prescription opioid abuse from 100 stand-alone (i.e., self-pay or insurance) drug abuse treatment programs around the country to determine whether they misused buprenorphine in the past 30 days to get high. The results indicate that there was a time-related increase in the number of subjects who used buprenorphine to get high, reaching 30-35 percent of individuals completing a questionnaire in the second quarter of 2006. At this time, it was equivalent to the misuse of methadone, both of which, however, were considerably lower than hydrocodone and oxycodone. Thereafter, the number of individuals using buprenorphine to get high dropped in a near linear fashion to less than 20 percent of those completing a questionnaire in the second quarter of 2007, significantly lower than that for methadone, oxycodone, and hydrocodone. The most likely interpretation of these data is that the poly-substance-abusing population, for whom buprenorphine is intended, experimented with this medication for its mood-altering effects for a period of time, but presumably because of its lack of euphorogenic properties, its use has now dissipated. Additionally, support for this conclusion is the very rare endorsement of buprenorphine as a primary drug (<3 percent of the total sample). Thus, the results indicate that it is unlikely that buprenorphine abuse will ever reach the epidemic that was feared by some regulatory groups and that its use in opioid detoxification and maintenance should continue.

Two studies have shown that in the 1990s the number of market withdrawals due to adverse effects increased while the time regulatory agencies have taken to approve new drugs decreased. More recent examples confirm that hasty approvals place patients at an increased risk of serious adverse effects.

Substantial resources have been spent to improve pain control for dying patients, and increased opioid administration has been presumed. Oregon has been a consistent leading state in per capita use for morphine for the past 10 years, as recorded by the Automation of Reports and Consolidated Orders System (ARCOS). Health policy experts, extrapolating from World Health Organization methods, have suggested these data are indicative of the quality of end-of-life care in Oregon. To determine whether trends in opioid prescription at the state and national levels reflect increased opioid use for inpatients during the final week of life, chart reviews were conducted to record all opioid medications administered in the last week of life to 877 adult inpatients who died from natural causes between January 1, 1997 and December 31, 1999. Inpatient morphine use did not increase significantly for dying patients from 1997 to 1999. However, overall morphine use for both Oregon and the United States as measured by ARCOS data increased significantly. Comparisons revealed no significant difference between linear trends for Oregon and U.S. morphine use, but both were significantly greater than the dying inpatients. This pattern was also found for all other opioids. These findings suggest that ARCOS data do not necessarily provide information about opioid use for specific subpopulations of patients and raise questions about the meaning of observed increases in ARCOS data.

Objectives: To examine trends in the licit consumption of the psychostimulants dexamphetamine and methylphenidate in Australia and nine other countries from 1994 to 2000 and in each State and Territory of Australia from 1984 to 2000., Design: Annual rates of consumption of psychostimulants were compared using Poisson regression models. All drug consumption was standardised to defined daily doses per 1000 population per day., Main Outcome Measures: Rates of consumption of each psychostimulant in each country and in each Australian State and Territory., Results: For the 10 countries from 1994 to 2000, total psychostimulant consumption increased by an average 12% per year, with the highest increase from 1998 to 2000. Australia and New Zealand ranked third in total psychostimulant use after the United States and Canada. Australia consumed significantly more than the United Kingdom, Sweden, Spain, the Netherlands, France or Denmark. In Australia, from 1984 to 2000, the rate of consumption of licit psychostimulants increased by 26% per year, with an 8.46-fold increase from 1994 to 2000. Western Australia ranked first, with nearly twice the consumption rate of total psychostimulants as New South Wales, which ranked second. Methylphenidate is the main psychostimulant consumed in the US and Canada, and dexamphetamine in Australia., Conclusions: The consumption of psychostimulants in Australia is high internationally and varies significantly between States and Territories. The results imply varied jurisdictional prescribing determinants and supply processes throughout Australia, which may require new national prescribing standards and access to online patient data for prescribers and dispensers.

Objectives: This study assessed the impact of national policy shifts on state policies and practices regarding substance-using mothers., Methods: A 1995 telephone survey of substance abuse and child protective services directors in all 50 states and the District of Columbia was compared with a similar 1992 survey., Results: There have been significant increases in state interventions for drug-using pregnant women (e.g., criminal prosecution, toxicology testing of women and neonates). Federal resources for treatment and oversight are being replaced by state control of reduced funds for treatment., Conclusions: The earlier policy of expanding treatment for addicted women is being replaced by reduction of services and increased state intervention.

The overall objective of this research project was to measure the types and amounts of Mexican drug products being purchased and declared to US Customs by US residents crossing the border in Laredo, Texas. Data for this study were obtained from the US Customs Declaration Form, which each person completes as he or she reenters the United States. Data included demographic information as well as the types and quantities of medications purchased. Data were collected from a randomly selected sample of 84 days between July 1994 and June 1995. A total of 5624 declaration forms were analyzed. The average age of people who declared medications was 34.5 years. Only 9.3% of the people were 50 years of age or older. Fourteen of the top 15 drug products declared are classified in the United States as "controlled" substances. In examining the quantities of medications being declared, on average 11,057 diazepam tablets were declared each day, which is equivalent to 4,035,842 diazepam tablets per year. On average 4033 tablets of flunitrazepam were declared each day, which is equivalent to 1,472,045 tablets a year declared at one US port of entry. On average, there were 2.48 drug products listed on each declaration form. The majority of the drug products were controlled substances and, based on the types and quantities of products being declared, many questions can be raised with regard to US policies on the control and safety of Mexican drugs coming into the United States.

The established international and national drug control systems have been successful in preventing diversion from legitimate producers of opioids to illicit channels. This has contributed to a reduction of opioid abuse and related illegal activities. However, the systems have fostered concepts and attitudes that have limited access to opioid drugs, which the international treaties recognize are indispensable for the reduction of pain and the treatment of other conditions. Patients who have a legitimate need for the relief that these drugs can provide have become the unintended victims of the drug control systems.