br Introduction Fatal drug overdoses have reached

Introduction Fatal drug overdoses have reached epidemic levels in the United States, increasing 137% from 2000–2014 (Rudd, Aleshire, Zibbell, & Gladden, 2016). Growth in poisoning deaths, around 90% of which are now caused by drugs (Warner, Chen, Makuc, Anderson, & Miniño, 2011), were the most important source of the rise in the all-cause mortality rates of 45–54-year-old non-Hispanic whites occurring between 1999 and 2013 (Case & Deaton, 2015). The involvement of opioid analgesics (hereafter referred to as “opioids”) and, more recently, heroin have received particular attention (Centers for Disease Control and Prevention, 2011, 2012; Jones, Logan, Gladden, & Bohm, 2015; Rudd et al., 2016; Volkow, Frieden, Hyde, & Cha, 2014), including a White House Summit in August 2014 (Hardesty, 2014). Concerted efforts to lessen the severity of the opioid epidemic include establishing prescription drug monitoring programs, restricting the ability of pain clinics and online pharmacies to dispense oxycodone and other controlled substances, and developing abuse-deterrent formulations of some prescription drugs (Centers for Disease Control and Prevention, 2013; Finklea, Bagalman, & Sacco, 2013; Rannazzisi, 2013; Kirschner, Ginsburg, & Sulmasy, 2014). The federal Comprehensive Addiction and Recovery Act of 2016 (S. 524) supports expansions of drug diversion programs (reducing the criminality of low-level drug violations), medication assisted treatments, and the availability of naloxone administration for opioid overdoses. However, there remain significant barriers to formulating effective policies to reverse or slow the rise in drug fatalities. One is that purchase Erlotinib deadly overdoses frequently involve combinations of drugs in ways that are not fully understood (Jones, Mack, & Paulozzi, 2013; Paulozzi, Mack, & Hockenberry, 2014). Second, we lack reliable knowledge of the specific drugs involved in poisoning fatalities because the drugs responsible are frequently left unspecified on death certificates. As a result, the contributions of specific drug categories or of drug combinations are understated. Misunderstanding about these issues results in frequent erroneous statements being made about the nature of drug poisoning fatalities. In a typical example, Olsen (2016) states: “In 2014, nearly 20,000 deaths due to overdose of prescription opioids occurred in the United States”. This is incorrect. An accurate characterization is that a prescription opioid was mentioned on the death certificates of around 20,000 fatalities classified as drug poisonings in that year. However, the actual number of cases involving opioids was certainly larger than this, because the drugs involved in these deaths were frequently not recorded. Conversely, prescription opioids may have caused either more or fewer fatalities because other drugs (particularly sedatives and psychotropic medications) were also implicated in many of these deaths. These issues become even more problematic when considering trends in fatal drug overdoses, since patterns of drug reporting and combination use have changed over time. This analysis provides a first step in addressing several of these shortcomings and is innovative in three ways. First, statistical adjustment procedures recently developed by Ruhm (2016a) are extended and applied here to provide more accurate information on the drugs and drug combinations involved in fatal overdoses. These methods raise estimates of the involvement of specific drugs by 30% to >50% and emphasize the importance of drug “cocktails”. Second, the adjusted estimates are used to examine which drug categories are responsible for the rapid rise in fatal overdoses. The frequency of multiple drug-taking introduces uncertainty, so a distinction is made between any versus exclusive drug involvement. Third, the investigation highlights the sensitivity of the findings to the choice of starting and ending years, revealing a key role of prescription opioids early in the data period but with other drugs, particularly heroin, and drug combinations being more important later.