Polysubstance use trends and variability among individuals with opioid use disorder in rural versus urban settings.

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.

Polysubstance Use: A Broader Understanding of Substance Use During the Opioid Crisis.

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.

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

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

Trends in opioid analgesic abuse and mortality in the United States.

BACKGROUND: The use of prescription opioid medications has increased greatly in the United States during the past two decades; in 2010, there were 16,651 opioid-related deaths. In response, hundreds of federal, state, and local interventions have been implemented. We describe trends in the diversion and abuse of prescription opioid analgesics using data through 2013. METHODS: We used five programs from the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System to describe trends between 2002 and 2013 in the diversion and abuse of all products and formulations of six prescription opioid analgesics: oxycodone, hydrocodone, hydromorphone, fentanyl, morphine, and tramadol. The programs gather data from drug-diversion investigators, poison centers, substance-abuse treatment centers, and college students. RESULTS: Prescriptions for opioid analgesics increased substantially from 2002 through 2010 in the United States but then decreased slightly from 2011 through 2013. In general, RADARS System programs reported large increases in the rates of opioid diversion and abuse from 2002 to 2010, but then the rates flattened or decreased from 2011 through 2013. The rate of opioid-related deaths rose and fell in a similar pattern. Reported nonmedical use did not change significantly among college students. CONCLUSIONS: Postmarketing surveillance indicates that the diversion and abuse of prescription opioid medications increased between 2002 and 2010 and plateaued or decreased between 2011 and 2013. These findings suggest that the United States may be making progress in controlling the abuse of opioid analgesics. (Funded by the Denver Health and Hospital Authority.).

Abuse-deterrent Opioid Formulations.

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.

Tissue-specific DNA methylation is conserved across human, mouse, and rat, and driven by primary sequence conservation.

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.

Relative preferences in the abuse of immediate-release versus extended-release opioids in a sample of treatment-seeking opioid abusers.

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.

Reductions in prescription opioid diversion following recent legislative interventions in Florida.

PURPOSE: Florida has been at the center of the nation's ongoing prescription opioid epidemic, with largely unregulated pain clinics and lax prescribing oversight cited as significant contributors to the opioid problem in the state. METHODS: In an effort to mitigate prescription opioid abuse and diversion in Florida, legislative interventions were implemented during 2010 and 2011, which included two primary elements: (i) comprehensive legislation to better regulate the operation of pain clinics; and (ii) a statewide prescription drug monitoring program to promote safer prescribing practices. Using systematic longitudinal data collected on a quarterly basis from law enforcement agencies across Florida, this report examined changes in prescription opioid diversion rates following implementation of these regulatory initiatives. Quarterly diversion rates for buprenorphine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and tramadol were calculated, and subsequently, hierarchical linear models were fit to test for differences in diversion rates over the 15 quarter period of interest. RESULTS: Significant declines in diversion rates were observed for oxycodone, methadone, and morphine; hydrocodone displayed a marginally significant decline. CONCLUSIONS: This study documented reductions in statewide opioid diversion rates following implementation of Florida's pain clinic and prescription drug monitoring program legislative interventions. Although these initial findings appear promising, continued surveillance of diversion is clearly warranted.

Antiretroviral medication diversion among HIV-positive substance abusers in South Florida.

The high cost of life-saving antiretroviral (ARV) therapy for HIV represents an expense that impedes accessibility and affordability by patients. This price structure also appears to motivate the diversion of ARVs and the targeting of HIV-positive patients by pill brokers in the illicit market. Our field research with indigent, HIV-positive substance abusers links ARV diversion to high levels of competing needs, including psychiatric disorders, HIV stigma, and homelessness. Interventions to reduce diversion must address the needs of highly vulnerable patients.

Witnessed versus unwitnessed random urine tests in the treatment of opioid dependence.

BACKGROUND AND OBJECTIVES: Clinics licensed to provide pharmacotherapy for opiate dependence disorder are required to perform random urine drug screen (RUDS) tests. The results provide the empirical basis of individual treatment and programmatic effectiveness, and public health policy. Patients consent to witnessed testing but most tests are unwitnessed. The purpose of the present study was to compare treatment effectiveness estimates derived from witnessed versus unwitnessed urine samples. METHODS: We adopted a policy requiring visually witnessed urine drug screens (WUDS) and studied its impact (a single group, pretest-posttest design) on the RUDS test results in 115 male veterans enrolled in the St. Louis VA Opioid Treatment Program. RESULTS: The percentage of opioid-positive urine samples increased significantly following implementation of WUDS (25% vs. 41%, χ(2) = 66.5, p < .001). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Results of this preliminary study suggest that random testing alone does not ensure the integrity of UDS testing. Outcome calculations based on random unwitnessed tests may overestimate the effectiveness of opioid dependence disorder treatment.

Differences in Self-identification of Opioid Overdose Risk and Naloxone Perceptions Between Therapeutic and Nontherapeutic Opioid Populations.

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.

Abuse of tapentadol compared to other atypical opioids among individuals entering treatment for opioid use disorders.

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.

Health outcomes in patients using no-prescription online pharmacies to purchase prescription drugs.

BACKGROUND: Many prescription drugs are freely available for purchase on the Internet without a legitimate prescription from a physician. OBJECTIVE: This study focused on the motivations for using no-prescription online pharmacies (NPOPs) to purchase prescription drugs rather than using the traditional doctor-patient-pharmacy model. We also studied whether users of NPOP-purchased drugs had poorer health outcomes than those who obtain the same drug through legitimate health care channels. METHODS: We selected tramadol as a representative drug to address our objective because it is widely prescribed as an unscheduled opioid analgesic and can easily be purchased from NPOPs. Using search engine marketing (SEM), we placed advertisements on search result pages stemming from the keyword "tramadol" and related terms and phrases. Participants, who either used the traditional doctor-patient-pharmacy model to obtain tramadol (traditional users, n = 349) or purchased it on the Web without a prescription from their local doctor (ie, nontraditional users, n = 96), were then asked to complete an online survey. RESULTS: Respondents in both groups were primarily white, female, and in their mid-forties (nontraditional users) to upper forties (traditional users). Nearly all nontraditional users indicated that their tramadol use was motivated by a need to treat pain (95%, 91/96) that they perceived was not managed appropriately through legitimate health care channels. A majority of nontraditional users (55%, 41/75) indicated they used NPOPs because they did not have access to sufficient doses of tramadol to relieve pain. In addition, 29% (22/75) of nontraditional users indicated that the NPOPs were a far cheaper alternative than seeing a physician, paying for an office visit, and filling a prescription at a local pharmacy, which is often at noninsured rates for those who lack medical insurance (37%, 35/96, of NPOP users). The remainder of participants (16%, 12/96) cited other motivations (eg, anonymity) for using NPOPs. In terms of health outcomes, nontraditional users experienced a significantly (P < .01) greater number and severity of adverse events, including life-threatening seizures: 7% (7/96) of nontraditional users reported seizures, while none of the traditional users reported seizures. CONCLUSIONS: Although online pharmacies can offer distinct advantages in terms of convenience and cost, users of these "rogue" pharmacies that offer drugs with no prescription or doctor supervision do so at great risk to their health, as evidenced by much higher rates of adverse events. The most logical explanation for these findings is that the lack of physician oversight of dosage schedules, contraindicated conditions, and concomitant medications, were responsible for the increased intensity and frequency of adverse events in the nontraditional users. Although we only examined tramadol, it is logical to postulate that similar results would be observed with dozens of equally accessible prescription drugs. As such, the geometric growth in the use of online pharmacies around the world should prompt intense medical and regulatory discussion about their role in the provision of medical care.

Association between recent overdose and chronic pain among individuals in treatment for opioid use disorder.

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.

Role of key informants and direct patient interviews in epidemiological studies of substance abuse.

PURPOSE: The present study was undertaken to assess the degree to which key informants' perceptions of relative abuse liability of opioids in their communities correspond to actual drug use in their patients. METHODS: Key informants (n = 49) and their patients (n = 738) were asked to complete anonymous, independent paper surveys about perceived or actual abuse of nine targeted opioid drugs: buprenorphine, fentanyl, heroin, hydrocodone, hydromorphone, methadone, morphine, oxycodone and tramadol. RESULTS: There was a strong correspondence (R = 0.98) between KI rankings of relative abuse of opioids in their patient population and the actual rank order calculated from their patients' selection of a primary euphorigenic opioid. The patient surveys not only validated the KI's conclusions, but also provided a great deal of important information about the nature of the abuse patterns. Notably, significant co-morbidity was found in the patient population: 55% had a history of psychiatric problems; chronic pain of moderate intensity was common; 67% were nicotine dependent; and 43% were diagnosed alcoholics. DISCUSSION: Our results demonstrate that KI's perceived rank order of drugs of choice correlated almost perfectly with their patients' choice of a primary drug. These data suggest that key informants, as they have for decades in epidemiological research, provide a reliable, high-level view of substance abuse in their catchment area. As such, KIs provide valid and reliable information on scope and patterns of abuse, but if more detail is required about the characteristics of abuse, such as that required for FDA-mandated Risk Evaluation and Mitigation Strategies, then direct interviews with the abusers themselves seem more appropriate.

Multiple Determinants of Specific Modes of Prescription Opioid Diversion.

Numerous national surveys and surveillance programs have shown a substantial rise in the abuse of prescription opioids over the past 15 years. Accessibility of these drugs to non-patients is the result of their unlawful channeling from legal sources to the illicit marketplace (diversion). Empirical data on diversion remain absent from the literature. This paper examines abusers' sources of diverted drugs from two large studies: 1) a national sample of opioid treatment clients (N=1983), and 2) a South Florida study targeting diverse populations of opioid abusers (N=782). The most common sources of diverted medications were dealers, sharing/trading, legitimate medical practice (e.g., unknowing medical providers), illegitimate medical practice (e.g., pill mills), and theft, in that order. Sources varied by users' age, gender, ethnicity, risk-aversiveness, primary opioid of abuse, injection drug use, physical health, drug dependence, and either access to health insurance or relative financial wealth. Implications for prescription drug control policy are discussed.