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A variety of surveys and studies are examined in an effort to better understand the scope of prescription drug diversion and to determine whether there are consistent patterns of diversion among various populations of prescription drug abusers. Data are drawn from the RADARS System, the National Survey of Drug Use and Health, the Delaware School Survey, and a series of quantitative and qualitative studies conducted in Miami, Florida. The data suggest that the major sources of diversion include drug dealers, friends and relatives, smugglers, pain patients, and the elderly, but these vary by the population being targeted. In all of the studies examined, the use of the Internet as a source for prescription drugs is insignificant. Little is known about where drug dealers are obtaining their supplies, and as such, prescription drug diversion is a 'black box' requiring concentrated, systematic study. [ABSTRACT FROM AUTHOR]

Ultram (tramadol HCL) was approved by the Food and Drug Administration in 1994 as a non-scheduled drug under the Controlled Substance Act. The non-scheduled status was contingent on the development and implementation of a comprehensive post-marketing surveillance program by an Independent Steering Committee external to Ortho-McNeil Pharmaceutical charged with monitoring abuse and recommending scheduling if unexpectedly high abuse occurred. The program developed by this committee was composed of a variety of studies, and the results of the first three years of the surveillance efforts revealed that the rate of Ultram abuse was low. At a meeting of the FDA in 1998 to reexamine the scheduling status of Ultram, it was recommended that the scope of the postmarketing surveillance program be broadened to include data on diversion. After a 1-year pilot study, by January 2002, a nationwide diversion survey was fully operational. This brief communication describes the experiences of this diversion study, and compares the findings on the diversion of Ultram and other tramadol HCL products with that of more widely abused drugs. Survey data suggest that the diversion of Ultram and other tramadol products is low, and overall, diversion investigators did not consider tramadol to be a problem in their respective jurisdictions. [ABSTRACT FROM AUTHOR]

OxyContin (Purdue Pharma L.P., Stamford, Conn) was approved by the Food and Drug Administration (FDA) in 1995 as a sustained-release preparation of oxycodone hydrochloride and was thought to have much lower abuse potential than immediate-release oxycodone because of its slow-release properties. However, beginning in 2000, widespread reports of OxyContin abuse surfaced. In response, Purdue Pharma L.P. sponsored the development of a proactive abuse surveillance program, named the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) system. In this paper, we describe results obtained from one aspect of RADARS--the use of drug abuse experts (ie, key informants)--as a source of data on the prevalence and magnitude of abuse of prescription drugs. The results indicate that prescription drug abuse has become prevalent, with cases reported in 60% of the zip codes surveyed. The prevalence of abuse was rank ordered as follows: OxyContin >or= hydrocodone > other oxycodone > methadone > morphine > hydromorphone > fentanyl > buprenorphine. In terms of the magnitude of abuse (>or=5 cases/100,000 persons in a 3-digit zip code), modest growth was seen with all analgesics over the 10 calendar quarters we monitored, but was most pronounced with OxyContin and hydrocodone. These results indicate that OxyContin abuse is a pervasive problem in this country, but that it needs to be considered in the context of a general pattern of increasing prescription drug abuse. PERSPECTIVE: Over the past 5 years, there have been reports, frequently anecdotal, that opioid analgesic abuse has evolved into a national epidemic. In this study, we report systematic data to indicate that opioid analgesic abuse has in fact increased among street and recreational drug users, with OxyContin and hydrocodone products the most frequently abused. Steps need to be taken to reduce prescription drug abuse, but very great care needs to be exercised in the nature of these actions so the legitimate and appropriate use of these drugs in the treatment of pain is not compromised as a result. [ABSTRACT FROM AUTHOR]

Assessing actual abuse of prescribed medications requires postmarketing surveillance. In this article we discuss general systems of postmarketing surveillance that exist as of the end of 2002 in the United States and two medication-specific surveillance systems that were devised and tested. The two specific surveillance systems are compared with limitations highlighted. Postmarketing surveillance is in its infancy and requires more research on ways to improve its validity without inducing illicit experimentation. Information on comparator medications is highly recommended both to validate the system and to place the results in context. [ABSTRACT FROM AUTHOR]

Objective: Assess the validity of medical products reporting program (MEDWatch) reports of abuse/dependence and withdrawal associated with Ultram (tramadol).Methods: Reports of possible abuse/dependence or withdrawal associated with Ultram during 13 quarters following launch were spontaneously reported to the manufacturer Ortho-McNeil Pharmaceutical (OMP) and also solicited from 255 NIDA grantees and addiction treatment professionals by an Independent Steering Committee (ISC). Reports were classified by the ISC using DSM-IV criteria, by the Drug Safety and Surveillance (DSS) units of Robert Wood Johnson Pharmaceutical Research Institute (PRI) using World Health Organization Adverse Reaction Terms (WHOART) terms, and reported to the food and drug administration (FDA) via MEDWatch. Rates of abuse/dependence and withdrawal per 100000 persons exposed were calculated separately for classifications made by the PRI and the ISC, and confidence intervals calculated to determine the degree to which they agreed.Results: For 681 reports submitted to PRI, confidence intervals of ISC ratings contained PRI ratings 12 of 13 times for abuse/dependence, and 12 of 13 times for withdrawal. For 242 reports submitted to the ISC, confidence intervals of ISC ratings contained PRI ratings 10 of 13 times for abuse/dependence, and 12 of 13 times for withdrawal. Proactive surveillance increased the total number of cases of abuse/dependence but not withdrawal. Many cases of withdrawal without signs or symptoms of abuse/dependence were identified.Conclusions: There was good/excellent concordance between MEDWatch and ISC classifications. Proactive surveillance increased cases of abuse/dependence but not withdrawal. Withdrawal with no signs or symptoms of dependence was common. More use of proactive surveillance is likely to improve assessments of public health risks associated with adverse events. [ABSTRACT FROM AUTHOR]

In 1994, the Drug Abuse Advisory Committee (DAAC) of the Food and Drug Administration (FDA) concluded that Ultram (tramadol hydrochloride) could be marketed as an analgesic drug without scheduling under the Controlled Substances Act based upon extensive pre-clinical, clinical and European epidemiological data. However, to guard against unexpectedly high levels of abuse in the United States, the DAAC recommended that an independent steering committee (ISC) be appointed to proactively monitor abuse/dependence. In the event that high rates of abuse were found, this ISC was given the authority to immediately recommend to the FDA that Ultram be scheduled. In the course of the surveillance project, the ISC received reports of withdrawal following abrupt discontinuation of Ultram and in some instances, following dose reductions. In most cases, the withdrawal symptoms consisted of classical opioid withdrawal, but in some cases were accompanied by withdrawal symptoms not normally observed in opiate withdrawal, such as hallucinations, paranoia, extreme anxiety, panic attacks, confusion and unusual sensory experiences such as numbness and tingling in one or more extremities. Withdrawal symptoms of either type were one of the more prevalent adverse events associated with chronic Ultram use, comprising nearly 40% of all adverse events reported with Ultram. Most of these consisted of typical opiate withdrawal symptoms, but 1 in 8 cases presented as atypical. These results indicate that physicians and other healthcare professionals need to be aware of the potential of Ultram to induce withdrawal of the classical opioid type, and that atypical withdrawal may also occur. [ABSTRACT FROM AUTHOR]

Objective: Tapentadol is an atypical opioid analgesic thought to have dual mechanisms of action: µ-receptor agonism and inhibition of norepinephrine reuptake. Unlike other atypical opioids, tapentadol is a schedule II-controlled substance. We compared the prevalence of abuse (use to get high) of tapentadol to other atypical opioids used to treat pain (buprenor-phine and tramadol)., Design: An observational, serial cross-sectional study., Setting: Individuals enrolling in treatment programs for opioid use disorder in 2019. Each completed a self-administered, paper questionnaire assessing prescription drug abuse and illegal drug use within 1 week of enrollment., Main Outcome Measures: Indication of past month abuse of tapentadol or comparator drugs on a self-administered ques-tionnaire., Results: There were 6,987 respondents. Unadjusted and utilization-adjusted logistic regression models were used to compare odds of endorsement of tapentadol to tramadol and buprenorphine products indicated for the management of pain. Unadjusted abuse prevalence was 0.20 percent for total tapentadol (0.03 percent for NUCYNTA® and 0.06 percent for NUCYNTA ER). Relative to total tapentadol, the odds of abuse of buprenorphine for pain was 2.9 times greater (95 percent CI: 1.6 to 5.3, p < 0.001), and for tramadol, 43.1 times greater (95 percent CI: 25.3 to 73.3, p < 0.001). Adjusting for prescriptions dispensed, differences in odds of abuse were not statistically significant (odds ratio (OR) = 1.6, 95 per-cent CI: 0.9 to 3.0, p = 0.108 for buprenorphine for pain and OR = 0.7, 95 percent CI: 0.4 to 1.2, p = 0.209 for tramadol)., Conclusions: Tapentadol use to get high is less frequent than other atypical opioids. Findings suggest tapentadol is rarely the primary drug abused by an individual.

Objectives: Efforts to improve low naloxone uptake to mitigate the current opioid crisis have included coprescribing naloxone with opioid medications and, more recently, expansion through over-the-counter availability, the latter of which necessitates self-identification of overdose risk by consumers. This study sought to understand perceptions of opioid overdose risk and naloxone among distinct opioid populations at elevated risk for overdose., Methods: A cross-sectional, online survey was provided to 2 opioid populations in June 2020. First, chronic pain opioid managed (CPOM; n = 190) individuals currently treated with an opioid prescription (either >50 daily morphine milligram equivalents [73.2%] or benzodiazepine co-use [52.6%]), restricted by confounders. Second, individuals with a history of opioid use disorder (OUD; n = 152) previously participating in a national opioid surveillance study of new entrants to substance use treatment centers., Results: Risk perceptions significantly differed, with 60.0% (CPOM) versus 28.9% (OUD) reporting that they were "not at all concerned about overdosing," and 62.1% (CPOM) versus 19.1% (OUD) perceiving themselves as having "no risk" of overdose. Perceived need for naloxone was lower among CPOM versus OUD patients (48.3% and 71.8%, respectively), whereas 22.6% and 35.0%, respectively, indicated any likelihood of obtaining naloxone in the future., Conclusions: Results suggest that a significant proportion of both samples lacked the ability to self-identify their risk of overdose and self-select themselves as needing naloxone, with gaps being more prominent in the CPOM sample. A multi-intervention framework that addresses distinct pathways of behavioral change between unique opioid populations should be considered in conversations surrounding potential transitions to over-the-counter naloxone., (Copyright © 2022 American Society of Addiction Medicine.)

Chronic pain increases risk for opioid overdose among individuals with opioid use disorder. The purpose of this study is to evaluate the relationship between recent overdose and whether or not chronic pain is active. 3,577 individuals in treatment for opioid use disorder in 2017 or 2018 were surveyed regarding recent overdoses and chronic pain. Demographics from the 2017 Treatment Episode Data Set, which includes all U.S. facilities licensed or certified to provide substance use care, were used to evaluate the generalizability of the sample. χ2 tests and logistic regression models were used to compare associations between recent overdoses and chronic pain. Specifically, active chronic pain was associated with opioid overdose among people in treatment for opioid use disorder. Individuals with active chronic pain were more likely to have had a past month opioid overdose than those with no history chronic pain (adjusted OR = 1.55, 95% CI 1.16-2.08, p = 0.0003). In contrast, individuals with prior chronic pain, but no symptoms in the past 30 days, had a risk of past month opioid overdose similar to those with no history of chronic pain (adjusted OR = 0.88, 95% CI 0.66-1.17, p = 0.38). This suggests that the incorporation of treatment for chronic pain into treatment for opioid use disorder may reduce opioid overdoses., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Hartz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

While current opioid prescribing guidelines highlight a dose-response relationship between therapeutic management and overdose risk, other concurrent risk factors have also been identified. However, there is little data in assessing the relationship between risk factor prevalence, associated provider communication, and subsequent perceptions of overdose risk among chronic pain, opioid-managed (CPOM) patients. An online questionnaire was distributed in June 2020 to a sample of CPOM individuals (n = 190) treated with an opioid prescription at or above 50 daily MME, or any dosage alongside benzodiazepines. CPOM individuals reported a mean daily MME of 470, with half (52.6%) receiving a concurrent benzodiazepine prescription. All patients reported past month alcohol use, and 67.4% indicated a risk-elevating diagnosed medical condition. In assessing provider communication, 41.6% reported no discussion focusing on the risks of one's opioid therapy. Subsequently, 62.1% perceived themselves as having "no risk", and 60.0% were "not at all concerned" (60.0%) about experiencing an opioid overdose. Organizational policies should focus on implementing consistent methods of patient education regarding overdose risk, as well as assessments of behaviors or characteristics that my increase an individual's risk of opioid overdose. These policies should also include other forms of evidence-based overdose risk prevention such as co-prescriptions of naloxone.

Objective: The majority of prescription drugs, including prescription stimulants, are marketed using multiple brand names, doses, and formulations. There is limited research on the extent to which individuals correctly identify medication by brand name or packaging, but such identification is important for epidemiological studies especially among youth. Testing the ability of youth to identify medications was one aim of the National Monitoring of Prescription Stimulants Study, which focused on the prevalence of prescription stimulant use among youth., Methods: Using the entertainment venue intercept method, youth 10 to 18 years of age (n = 11,048) were recruited across 10 metropolitan areas throughout the United States, shown pictures of eight formulations of prescription stimulants, and asked to identify them by name, dosage, and formulation., Results: Overall, 27% of youth reported having seen one of the eight stimulant formulations and between 2% and 70% correctly identified name, dose, and formulation. Youths' reports of having seen and correctly identifying medication increased with age except for Daytrana ® . Specifically, while 2.8% of youth reported using Adderall ® in the past 30 days, only 71.4% correctly identified it., Conclusions: These results provide strong evidence of the need for more stringent methods for youth to report drug use., (© 2021 The Authors. International Journal of Methods in Psychiatric Research published by John Wiley & Sons Ltd.)

Rural areas of the United States have been disproportionately impacted by the opioid epidemic, exacerbated by COVID-19-related economic upheavals. While polysubstance use is an important determinant of overdose risk, variability in polysubstance use as a result of numerous factors (e.g., access, preference) has yet to be described, particularly among rural persons with opioid use disorder (PWOUD). Survey data on past-month use of prescription and illicit opioids and 12 non-opioid psychoactive drug classes were analyzed from a national sample of rural (n = 3872) and urban (n = 8153) residents entering treatment for OUD from 2012 to 2019. Trend analyses for opioid and stimulant use were compared between rural and urban PWOUD. Latent class analyses assessed substance use trends through identified typologies of rural/urban PWOUD, which then underwent comparative analyses. By 2019, prescription opioid use remained greater in rural versus urban PWOUD, and methamphetamine use showed greater growth in rural, compared to urban areas. Latent class analyses identified variability in polysubstance use, with five identical subgroups in rural/urban PWOD: high polysubstance, polyprescription, prescription opioid-focused, prescription opioid-focused with polysubstance use, and illicit opioid-focused. Polyprescription was highest in rural areas, with illicit opioid-focused use highest in urban areas. Demographic characteristics, co-morbid conditions and healthcare coverage were all associated with between-group differences. There is significant variability in polysubstance use that may identify specific prevention and treatment needs for subpopulations of OUD patients: interventions focused on reducing opioid prescriptions, early engagement with mental health resources, wider distribution of naloxone, and screening/treatment plans that take into account the use of multiple substances., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives. To understand important changes in co-occurring opioid and nonopioid drug use (i.e., polysubstance use) within the opioid epidemic in the United States. Methods. We analyzed survey data on the past month co-use of prescription and illicit opioids and 12 nonopioid psychoactive drug classes from a national sample of 15 741 persons entering treatment of opioid use disorder. Results. Past-month illicit opioid use increased from 44.8% in 2011 to 70.1% in 2018, while the use of prescription opioids alone dropped from 55.2% to 29.9%, yet overall remained high (94.5% to 85.2%). Past-month use of at least 1 nonopioid drug occurred in nearly all participants (> 90%), with significant increases in methamphetamine (+85%) and decreases across nonopioid prescription drug classes (range: -40% to -68%). Conclusions. Viewing opioid trends in a "silo" ignores the fact not only that polysubstance use is ubiquitous among those with opioid use disorder but also that significant changes in polysubstance use should be monitored alongside opioid trends. Public Health Implications. Treatment, prevention, and policymaking must address not only the supply and demand of a singular drug class but also the global nature of substance use overall.

Background/aims: Adolescents and young adults have the highest rates of opioid use, and despite shared risk-factors such as mental health and social pressures, there is little information on the relationship between education and opioid use disorder. In this study, we sought to assess differences in educational attainment between opioid users and the general population, and the impact of opioid use on one's education., Methods: Patients (N = 14,349) entering opioid treatment programs across the United States were surveyed on educational attainment from 2010 to 2018. Data were compared to estimates from an annual survey administered by the US Census. A follow-up sub-set of opioid users (N = 240) was interviewed to add context and expand on the structured survey., Results: Nearly one-third (32.2%) of the US population is estimated to have earned a bachelor's/advanced degree, compared to just 7.8% of treatment-seeking opioid users. Over half of follow-up respondents (57.5%) reported initiating regular opioid use while attending an educational institution. The majority (68.0%) also indicated opioids negatively impacted their education, with drug-seeking behavior prioritized over attendance and academic performance. Perceived benefits included cognitive enhancement and therapeutic value for anxiety/depression., Conclusions: Our data suggest that opioid users achieve lower levels of education, which may result in both individual and economic costs. Prevention programs need to not only include education-specific risk factors (e.g., social norms), but underlying precipitators such as mental health, stigma, and the myth of risk-free cognitive enhancement. Opioid specific services should be available and disseminated to student populations, including certification of campus physicians to provide buprenorphine maintenance., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims: Gabapentin is used in the treatment of seizures and neuralgia, and it is prescribed off-label to treat substance use disorders and withdrawal symptoms. Recent research documents misuse of gabapentin, especially among prescription opioid misusers. The present study contributes to this literature by examining the initiation of gabapentin misuse., Methods: Qualitative interviews were conducted with prescription and/or illicit opioid (mis)users who reported a history of gabapentin misuse (N = 62) and who did not (N = 29). During semi-structured interviews, respondents provided descriptions of the first time they misused gabapentin. An ethnographic decision model was constructed to illustrate the factors that influence the initiation decision., Results: Multiple individual, social, and environmental factors influence the decision to initiate gabapentin misuse. Respondents described the initiation decision related to: a) wanting to feel a psychoactive high during times of limited access to one's preferred drug because of institutional barriers (e.g., substance abuse treatment; jail; transitional living facility; N = 18); b) the desire to use multiple drugs, including for experimentation or to potentiate another substance (N = 18); and c) the need to self-treat withdrawal symptoms during periods of opioid nonuse or when opioids were unavailable (N = 16). Respondents also initiated gabapentin misuse to self-treat physical pain (N = 10)., Conclusions: Multiple approaches are needed to mitigate gabapentin misuse, including limiting availability in institutional settings and informal channels as well as addressing the needs of drug users who experience physical pain and withdrawal symptoms. Continued research is needed to examine therapeutic uses of gabapentin and behaviors related to misuse., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Gabapentin, a prescription medication approved for the treatment of seizures and neuralgia, is often prescribed off-label for substance use treatment, mental health problems, and pain. Emerging reports also suggest it is misused for the purpose of getting high. The present study examines substance abuse treatment provider key informants' experiences with gabapentin prescribed to clients in treatment. The focus of this exploratory study is to ascertain how gabapentin is used in these settings and the benefits and risks for clients., Methods: Key informants from South Florida participated in confidential, in-depth interviews (N = 12). Data analyses included descriptive and in vivo coding schemes and employed a descriptive qualitative approach., Results: All key informants recognized the benefits of prescribing gabapentin to clients in treatment for problems related to withdrawal symptoms, mental distress and pain. At the same time, half of participants described gabapentin misuse among clients and four key informants described such misuse as a first marker of relapse. Key informants also stated that more research must be done about how to use gabapentin effectively in treatment settings., Conclusions: These findings illustrate the lack of clarity about the efficacy of administration of gabapentin in treatment settings. Additional research about how to best use gabapentin, for whom it may be beneficial, and the effect of prescribed gabapentin on addiction recovery is needed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Opioids with abuse-deterrent properties may reduce widespread abuse, misuse, and diversion of these products. This study aimed to quantify misuse, abuse, dependence, and health resource use of extended-release morphine sulfate with sequestered naltrexone hydrochloride (ER-MSN; EMBEDA®), compared with non-abuse-deterrent extended-release morphine (ERM) products in Medicaid non-cancer patients., Methods: Administrative medical and pharmacy claims data were analyzed for 10 Medicaid states from 1 January 2015, to 30 June 2016. Patients were included if they received a prescription for ER-MSN or any oral, non-abuse-deterrent ERM. Index date was the date of first prescription for an ER-MSN or ERM. Abuse/dependence, non-fatal overdose, emergency department (ED) visits, and ED/inpatient readmissions were determined for each participant. An overall measure of misuse and abuse was also calculated. To account for differences in follow-up, all counts are expressed per 100 patient-years., Results: There were 4,857 patients who received ER-MSN and 10,357 who received an ERM. The average age in the two cohorts was approximately 45 years old. From pre-index to follow-up, the number of patients per 100 patient-years with a diagnosis code indicating abuse or dependence increased by 0.91 (95% confidence interval [CI]: 0.85, 0.97) in the ER-MSN cohort and 2.23 (95% CI: 2.14, 2.32) in the ERM cohort. The number of patients per 100 patient-years with an opioid-related non-fatal overdose increased by 0.05 (95% CI: 0.04, 0.06) in the ER-MSN cohort compared with 0.11 (95% CI: 0.09, 0.13) in the ERM cohort. The opioid abuse overall composite score increased by 1.36 (95% CI: 1.24, 1.48) in the post-index period in the ER-MSN cohort compared to 3.21 (95% CI: 3.10, 3.32) in the ERM cohort., Conclusion: Misuse, abuse, and dependence events were numerically lower in patients receiving ER-MSN compared with those receiving ERM products.

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., (© 2018 John Wiley & Sons, Ltd.)

Introduction: Previously, we reported a marked increase in the use of heroin as an initiating opioid in non-tolerant, first time opioid users. In the current paper, we sought to update and expand upon these results, with a discussion of the policy implications on the overall opioid epidemic., Methods: Opioid initiation data from the original study were updated to include surveys completed through 2017 (N = 8382) from a national sample of treatment-seeking opioid users. In addition, past month abuse of heroin and prescription were analyzed as raw numbers of treatment program entrant in the last five years (2013-2017), drawing from only those treatment centers that participated every year in that time frame., Results: The updated data confirm and extend the results of our original study: the use of heroin as an initiating opioid increased from 8.7% in 2005 to 31.6% in 2015, with increases in overall Ns per initiation year reflecting a narrowing of the "treatment gap", the time lag between opioid initiation from 2005 to 2015 and later treatment admission (up to 2017). Slight decreases were observed in treatment admissions, but this decline was totally confined to prescription opioid use, with heroin use continuing to increase in absolute numbers., Conclusions: Given that opioid novices have limited tolerance, the risk of fatal overdose for heroin initiates is elevated compared to prescription opioids, particularly given non-oral administration and often unknown purity/adulterants (i.e., fentanyl). Imprecision of titrating dose among opioid novices may explain observed increases opioid overdoses. Future policy decisions should note that prescription opioid-specific interventions may have little impact on a growing heroin epidemic., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Buprenorphine is approved in many countries for the treatment of opioid use disorder (OUD), but problems with diversion and abuse exist. There is a need to understand how and why patients use diverted buprenorphine, and whether barriers to access contribute to illicit use., Methods: Adults >18 years with DSM-IV criteria for substance use disorder and primarily using an opioid completed the online Survey of Key Informants' Patients (SKIP) between August and September 2016. The survey included closed- and open-ended questions regarding reasons for buprenorphine use with and without a prescription, sources of buprenorphine, route of administration, and barriers to treatment., Results: Of 303 respondents, 175 (58%) reported a history of diverted buprenorphine use, 65 (37%) of whom reported never receiving a prescription. The most common reasons for illicit buprenorphine use were consistent with therapeutic use: to prevent withdrawal (79%), maintain abstinence (67%), or self-wean off drugs (53%). Approximately one-half (52%) reported using buprenorphine to get high or alter mood, but few (4%) indicated that it was their drug of choice. Among respondents who had used diverted buprenorphine, 33% reported that they had issues finding a doctor or obtaining buprenorphine on their own. Most (81%) of these participants indicated they would prefer using prescribed buprenorphine, if available., Conclusions: Although 58% of survey respondents reported a history of using diverted buprenorphine, the most frequently cited reasons for non-prescription use were consistent with therapeutic use. Diversion was partially driven by barriers to access, and an unmet need for OUD treatment persists., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background/aims: Recent supply-side efforts enacted to curb the opioid epidemic have had both positive (i.e., prescription opioid abuse is on the decline) and negative outcomes (i.e., shifts to other drugs). Given methamphetamine is notably increasing in use across the United States, we sought to understand whether use of methamphetamine has increased among opioid users and whether there is an association between these two epidemics., Methods: Patients (N = 13,521) entering drug treatment programs across the United States completed an anonymous survey of drug use patterns from 2011 to 2017. A subset of these patients (N = 300) was also interviewed to add context and expand on the structured survey., Results: Past month use of methamphetamine significantly increased among treatment-seeking opioid users (+82.6%, p < .001), from 18.8% in 2011 to 34.2% in 2017. The Western region had the greatest increase in past month methamphetamine use (+202.4%, p < 0.001) and the highest prevalence rate in 2017 (63.0%). Significant increases (p < .001) in methamphetamine use were seen among males (+81.8%), females (+97.8%), whites (+100.6%), urban residents (+123.0%) and rural residents (+93.7%)., Conclusions: Our studies show that there has been a marked increase in the past month use of methamphetamine in individuals with a primary indication of opioid use disorder. Qualitative data indicated that methamphetamine served as an opioid substitute, provided a synergistic high, and balanced out the effects of opioids so one could function "normally". Our data suggest that, at least to some extent, efforts limiting access to prescription opioids may be associated with an increase in the use of methamphetamine., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Abuse-deterrent opioid formulations have been suggested as one way to decrease the abuse, addiction, and overdose of orally prescribed opioids. Ten oral opioid formulations have received abuse-deterrent labeling by the U.S. Food and Drug Administration (FDA). Their properties consist of physical and/or chemical means by which the pills resist manipulation and create a barrier to unintended administration, such as chewing, nasal snorting, smoking, and intravenous injection. In this review, we describe the mechanisms of abuse-deterrent technology, the types of premarketing studies required for FDA approval, the pharmacology of the currently approved abuse-deterrent opioid formulations, and the evidence for and against their influence on opioid abuse. We conclude that there is currently insufficient evidence to indicate that the availability of abuse-deterrent opioid formulations has altered the trajectory of opioid overdose and addiction; however, postmarketing studies are in their infancy, and novel deterrent formulations are continually being developed and submitted for marketing approval.

Tapentadol, a Schedule II opioid with a combination of µ-opioid activity and norepinephrine reuptake inhibition, is used for the management of moderate to severe acute and chronic pain. Its dual mechanism of action is thought to reduce opioid-related side effects that can complicate pain management. Since approval, tapentadol has been tracked across multiple outcomes suggesting abuse liability, and a pattern of relatively low, although not absent, abuse liability has been found. This retrospective cohort study further details the abuse liability of tapentadol as an active pharmaceutical ingredient (API) when immediate-release as well as extended-release formulations were on the market together (fourth quarter of 2011 to second quarter of 2016). Tapentadol (API) was compared with tramadol, hydrocodone, morphine, oxycodone, hydromorphone, and oxymorphone across Poison Center, Drug Diversion, and Treatment Center Programs Combined data streams from the Researched Abuse, Diversion and Addiction-Related Surveillance system. Findings suggest the public health burden related to tapentadol to date is low, but present. Event rates of abuse per population-level denominators were significantly lower than all other opioids examined. However, when adjusted for drug availability, event rates of abuse were lower than most Schedule II opioids studied, but were not the lowest. Disentangling these 2 sets of findings further by examining various opioid formulations, such as extended-release and the role of abuse-deterrent formulations, is warranted., Perspective: This article presents the results from an examination of tapentadol API across the Researched Abuse, Diversion and Addiction-Related Surveillance System: a broad and carefully designed postmarketing mosaic. Data to date from Poison Center, Drug Diversion, and Treatment Centers combined suggest a low, but present public health burden related to tapentadol., (Copyright © 2018. Published by Elsevier Inc.)

Objective: We performed a systematic review to answer the question, "Does the introduction of an opioid analgesic with abuse deterrent properties result in reduced overall abuse of the drug in the community?", Design: We included opioid analgesics with abuse deterrent properties (hydrocodone, morphine, oxycodone) with results restricted to the metasearch term "delayed onset," English language, use in humans, and publication years 2009-2016. All articles that contained data evaluating misuse, abuse, overdose, addiction, and death were included. The results were categorized using the Bradford-Hill criteria., Results: We included 44 reports: hydrocodone (n = 7), morphine (n = 5), or oxycodone (n = 32) with Food and Drug Administration-approved Categories 1, 2, or 3 abuse deterrent labeling. The data currently available support the Hill criteria of strength (effect size), consistency (reproducibility), temporality, plausibility, and coherence. There was insufficient or no information available for the criteria of biological gradient, experiment, and analogy. We also assessed confounding factors and bias, which indicated that both were present and substantial in magnitude., Conclusions: Our analysis found that only oxycodone extended release (ER) had information available to evaluate abuse deterrence in the community. In Australia, Canada, and the United States, reformulation of oxycodone ER was followed by marked reduction in measures of abuse. The precise extent of reduced abuse cannot be calculated because of heterogeneous data sets, but the reported reductions ranged from 10 to 90 percent depending on the measure and the duration of follow-up.

Introduction: Given the relatively recent growth in access to heroin and a more permissive atmosphere surrounding its use, we hypothesized that an increasing number of persons with limited experience and tolerance to opioids would experiment with heroin as their first opioid rather than more common prescription opioid analgesics., Methods: Individuals entering substance abuse treatment for an opioid use disorder in the period 2010-2016 (N=5885) were asked about the specific opioid they first regularly used to get high. To limit long-term recall and survival bias, analyses was restricted to opioid initiation that occurred in the past ten years (2005-2015)., Results: In 2005, only 8.7% of opioid initiators started with heroin, but this sharply increased to 33.3% (p<0.001) in 2015, with no evidence of stabilization. The use of commonly prescribed opioids, oxycodone and hydrocodone, dropped from 42.4% and 42.3% of opioid initiators, respectively, to 24.1% and 27.8% in 2015, such that heroin as an initiating opioid was now more frequently endorsed than prescription opioid analgesics., Conclusions: Our data document that, as the most commonly prescribed opioids - hydrocodone and oxycodone - became less accessible due to supply-side interventions, the use of heroin as an initiating opioid has grown at an alarming rate. Given that opioid novices have limited tolerance to opioids, a slight imprecision in dosing inherent in heroin use is likely to be an important factor contributing to the growth in heroin-related over dose fatalities in recent years., (Copyright © 2017. Published by Elsevier Ltd.)

Background: Nonmedical prescription opioid use (NMPOU) is well documented among participants in the club scene, yet prior studies have not examined transition to heroin use. We prospectively examined heroin initiation among a sample of young adults with drug involvement associated with participation in the club scene, to understand factors that influence transition from NMPOU to heroin and to identify opportunities for intervention., Methods: Data were drawn from a randomized trial that enrolled 750 Miami-based club and prescription drug users through respondent driven sampling, and tested the efficacy of assessment interventions in reducing risk. Participants reported current substance use at baseline, 3, 6, and 12 month follow-ups. We examined predictors of heroin initiation among participants reporting NMPOU at baseline, with no lifetime history of heroin use (N=323)., Results: The mean age was 25.0 years; 67.5% met DSM-IV criteria for substance dependence. About 1 in 13 participants (7.7%) initiated heroin use at follow-up. In univariable comparisons, frequent LSD use, history of drug overdose, high frequency NMPOU, using oral tampering methods, and endorsing a primary medical source for prescription opioids were associated with greater likelihood of heroin initiation. LSD use, oral tampering, and primary medical source were significant predictors in a Cox regression model., Conclusions: Heroin initiation of 7.7% suggests a high level of vulnerability for transition among young adult NMPO users in the club scene. The importance of oral tampering methods in the trajectory of NMPOU may indicate a need to further examine the role of abuse deterrent formulations in prevention efforts., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Uncovering mechanisms of epigenome evolution is an essential step towards understanding the evolution of different cellular phenotypes. While studies have confirmed DNA methylation as a conserved epigenetic mechanism in mammalian development, little is known about the conservation of tissue-specific genome-wide DNA methylation patterns., Results: Using a comparative epigenomics approach, we identified and compared the tissue-specific DNA methylation patterns of rat against those of mouse and human across three shared tissue types. We confirmed that tissue-specific differentially methylated regions are strongly associated with tissue-specific regulatory elements. Comparisons between species revealed that at a minimum 11-37% of tissue-specific DNA methylation patterns are conserved, a phenomenon that we define as epigenetic conservation. Conserved DNA methylation is accompanied by conservation of other epigenetic marks including histone modifications. Although a significant amount of locus-specific methylation is epigenetically conserved, the majority of tissue-specific DNA methylation is not conserved across the species and tissue types that we investigated. Examination of the genetic underpinning of epigenetic conservation suggests that primary sequence conservation is a driving force behind epigenetic conservation. In contrast, evolutionary dynamics of tissue-specific DNA methylation are best explained by the maintenance or turnover of binding sites for important transcription factors., Conclusions: Our study extends the limited literature of comparative epigenomics and suggests a new paradigm for epigenetic conservation without genetic conservation through analysis of transcription factor binding sites.

Most research designed to answer the "why" of the prescription opioid epidemic has relied on structured interviews, which rigidly attempt to capture the complex reasons people use opioids. In contrast this systematic literature review focuses on peer-reviewed studies that have used a qualitative approach to examine the development of an opioid-use disorder from the point of initial exposure. Rather than simply providing a "high," opioids reportedly relieve psychological/emotional problems or provide an escape from life stressors. As use continues, avoidance of withdrawal sickness becomes an overriding concern, with all other benefits playing minor roles in persistent use. These studies indicate that terms used in structured interviews, such as "nontherapeutic use" or variations thereof, poorly capture the complex range of needs opioids satisfy. Both quantitative/structured studies and more qualitative ones, as well as more focused studies, have an important role in better informing prevention and treatment efforts.

Background/purpose: Recent reports indicate a sharp increase in fentanyl-related overdose deaths across the United States, much of which is likely related to the introduction of cheap, illicitly manufactured fentanyl derivatives. In this study, we sought to estimate the magnitude of illicit fentanyl use from 2012 to 2016 using a national opioid abuse surveillance system., Methods: The study program surveyed 10,900 individuals entering substance abuse treatment for opioid use disorder, with participants asked to endorse past month 'use to get high' of fentanyl drugs, stratified by identifiable (i.e., branded) fentanyl formulations or a 'type unknown' drug alleged to contain fentanyl., Main Findings: Total past-month fentanyl-use rose modestly from 2012 to 2016. While use of known fentanyl products remained relatively stable (mean=10.9%; P=0.25), endorsements of 'unknown' fentanyl products nearly doubled from 9% in 2013 to 15.1% by 2016 (P<0.001). Data show no discernable indication that this increase is diminishing or stabilizing., Conclusions: This first attempt to assess the prevalence of illicit fentanyl use shows that recent increases in fentanyl use seem to be due almost entirely to 'unknown' fentanyl presumed to be illicitly manufactured. Given that it is difficult to assess the extent to which fentanyl may have been substituted for another drug (i.e., oxycodone, alprazolam, etc.) or was used as a heroin admixture, our data likely represent an underestimation of the full magnitude of illicit fentanyl abuse. As such, this growing public health problem requires immediate attention and more systematic efforts to identify and track its abuse., (Copyright © 2017. Published by Elsevier B.V.)

Background: These studies were carried out to examine whether the onset and progression of an opioid substance use disorder (SUD) differed in those who first used opioids to get "high" compared to those who received a prescription from a doctor to relieve pain (Non-Rx vs. Rx groups, respectively)., Methods: A subset of patients (N=214) from an ongoing larger study of patients entering one of 125 drug treatment programs for opioid use disorder across the country agreed to give up their anonymity and participate in structured and open-ended online interviews examining drug abuse patterns., Results: With the exception that the Non-Rx group began their opioid abuse at a younger age than the Rx group and more quickly evolved from initial exposure to regular opioid abuse, there were relatively few differences in the characteristics, patterns and trajectories of opioid abuse. The vast majority of patients in both groups, most of whom had serious, antecedent psychiatric disorders, indicated that they used opioids to self-medicate psychological problems (67-73%) and/or stated that opioids provided a means to "escape" from the stresses of everyday life (79-85%). As the SUD progressed, for many individuals any "positive" attributes of opioids waned and avoidance of withdrawal became the overriding concern, often serving as the impetus for treatment., Conclusions: Our results suggest that self-treatment of co-morbid psychiatric disturbances is a powerful motivating force to initiate and sustain abuse of opioids and that the initial source of drugs-a prescription or experimentation-is largely irrelevant in the progression to a SUD., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Physicians are frequently thought to be a major source of opioids diverted for non-therapeutic purposes, largely because it is so difficult for them to discern which patients might abuse them. In this study we sought to determine whether those who were first exposed to an opioid through a physician's prescription, and subsequently developed a substance use disorder, had a history of using psychoactive drugs prior to abusing opioids. Patients entering one of 125 drug treatment programs across the country for opioid abuse were asked to provide detailed histories of psychoactive drug use prior to their initial opioid exposure. Nearly half (47.1%, N=4493) indicated they were first exposed to opioids through a prescription from their physician to treat pain. Of these, 94.6% indicated experience with at least one other psychoactive substance (mean=4.55±0.05) prior to, or coincident with, their first exposure to an opioid from a physician. Alcohol (92.9%), nicotine and/or tobacco (89.5%), and marijuana (87.4%) were used by nearly all patients prior to, or coincident with, their first opioid prescription. If one excludes these drugs, 70.1% (N=2913) still reported some psychoactive drug use of licit or illicit stimulants (77.8%), benzodiazepines (59.8%) or hallucinogens (55.2%). Our results indicate that pain patients who developed a substance use disorder were rarely drug naïve prior to receiving their first opioid prescription. Rather, most have an extensive history of psychoactive drug use. As such, physicians should routinely ascertain complete licit and illicit drug histories in patients for whom they prescribe opioids., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: Although differences in the pharmacological properties of immediate-release (IR) and extended-release (ER) opioid formulations have been reported, there are few studies comparing the real world abuse and relative preferences for these formulations., Methods: To examine drug preferences, we used a structured survey of 8304 individuals entering treatment (2011-2014) for opioid use disorder followed by a more focused online survey (2014-2015) with a subset of these patients (N = 301)., Results: Our results demonstrated that both ER and IR opioids were frequently abused by those with an opioid use disorder in terms of lifetime (91.0% vs. 98.7%, respectively) or past month (46.1% vs. 67.4%, respectively) abuse, but given the choice, only 4% of the sample selected ER compounds as their preferred formulation. The remainder had no preference (29.9%) or a distinct preference for IR formulations (66.1%), regardless of route of administration-oral or non-oral (smoking/snorting or injecting). This preference for IR formulations seems to be related to: (i) the perceived immediacy and quality of the high (73.0%) from IR products; and (ii) they were easier to use, particularly when manipulated for non-oral abuse, than ER products (31.2%)., Conclusions: Based on these results, while most abusers have experience with both formulations, there is a greater preference for IR formulations, compared to ER, regardless of route of administration. As a result, it may not be unreasonable to suggest that supply-side initiatives to restrict the diversion and abuse of prescription opioids may be just as important for both IR and ER opioids. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: Therapeutic use and abuse of prescription opioids in the United States increased substantially between 1990 and 2010. The Centers for Disease Control estimated deaths related to pharmaceutical opioids reached nearly 19,000 in 2014. Of prescription opioids sold, 10% are extended release (ER) and 90% immediate release (IR). However, most regulations and interventions have focused on decreasing ER abuse. Our objective was to compare rates of abuse and diversion of ER and IR opioid analgesics over time using multiple surveillance programs., Methods: Rates of abuse and diversion of ER and IR opioid formulations were compared using data from four surveillance programs in the Researched Abuse, Diversion and Addiction Related Surveillance (RADARS®) System. Data were evaluated from 2009 through 2015, and Poisson regression used to compare IR and ER opioid cases over time., Results: From 2009 to 2015, IR opioids were prescribed at a rate 12 to 16 times higher than ER. In the Poison Center Program, population-adjusted rates of Intentional Abuse for IR were 4.6 fold higher than ER opioids (p<0.001). In the Drug Diversion Program, population-adjusted rates of diversion were 6.1 fold higher for IR than ER opioids (p<0.001). In the Opioid Treatment Program, population-adjusted rates of endorsements for abuse were 1.6 fold higher for IR opioids than ER (p = 0.002). In the Survey of Key Informants' Patients Program, population-adjusted rates of endorsements for abuse were 1.5 fold higher for IR opioids than ER (p<0.001)., Conclusions: Between 2009 and 2015, IR opioids were prescribed at a much higher rate than ER opioids. Results from four surveillance programs show population-adjusted rates of prescription opioid abuse were markedly higher for IR than ER medications. For the greatest public health benefit, future interventions to decrease prescription opioid abuse should focus on both IR and ER formulations., Competing Interests: The authors have declared that no additional competing interests exist.

Background: The development of abuse deterrent formulations is one strategy for reducing prescription opioid misuse and abuse. A putative abuse deterrent formulation of oxycodone extended release (OxyContin ® ) was introduced in 2010. Early reports demonstrated reduced abuse and diversion, however, an analysis of social media found 32 feasible methods to circumvent the abuse deterrent mechanism. We measured trends of diversion, abuse and street price of OxyContin to assess the durability of the initial reduction in abuse., Methods: Data from the Poison Center Program, Drug Diversion Program, Opioid Treatment Program, Survey of Key Informant Patients Program and StreetRx program of the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS ® ) System were used. The average quarterly rates of abuse and diversion for OxyContin were compared from before reformulation to the rate in second quarter 2015. Rates were adjusted for population using US Census data and drug availability., Results: OxyContin abuse and diversion declined significantly each quarter after reformulation and persisted for 5 years. The rate of abuse of other opioid analgesics increased initially and then decreased, but to lesser extent than OxyContin. Abuse through both oral and non-oral routes of self-administration declined following the reformulation. The geometric mean difference in the street price of reformulated OxyContin was 36% lower than the reformulated product in the year after reformulation., Discussion: Despite methods to circumvent the abuse deterrent mechanism, abuse and diversion of OxyContin decreased promptly following the introduction of a crush- and solubility- resistant formulation and continued to decrease over the subsequent 5 years., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

The introduction of extended-release opioid analgesics helped initiate an epidemic of prescription opioid abuse in the United States. To make access to the drug by crushing or dissolution more difficult, abuse-deterrent formulations (ADFs) of OxyContin (Purdue Pharma, Stamford, CT) and Opana ER (Endo Pharmaceuticals Inc., Malvern, PA), which use the same foundation technology (Intac, Grunenthal, Aachen, Germany), were introduced in 2010 and 2012, respectively. To examine their relative effectiveness, we used a structured survey of 12,124 individuals entering treatment for opioid use disorder followed by a more focused online survey with a subset of these patients (N = 129) using both structured and open-ended questions. Data showed that the OxyContin ADF was highly effective in reducing nonoral abuse (91.4% before the ADF, 47.9% afterwards), particularly with insufflation (78%-28.8%) and intravenous injection of the active drug (42.7%-21.4%). However, although the Opana ER ADF was effective in reducing insufflation (80%-37.1%), injection (60.0%-51.4%), and overall nonoral abuse (94.3%-77.1%), it showed no significant decrease over time. Bearing in mind that the Opana ER sample was smaller in size than that for OxyContin, our results nonetheless suggest disparate outcomes resulting from the introduction of the ADFs, which could indicate that an ADF's effectiveness may be drug-specific. Given the public health impact of prescription opioids and the considerable effort being expended to develop ADFs as a partial solution to the problem, our preliminary studies suggest that each ADF must be evaluated on its own merits even if the same proprietary technology is used.

From teenagers dying from heroin overdoses to crime tied to Vicodin and OxyContin addiction to road fatalities in which sedatives and muscle relaxants are involved, 20,000 deaths in the United States in 2014 were attributed to problems associated with narcotics and prescription drug use. Our author, whose research involves the neurobiological basis of drug addiction, traces the history and evolution of narcotics and leans on his clinical experience to discuss why certain drugs are powerful, addicting-and dangerous.