"Among the 342 known SSPs operating at the beginning of 2019, 263 (77%) responded to the online survey; of these, 247 (94%) had an OEND program, 160 (65%) of which had been implemented since 2016 (Figure 1). With regard to phases of OEND implementation, 173 (66%) responding SSPs had been implementing OEND for 12 months or more, 74 (28%) had implemented OEND within the last 12 months, eight (3%) were actively preparing for OEND implementation, and eight (3%) were exploring OEND implementation (Table). Of the 16 SSPs not yet offering OEND, four had previously implemented naloxone distribution but stopped because of an inadequate naloxone supply or funding.

"Among the 247 SSPs with an OEND program, 191 (77%) offered OEND every time syringe services were offered, and 214 (87%) provided naloxone refills as often as participants requested them (Table). SSPs reported offering OEND for a median of 15 of the past 28 days. Only 29 (12%) SSPs entered OEND data directly into an electronic data system. During the preceding 12 months, 237 (96%) of 247 SSPs with OEND programs reported distributing 702,232 naloxone doses, including refills, to 230,506 persons (an average of 3 doses per person). Sixty-two (26%) SSPs reported distributing naloxone to >1,000 persons in the last 12 months; these programs had distributed naloxone to 186,603 laypersons, who represented 81% of all recipients in the past 12 months. Overall, 14 (6%) SSPs reported distribution of ≥10,000 naloxone doses during the last 12 months, accounting for 382,132 naloxone doses, 54% of all doses distributed by SSPs in the past 12 months. These 14 SSPs are located throughout six of the nine census divisions. Seventy-two (29%) SSPs ran out of naloxone or needed to ration their naloxone in the preceding 3 months."

"A 2014 meta-analysis of 75 studies concluded that OPCs have largely fulfilled their initial objectives;³⁹ the implementation of new OPCs in places with high rates of IDU and its associated harms appears to be supported by the existing evidence.³⁹ Methodological caveats notwithstanding, drug use supervision and overdose management have the potential to provide health benefits to at-risk PWID as well as economic advantages to the larger community. The preponderance of the evidence suggests these sites are able to provide sterile equipment, overdose reversal, and linkage to medical care for addiction, in the virtual absence of significant direct risks like increases in drug use, drug sales, or crime. OPCs may represent a novel way of addressing some of the many challenges presented by the overdose crisis, and they could contribute to reduced morbidity and mortality, and improved public health.

"Based on the above considerations, there is a clear need for more rigorous research and evaluation of OPCs. Given the amount and quality of the existing data, it may be prudent to consider the American Medical Association’s recommendation of developing and implementing OPC pilot programs in the United States designed, monitored, and evaluated to generate locality-relevant data to inform policymakers on the feasibility and effectiveness of OPCs in reducing harms and health care costs related to IDU.⁹⁴

"• In 2017, there were 70,237 drug overdose deaths in the United States.

"• The age-adjusted rate of drug overdose deaths in 2017 (21.7 per 100,000) was 9.6% higher than the rate in 2016 (19.8).

"• Adults aged 25–34, 35–44, and 45–54 had higher rates of drug overdose deaths in 2017 than those aged 15–24, 55–64, and 65 and over.

"• West Virginia (57.8 per 100,000), Ohio (46.3), Pennsylvania (44.3), and the District of Columbia (44.0) had the highest age-adjusted drug overdose death rates in 2017.

"• The age-adjusted rate of drug overdose deaths involving synthetic opioids other than methadone (drugs such as fentanyl, fentanyl analogs, and tramadol) increased by 45% between 2016 and 2017, from 6.2 to 9.0 per 100,000."

"Our review found at the individual-level that SCFs were efficacious in reducing drug use related infection and disease transmission, enhancing access to addiction and other health services, and reducing the risk of non-fatal overdoses, and were not associated with a significant increase in drug use. These findings challenge the notion that SCFs may perpetuate substance use and lead to increased use among PWID. With regard to non-fatal overdose, the evidence over the past ten years have been largely been qualitative and would benefit from the use of quantitative methods that help to approximate causality. For example, the use of a propensity score modeling may help to determine the effectiveness of SCFs for individual-level outcomes based on observational or cross-sectional data (Hullsiek and Louis, 2002). Future studies may also want to consider the use of comparison groups or cities to examine the different factors influencing the effectiveness of SCFs. Additionally, we found emerging evidence that SCFs provide PWID with a sense of community that may support their overall wellbeing, thereby increasing their chances of accessing addiction treatment services. However, this evidence came qualitative studies (Rance and Fraser, 2011; Jozaghi and Andresen, 2013; Davidson et al., 2018; Kerman et al., 2020), and provides a future direction for research examining the impact of SCFs. Future quantitative studies may want to include a validated measure of wellbeing and sense of belonging. In particular, longitudinal studies should examine the degree to which a sense of belonging and having a supportive community may play a role in injection cessation and help-seeking behaviors for SCF attenders. At the community level, the evidence shows that SCFs were not associated with an increased rate of drug-related crime, and were linked to a decrease use of other costly public services (e.g. ambulance transport to hospital following an overdose). However, this evidence is still growing and requires additional research that accounts for other cofounding relationships using a longitudinal, inferential research design. Furthermore, we found that SCFs were associated with a reduction in public disorder, including less public disposal of syringes and use in public spaces. Future research should consider the gathering information from multiple sources (e.g. community members, service providers, police services) to examine the impact of SCFs on the public. Finally, there appear to be significant cost-benefits associated with SCFs, yet all of these studies have focused on the benefits related to the reduction of infectious disease transmission and injection-related death. Future studies should consider additional benefits related to the families of SCF attenders and reduction in community costs associated with decrease in public disorder."

"A public health intervention operating for more than 50 years, drug checking services (DCS) allow the public to submit drug samples from unregulated drug markets (i.e. illegal and legal drugs sold through criminal channels) for chemical analysis. DCS emerged across the United States in the late 1960s and early 1970s during the rise of a psychedelic counterculture that championed the use of psychoactive substances to expand consciousness [1, 2]. DCS were later expanded in European settings throughout the 1990s, beginning in the Netherlands, primarily in response to the popularity of dance events and associated use of 3,4-methylenedioxymethamphetamine (MDMA) and other drugs [3, 4]. More recently, DCS have been implemented in Australasia, the Americas and the United Kingdom, often with an emphasis on preventing harms from new psychoactive substances (NPS), including synthetic opioids. A global review of DCS conducted in 2017 identified 31 services operating across 20 countries [5]. Notably, the contamination of unregulated drug markets with fentanyl and the resulting opioid overdose crisis has motivated the recent expansion of DCS in Canada [6] and the United States [7].

"DCS provide people who use drugs (PWUD) with information on the chemical composition of their drug samples to facilitate more informed decision-making [8]. While some analysis methods can be operated by PWUD, DCS typically offer tailored harm reduction advice with the provision of analysis results to PWUD [9]. By aggregating data on the composition of drug samples, DCS provide insight into trends in the unregulated drug supply and inform policymaking and harm reduction activities at the population level [10]. DCS can inform public health alerts [11] when drugs of concern are detected, thus offering potential benefits to the broader community of PWUD and service providers [12]. DCS differ globally in terms of their legality and degree of government support, as well as where and how samples are collected and analysed. Models include mobile services at events, fixed services where samples can be dropped off or mailed and the distribution of analysis methods for personal use, all of which employ a variety of technologies with differing benefits and drawbacks [8, 13, 14]."

"Harm reduction refers to interventions aimed at reducing the negative effects of health behaviors without necessarily extinguishing the problematic health behaviors completely or permanently. Though the harm reduction model as we know it rose in prominence in the 1970s and 1980s in response to infectious diseases such as hepatitis B and HIV [1], its roots extend at least as far back as the early 1900s with narcotic maintenance clinics [2, 3]. In the context of substance use, harm reduction disentangles the notion that drug use equals harm and instead identifies the negative consequences of drug use as the target for intervention rather than drug use itself [4]. Harm reduction strategies include syringe exchange programs, safer injection facilities, overdose prevention programs and policies, and opioid substitution treatment. Harm reduction as an approach stands in opposition to the traditional medical model of addiction which labels any illicit substance use as abuse, as well as to the moral model, which labels drug use as wrong and therefore illegal [5]. While most often applied in treatment for illicit substance use, harm reduction is increasingly used in many different settings, with a variety of populations, and in instances where there is a desire to reduce the negative effects of legal/licit substances, such as in tobacco smoking reduction and e-cigarette substitution programs [6, 7], in programs to reduce the harms associated with alcohol [6, 8, 9], in interventions addressing eating disorders or domestic violence [10], or with people who exchange sex for drugs, money, or material goods [11,12,13]. Nevertheless, harm reduction has not been formally incorporated into the daily repertoires of healthcare providers who aim to improve health behaviors (e.g., physical activity, nutrition) among their patients."

"Studies found that DCS [Drug Consumption Services] influenced intended behaviour and, although less researched, enacted behaviour. Among studies of PWUD [People Who Use Drugs] in party settings (referred to as ‘partygoers’ in studies), greater intention to not use the analysed substance was consistently reported if analysis results were unexpected [33, 35, 40, 42, 43, 45, 48, 52] or ‘questionable’/‘suspicious’ [49–51]. For example, a cross-sectional study from Australia (n = 83) in 2018 found partygoers were more likely to change their intention to use when analysis results were unexpected [odds ratio (OR) = 2.63, 95% confidence interval (CI) = 0.85–8.16] [35], as did two cross-sectional studies from Portugal (n = 310, n = 100) in 2016 and 2014 [40, 43]. Similarly, other intended behaviour changes—such as using less of a substance or seeking more information about it—were more common among partygoers when analysis results from DCS suggested that substances were ‘questionable’/‘suspicious’ [49, 51].

"The proportion of participants reporting analysis results from DCS influenced their drug use varied by population and setting. Among partygoers, 16% of participants in the Netherlands in 1996 [29], 50% in Austria in 1997–99 [37] and 87% in New Zealand (n = 47) in 2018–19 [33] reported that analysis results impacted their drug use. A cross-sectional study in 2017 from the United States among people who inject drugs (n = 125) found 43% changed their behaviour, and this was more likely when fentanyl was detected [adjusted OR (aOR) = 5.08, 95% CI = 2.12–12.17] [22]. Qualitative and longitudinal studies of young PWUD (n = 81) in the United States in 2017 supported this finding, and found that fentanyl detection was associated with positive changes in overdose risk behaviours (i.e. using less, using with others, doing a test shot) [31, 34]. Overall, and in alignment with findings on intended drug use behaviour in response to ‘questionable’/‘suspicious’ analysis results, self-reported behaviour was more likely to change when analysis results detected fentanyl. Beyond individual analysis results, a repeated cross-sectional study from Colombia (n = 1533) in 2013 and 2016 examined the influence of alerts from DCS and found that a majority of partygoers reported an impact on their behaviour [36].

"Only one study linked intended behaviours to observed health outcomes for PWUD accessing DCS. A Canadian cross-sectional study of DCS at a supervised injection site (n = 1411) in 2016–17 found that people who inject drugs were more likely to report the intention to use a smaller quantity than usual when fentanyl was detected by DCS (OR = 9.36, 95% CI = 4.25–20.65) [41]. In turn, those intending to use a smaller quantity were found to be less likely to overdose (OR = 0.41, 95% CI = 0.18–0.89) and be administered naloxone (OR = 0.38, 95% CI = 0.15–0.96).

"Disposal of the analysed substance was observed [24, 26, 27, 32, 35] or self-reported [22, 31, 34] as an outcome of DCS in eight studies. Like other behaviours, disposal was more frequent when analysis results from DCS were unexpected [24, 27, 32, 52]."

"Our findings of a reduction of health problems, are consistent with harm reduction programs for people who inject drugs [19], including needle exchange programs and supervised injection sites, where they are effective in reducing overall negative health consequences. By providing users with high-quality smoking equipment and reducing the dependence on unsafe equipment, the unintended negative consequences, including exploding pipes, burns, and inhaling brillo fragments, are further reduced."

"Psychostimulant-related ED visits increased from 2.2 to 12.9 visits per 10,000 population from 2008 to 2018. This is consistent with studies showing increasing national rates of ED visits, hospitalizations, and deaths from psychostimulant overdose [2, 4, 5, 33]. The increasing use of the ED and other acute care settings is likely linked to rising methamphetamine availability and use [34]. National Forensic Laboratory Information System data found methamphetamine case submissions increased from 2011 to 2019, with methamphetamine as the most frequently reported drug [35]. While psychostimulant-related ED visits were predominantly among Western regions in our study, recent data highlights the emergence of psychostimulant-related overdose deaths in the Midwest and Northeast, suggesting methamphetamine is already a nationwide concern [8, 36]. Increases in cocaine-related ED visits were not significant, potentially due to the exclusion of visits related to opioid and cocaine co-use. Polysubstance use is common in among individuals using cocaine [30], and other studies found rates of fatal overdoses and ED visits for overdose involving cocaine and opioid use are rising [5, 33].

"We found stimulant-related ED visits were less likely to be identified as drug toxicity/withdrawal concerns, underscoring the differences in presentations between stimulant- and opioid-related visits. While the national surge in ED visits and deaths related to opioid overdose is linked to the rise in fentanyl in the drug supply [1, 33, 37], the main drivers of stimulant-related ED visits and overdoses are unclear. Possibilities include increased potency of fluctuating drug supplies [35], contamination or co-use with synthetic opioids like fentanyl [38], or the cumulative effects of chronic stimulant use over time [39]. Further, the term “overdose”, when applied to opioids commonly refers to an acute respiratory event from an episode of use, and this term is problematic when applied to stimulants, as it lacks specificity in capturing the diverse ways in which stimulant toxicity can present [16, 40]. Our data suggest that acute emergency presentations related to stimulant use are more likely due to the cumulative effect of stimulant use over time rather than from a single episode of use. Addressing acute stimulant toxicity may rely more on clinical management of various symptoms, rather than the development of a single reversal agent like naloxone for opioid overdose."

"Between November 30, 2021, and January 31, 2022, 613 individuals used OPC services 5975 times across 2 sites. Most individuals identified as male (78.0%), and 55.3% identified as Hispanic, Latino, or Latina. The mean (range) age was 42.5 (18-71) years. A plurality of individuals (36.9%) reported being street homeless. Fewer than one-fifth of individuals (17.8%) were living in their own rooms or apartments (Table).

"In self-reported data, the drug most commonly used across 2 sites was heroin or fentanyl (73.7%) and the most frequent route of drug administration at the OPC was injection (65.0%). Among all participants, 75.9% reported that they would have used their drugs in a public or semipublic location if OPC services had not been available (Figure).

"During the first 2 months of OPC operation, trained staff responded 125 times to mitigate overdose risk. In response to opioid-involved symptoms of overdose, naloxone was administered 19 times and oxygen 35 times, while respiration or blood oxygen levels were monitored 26 times. In response to stimulant-involved symptoms of overdose (also known as overamping), staff intervened 45 times to provide hydration, cooling, and de-escalation as needed. Emergency medical services responded 5 times, and participants were transported to emergency departments 3 times. No fatal overdoses occurred in OPCs or among individuals transported to hospitals.

"More than half of individuals using OPC services (52.5%) received additional support during their visit. This included, but was not limited to naloxone distribution, counseling, hepatitis C testing, medical care, and holistic services (eg, auricular acupuncture)."

"The percentage of deaths with concomitant involvement of other drugs varied by drug. For example, almost all drug overdose deaths involving alprazolam or diazepam (96%) mentioned involvement of other drugs. In contrast, 50% of the drug overdose deaths involving methamphetamine, and 69% of the drug overdose deaths involving fentanyl mentioned involvement of one or more other specific drugs.

"Table D shows the most frequent concomitant drug mentions for each of the top 10 drugs involved in drug overdose deaths in 2016.

"• Two in five overdose deaths involving cocaine also mentioned fentanyl.

"• Nearly one-third of drug overdose deaths involving fentanyl also mentioned heroin (32%).

"• Alprazolam was mentioned in 26% of the overdose deaths involving hydrocodone, 22% of the deaths involving methadone, and 25% of the deaths involving oxycodone.

"• More than one-third of the overdose deaths involving cocaine also mentioned heroin (34%).

"• More than 20% of the overdose deaths involving methamphetamine also mentioned heroin."

"For the top 15 drugs:

"• Among drug overdose deaths that mentioned at least one specific drug, oxycodone ranked first in 2011,heroin from 2012 through 2015, and fentanyl in 2016.

"• In 2011 and 2012, fentanyl was mentioned in approximately 1,600 drug overdose deaths each year, but mentions increased in 2013 (1,919 deaths),2014 (4,223 deaths), 2015 (8,251 deaths), and 2016(18,335 deaths). In 2016, 29% of all drug overdose deaths mentioned involvement of fentanyl.

"• The number of drug overdose deaths involving heroin increased threefold, from 4,571 deaths or 11% of all drug overdose deaths in 2011 to 15,961 deaths or 25% of all drug overdose deaths in 2016.

"• Throughout the study period, cocaine ranked second or third among the top 15 drugs. From 2014 through 2016, the number of drug overdose deaths involving cocaine nearly doubled from 5,892 to 11,316.

"• The number of drug overdose deaths involving methamphetamine increased 3.6-fold, from 1,887 deaths in 2011 to 6,762 deaths in 2016.

"• The number of drug overdose deaths involving methadone decreased from 4,545 deaths in 2011 to 3,493 deaths in 2016."

"Among the 42,249 opioid-related overdose deaths in 2016, 19,413 involved synthetic opioids, 17,087 involved prescription opioids, and 15,469 involved heroin. Synthetic opioid involvement in these deaths increased significantly from 3007 (14.3% of opioid-related deaths) in 2010 to 19,413 (45.9%) in 2016 (P for trend <.01). Significant increases in synthetic opioid involvement in overdose deaths involving prescription opioids, heroin, and all other illicit or psychotherapeutic drugs were found from 2010 through 2016 (Table).

"Among synthetic opioid–related overdose deaths in 2016, 79.7% involved another drug or alcohol. The most common co-involved substances were another opioid (47.9%), heroin (29.8%), cocaine (21.6%), prescription opioids (20.9%), benzodiazepines (17.0%), alcohol (11.1%), psychostimulants (5.4%), and antidepressants (5.2%) (Figure)."

"Preliminary estimates of U.S. drug overdose deaths exceeded 60,000 in 2016 and were partially driven by a fivefold increase in overdose deaths involving synthetic opioids (excluding methadone), from 3,105 in 2013 to approximately 20,000 in 2016 (1,2). Illicitly manufactured fentanyl, a synthetic opioid 50–100 times more potent than morphine, is primarily responsible for this rapid increase (3,4). In addition, fentanyl analogs such as acetylfentanyl, furanylfentanyl, and carfentanil are being detected increasingly in overdose deaths (5,6) and the illicit opioid drug supply (7). Carfentanil is estimated to be 10,000 times more potent than morphine (8). Estimates of the potency of acetylfentanyl and furanylfentanyl vary but suggest that they are less potent than fentanyl (9). Estimates of relative potency have some uncertainty because illicit fentanyl analog potency has not been evaluated in humans."

"According to the latest report from the United Nations Office on Drugs and Crime (UNODC), an estimated 11.3 million people inject drugs globally, while HIV prevalence is estimated to be 12.6% and hepatitis C prevalence 48.5% among this population. However, while 179 of 206 countries report some injecting drug use, 110 countries and territories worldwide have no data on its prevalence. This data gap highlights the need for more and higher quality data to inform our efforts to implement appropriate harm reduction services that can address public health issues, including HIV and hepatitis C, soft tissue infections, and overdose."

"A key factor underlying the recent increases in rates of heroin use and overdose may be the low cost and high purity of heroin.^45,46 The price in retail purchases has been lower than $600 per pure gram every year since 2001, with costs of $465 in 2012 and $552 in 2002, as compared with $1237 in 1992 and $2690 in 1982.⁴⁵ A recent study showed that each $100 decrease in the price per pure gram of heroin resulted in a 2.9% increase in the number of hospitalizations for heroin overdose.⁴⁶"

"Overarching structural problems also negatively affect access to services. Criminalisation, racism and discrimination against Indigenous, Black and brown people results in low household incomes, unemployment, food insecurity, poor housing and lower levels of education. This, in turn, results not only in worse health outcomes for these communities but also in people from these communities disengaging or actively avoiding health services.

"Women who use drugs are still frequently overlooked despite the complex harms, stigmatisation and structural violence they face. A substantial increase in gender-sensitive services is necessary to appropriately address their needs.

"For all people who use drugs, stigma and discrimination are public health issues creating barriers precisely where more support is needed. Harm reduction services are equipped to address these gaps, as non-judgmental, communitybased service delivery is among the core principles of harm reduction."

"In a large cohort of patients in the US prescribed stable, longterm, higher-dose opioids, undergoing opioid dose tapering was associated with statistically significant risk of subsequent overdose and mental health crisis, including suicidality."

"Few stimulant-specific harm reduction responses are implemented globally. Though NSPs and drug consumption rooms (DCRs) can be accessed by people who use stimulants, existing harm reduction services might not always be adequate for their needs.^[34] For example, stimulant use is associated with more frequent injection than opioids, but limits in NSPs on the number of syringes that can be acquired at any one time represent a particular barrier for those injecting stimulants. Stimulants are also more likely to be smoked or inhaled than opioids, but not all DCRs permit inhalation on premises, and smoking equipment is rarely distributed. However, safer smoking kits for crack cocaine, cocaine paste and ATS are distributed in several territories, including Portugal^[5][35] and harm reduction programmes for people who use non-injectable cocaine derivatives are in place in several countries in Latin America. There have been promising pilot programmes in Asia focusing on people who use methamphetamine, including outreach programmes distributing safer smoking kits, plastic straws, harm reduction education, and access to testing and treatment for HIV, hepatitis C, TB and other sexually transmitted diseases (see page 75 in Asia Chapter 2.1).

"Drug checking (services that enable people to voluntarily get the contents of their drugs analysed) is an important harm reduction intervention for people who use stimulants. These services are implemented in at least nine countries in Western Europe³, are available in the United States, Australia and New Zealand, and are increasingly available in Latin America⁴. Eight countries in Eurasia⁵ have some form of drug checking services through distribution of reagent test kits at music festivals and nightlife settings. Other methods of drug checking include the use of mobile testing equipment to determine the contents of what is sold using tiny samples of the product, allowing for identification of both drugs and contaminants. Though availability of drug checking is growing globally from a low baseline, implementation faces serious legal barriers in many countries as it involves handling controlled substances, and drug checking services often require formal exemption from drug laws in order to operate legally.

"No approved substitution therapy for ATS exists, although pharmacologically-assisted treatment with methylphenidate for ATS users was authorised by the government in Czechia during the COVID-19 pandemic, and in Canada, the British Columbia Centre on Substance Use released interim clinical guidance recommending the prescription of dexamphetamine and methylphenidate to people who use stimulants.^[36]"

"Fentanyl was detected in 56.3% of 5,152 opioid overdose deaths in the 10 states during July–December 2016 (Figure). Among these 2,903 fentanyl-positive deaths, fentanyl was determined to be a cause of death by the medical examiner or coroner in nearly all (97.1%) of the deaths. Northeastern states (Maine, Massachusetts, New Hampshire, and Rhode Island) and Missouri** reported the highest percentages of opioid overdose deaths involving fentanyl (approximately 60%–90%), followed by Midwestern and Southern states (Ohio, West Virginia, and Wisconsin), where approximately 30%–55% of decedents tested positive for fentanyl. New Mexico and Oklahoma reported the lowest percentage of fentanyl-involved deaths (approximately 15%–25%). In contrast, states detecting any fentanyl analogs in >10% of opioid overdose deaths were spread across the Northeast (Maine, 28.6%, New Hampshire, 12.2%), Midwest (Ohio, 26.0%), and South (West Virginia, 20.1%) (Figure) (Table 1).

"Fentanyl analogs were present in 720 (14.0%) opioid overdose deaths, with the most common being carfentanil (389 deaths, 7.6%), furanylfentanyl (182, 3.5%), and acetylfentanyl (147, 2.9%) (Table 1). Fentanyl analogs contributed to death in 535 of the 573 (93.4%) decedents. Cause of death was not available for fentanyl analogs in 147 deaths.†† Five or more deaths involving carfentanil occurred in two states (Ohio and West Virginia), furanylfentanyl in five states (Maine, Massachusetts, Ohio, West Virginia, and Wisconsin), and acetylfentanyl in seven states (Maine, Massachusetts, New Hampshire, New Mexico, Ohio, West Virginia, and Wisconsin). U-47700 was present in 0.8% of deaths and found in five or more deaths only in Ohio, West Virginia, and Wisconsin (Table 1). Demographic characteristics of decedents were similar among overdose deaths involving fentanyl analogs and fentanyl (Table 2). Most were male (71.7% fentanyl and 72.2% fentanyl analogs), non-Hispanic white (81.3% fentanyl and 83.6% fentanyl analogs), and aged 25–44 years (58.4% fentanyl and 60.0% fentanyl analogs) (Table 2).

"Other illicit drugs co-occurred in 57.0% and 51.3% of deaths involving fentanyl and fentanyl analogs, respectively, with cocaine and confirmed or suspected heroin detected in a substantial percentage of deaths (Table 2). Nearly half (45.8%) of deaths involving fentanyl analogs tested positive for two or more analogs or fentanyl, or both. Specifically, 30.9%, 51.1%, and 97.3% of deaths involving carfentanil, furanylfentanyl, and acetylfentanyl, respectively, tested positive for fentanyl or additional fentanyl analogs. Forensic investigations found evidence of injection drug use in 46.8% and 42.1% of overdose deaths involving fentanyl and fentanyl analogs, respectively. Approximately one in five deaths involving fentanyl and fentanyl analogs had no evidence of injection drug use but did have evidence of other routes of administration. Among these deaths, snorting (52.4% fentanyl and 68.8% fentanyl analogs) and ingestion (38.2% fentanyl and 29.7% fentanyl analogs) were most common. Although rare, transdermal administration was found among deaths involving fentanyl (1.2%), likely indicating pharmaceutical fentanyl (Table 2). More than one third of deaths had no evidence of route of administration."

"According to the Medical Expenditure Panel Survey, the annual share of US adults who were prescribed opioids decreased from 12.9 percent in 2014 to 10.3 percent in 2016, and the decrease was concentrated among adults with shorter-term rather than longer-term prescriptions. The decrease was also larger for adults who reported moderate or more severe pain (from 32.8 percent to 25.5 percent) than for those who reported lessthan-moderate pain (from 8.0 percent to 6.6 percent). In the same period opioids were prescribed to 3.75 million fewer adults reporting moderate or more severe pain and 2.20 million fewer adults reporting less-thanmoderate pain. Because the decline in prescribing primarily involved adults who reported moderate or more severe pain, these trends raise questions about whether efforts to decrease opioid prescribing have successfully focused on adults who report less severe pain."

"Crack users often use and share pipes made of various makeshift materials, including broken glass pipes, metal tubing, aluminum cans, car antennas, or glass ginseng bottles, all of which can cause cuts, sores, burns, and blisters in and around the user’s mouth (Faruque et al., 1996; Porter & Bonilla, 1993; Porter, Bonilla, & Drucker, 1997; Shannon, Kerr et al., 2008). A number of recent studies point to nonIDU equipment sharing as possible routes of infectious disease transmission (Fischer, Powis, Firestone-Cruz, Rudzinski, & Rehm, 2008; Macias et al., 2008; McMahon & Tortu, 2003; Roy et al., 2001; Shannon, Rusch et al. 2008: Tortu, Neaigus, McMahon, & Hagen, 2001). In a study of drug users with no history of drug injection, Tortu et al. (2004) found noninjection drug use equipment sharing to be a risk factor for HCV infection, suggesting that HCV transmission may occur through noninjection routes such as oral and intranasal drug use methods. This is particularly concerning given that HCV is almost 30 times more infective that HIV through blood contact (Sulkowski & Thomas, 2003)."

"There was significant advocacy work, including volunteer-run festival-based drug checking services by Pill Testing Australia, in the years leading up to the ACT [Australian Capital Territory] Government 2021 commitment to fund a fixed-site pilot. Upon the ACT Government announcement, a consortium of organisations (Pill Testing Australia, Directions Health Services and Canberra Alliance for Harm Minimisation and Advocacy) submitted a proposal for consideration. Negotiation with the Government included assessment of costs, what services could be provided, staffing and potential locations (see Figure 1 below). The result is a drug checking service in the City Community Health Centre at 1 Moore Street in the Canberra civic area. During the pilot status the service was to operate at specified regular times each week and to be staffed by a variety of professionals. Staff at each shift include one alcohol and other drug counsellor, one primary health nurse, one peer educator, two analytical chemists and a medical practitioner on-call. A senior chemical analyst and medical toxicologist are available on-call to provide feedback on analytical results of clinical concern (novel products for which there may not be community familiarity, potentially hazardous doses, and dangerous mixtures) as well as to assess whether ACT Health should be alerted on any drugs of concern. Directions Director of Service Delivery or CEO provides management oversight."

"Of 6774 total OODs [Opioid Overdose Deaths] (5033 males and 1741 females; 5233 aged <55 years and 1541 aged ≥55 years), alcohol was involved in 2073 OODs (30.6%). Decedent demographic characteristics are presented in Table 1. The model failed to identify any significant trend over time prior to the COVID-19 stay-at-home order nor any significant immediate changes in prevalence level or changes in trends after the implementation or withdrawal of the stay-at-home order (Table 2). The models that incorporated sex, race, ethnicity, and age revealed differences in alcohol involvement in the years prior to the order. The prevalence of alcohol use in OODs was higher for men than women (prevalence ratio [PR] for women, 0.51; 95% CI, 0.40-0.66), for non-Hispanic Black and Hispanic decedents than White decedents (non-Hispanic Black decedents: PR, 1.71; 95% CI, 1.39-2.09; Hispanic decedents: PR, 1.59; 95% CI, 1.22-2.07), and for decedents aged 55 years or older than decedents younger than 55 years (aged ≥55 years: PR, 1.38; 95% CI, 1.13-1.68). There were no significant changes by subgroup associated with COVID-19 policy changes."

"The overall aim of the service is to provide discreet and private advice to people wishing to have drugs tested and as such, CanTEST is free and confidential (Figure 2). Drug checking is offered on a range of drug types, in the form of pills, capsules, powders, crystals and liquids. Some substances such as plant material, blotters or dilute solutions cannot be tested (Panel 1). Drug checking requires a very small scraping/sample of the pill or drug (as little as a few mg) for analysis. The drug checking process can take around 20 minutes if both FTIR and UPLC-PDA analysis is conducted, but can take longer depending on the substance and number of service users waiting. Once the drug checking is complete, the analysts discuss the results with the service user and an alcohol and other drug counsellor and/or peer educator in order to provide service users with information about the results and discuss the risks associated with consuming the substance/s detected, as well as any other concerns service users may have. Service users can also receive non-drug checking health services, such as discussing any health needs, with the service nurse (Figure 3).

"CanTEST nurses are able to provide advice and care across a broad range of health concerns ranging from alcohol and drug assessments and harm reduction through to wound care or sexual health screening. The peer educators and AOD counsellors specialise interpretation of analytical results and advice on drug interactions, strategies to reduce harm associated with drug use and overdose prevention as well as support services available (Panel 2 and 3). The analytical chemists test the substances and provide information about and testing procedure as well as quantitative and qualitative information about the contents and purity of drug samples. Chemists also collect samples for further detailed laboratory analysis off-site at the Australian National University Research School of Chemistry and the ACT Government Analytical Laboratory (ACTGAL).

"During the first three months of operation, the service provider coalition along with ACT Health designed the level and type of public release of results. CanTEST has a protocol for identifying high-risk substances and notifying ACT Health. Upon notification of a potentially high-risk substance, ACT Health convenes relevant key experts to assess the notifications and determine whether risk communications are required. As necessary, public drug alerts or alerts for the health or AOD sector and/or clinical first responders will be prepared. No drug alerts were issued by ACT Health in the first three months of service. Several community notices have been issued by CanTEST on social media to provide targeted information for the community and service clients on particular substances identified. These notices also encourage the community to bring substances in to CanTEST for checking. Alongside the development of risk communications, the CanTEST Drug Early Warning Protocol was developed in conjunction ACT Government, which helps to identify the emergence of drugs of concern and potential changes on the local/regional drug market."

" ACT [Australian Capital Territory] Health provided the funds to meet the budget provided by the service provider. However, a number of increased costs were unanticipated at the time of initial funding. While a certain level of in-kind contribution was expected at the commencement of the pilot, there was more work carried out to design and implement the service than expected. The three organisations providing the service, and the evaluation team, needed to make substantial in-kind contributions of time and expertise, over and above that provided for in original budgets. For example, service management rapidly realised that the promotion of the service was important, but that this was not adequately funded in original planning and budgeting for the service. Further, the service originally budgeted for one analytic chemist, however two were needed to meet the level of service demand. In-kind contribution were essential for sound governance, service design, and implementation. A range of the additional funds expended by Directions Health Services are intended to be covered by ACT Health.

" Finally, the equipment used is not owned by Directions Health Services or ACT Health. The FTIR is leased from Pill Testing Australia and the UPLC was donated by Waters Australia for the duration of the pilot. Costs of either purchasing the equipment or leasing longer term will be considered at the end of the pilot."

"The US Drug Enforcement Administration introduced a schedule change for hydrocodone combination products in October 2014. During the period of our study, October 2013 to July 2016, the percentage of total drug sales represented by prescription opioids in the US doubled from 6.7% to 13.7%, which corresponds to a yearly increase of 4 percentage points in market share. It is not possible to determine the location of buyers from cryptomarket data. We cannot know, for example, if a drug shipped from a vendor in Europe was purchased by a US customer. Nevertheless, cryptomarket users often prefer buying and selling from vendors in the same country; international shipments carry risks of loss, interception by officials, and increased delivery times. A study of cryptomarkets in Australia found that local vendors were often preferred over international counterparts, despite substantially higher prices.²⁴ Another study³⁶ also noted the downward trends of international sales and therefore an increase in domestic sales, and yet another study⁴⁷ found that drug trading through cryptomarket is heavily constrained by offline geography. This preference for domestic trading, combined with the relatively large numbers of US drug vendors trading in cryptomarkets, leads us to presume that most sales of prescription drugs by US vendors will be sold to customers based in the US. Conversely, most transactions generated by non-US vendors will not be sold to US customers.

"The results of our interrupted time series suggest the possibility of a causal relation between the schedule change and the percentage of sales represented by prescription opioids on cryptomarkets. Our analysis cannot rule out other possible causal explanatory factors, but our results are consistent with the possibility that the schedule change might have directly contributed to the changes we observed in the supply of illicit opioids. This possibility is reinforced by the fact that the increased availability and sales of prescription opioids on cryptomarkets in the US after the schedule change was not replicated for cryptomarkets elsewhere.

"Our results are consistent with the possibility of demand led increases. The first increase observed for prescription opioids was for actual sales (fig 1); with increases for active listings, and then all listings, following. One explanation is that cryptomarket vendors perceived an increase in demand and responded by placing more listings for prescription opioids and thereby increasing supply. Our results are also consistent with the iron law of prohibition³⁴ insofar as we identified the largest sales increases for more potent prescription opioids—specifically, oxycodone and fentanyl. Cryptomarkets may function as a supply gateway⁴⁸: customers who initially sought out illicit hydrocodone on cryptomarkets after the schedule change might then have favoured more potent opioids available on the marketplace."

"Over the 15-year study period, 335,123 opioid-related deaths in the United States met our inclusion criteria, with an increase of 345% from 9489 in 2001 (33.3 deaths per million population) to 42,245 in 2016 (130.7 deaths per million population). By 2016, men accounted for 67.5% of all opioid-related deaths (n = 28,496), and the median (interquartile range) age at death was 40 (30-52) years. The proportion of deaths attributable to opioids increased over the study period, rising 292% (from 0.4% [1 in 255] to 1.5% [1 in 65]), and increased steadily over time in each age group studied (P < .001 for all age groups) (Figure). The largest absolute increase between 2001 and 2016 was observed among those aged 25 to 34 years (15.8% increase from 4.2% in 2001 to 20.0% in 2016), followed by those aged 15 to 24 years (9.4% increase from 2.9% to 12.4%). However, the largest relative increases occurred among adults aged 55 to 64 years (754% increase from 0.2% to 1.7%) and those aged 65 years and older (635% increase from 0.01% to 0.07%). Despite the fact that confirmed opioid-related deaths represent a small percentage of all deaths in these older age groups, the absolute number of deaths is moderate. In 2016, 18.4% (7762 of 42,245) of all opioid-related deaths in the United States occurred among those aged 55 years and older.

"In our analysis of the burden of early loss of life from opioid overdose, we found that opioid-related deaths were responsible for 1,681,359 YLL [Years of Life Lost] (5.2 YLL per 1000 population) in the United States in 2016 (Table); however, this varied by age and sex. In particular, when stratified by age, adults aged 25 to 34 years and those aged 35 to 44 years experienced the highest burden from opioid-related deaths (12.9 YLL per 1000 population and 9.9 YLL per 1000 population, respectively). We also found that the burden of opioid-related death was higher among men (1,125,711 YLL; 7.0 YLL per 1000 population) compared with women (555,648 YLL; 3.4 YLL per 1000 population). Importantly, among men aged 25 to 34 years, this rate increased to 18.1 YLL per 1000 population, and the total YLL in this population represented nearly one-quarter of all YLL in the United States in 2016 (411,805 of 1,681,359 [24.5%])."

"Opioids were frequently implicated in overdose deaths involving other pharmaceuticals. They were involved in the majority of deaths involving benzodiazepines (77.2%), antiepileptic and antiparkinsonism drugs (65.5%), antipsychotic and neuroleptic drugs (58.0%), antidepressants (57.6%), other analgesics, antipyretics, and antirheumatics (56.5%), and other psychotropic drugs (54.2%). Among overdose deaths due to psychotherapeutic and central nervous system pharmaceuticals, the proportion involving only a single class of such drugs was highest for opioids (4903/16 651; 29.4%) and lowest for benzodiazepines (239/6497; 3.7%)."

"Results from samples expected to be stimulants were divergent between testing groups. Crystal methamphetamine samples tested using take-home drug checking were reported as fentanyl positive more often than on-site samples (27.6% vs. 5.2%). The same pattern was seen for cocaine samples tested using take-home drug checking (17.2% vs. 1.1%). However, the study was underpowered to evaluate equivalence between these testing groups. A small portion of the test strips (3.8%) yielded an unclear or illegible response. It is unclear what the participants did in these cases, but the inclusion of multiple test strips would have allowed for repeat testing.

"Notably, when the results of take-home drug checking were stratified based on previous experience with fentanyl test strips, there was a trend towards a smaller difference between the results of take-home drug checking and on-site drug checking. For opioids, when only results from those who were using fentanyl test strips for the first time were included, there was a difference of 1.6% between take-home drug checking and on-site drug checking. This difference was reduced to 0.6% when only including samples from those who had self-reported prior experience with using fentanyl test strips. Similar results were seen for crystal methamphetamine (28.9% to 15.2%) and cocaine (28.3% to 7.8%)."

"Based on our findings, distributed fentanyl test strips would be reliable for the testing of samples identified as opioids and should be more widely distributed. There is growing evidence that fentanyl test strips may help prevent overdose when included with other evidence-based strategies (Peiper, 2019). Other informal techniques such as visual inspection of a substance have been applied by PWUD, but may not be effective in substances that contain traces of fentanyl (Peiper et al., 2019). Our study situated fentanyl test strips within sites that provide naloxone kits, drug use supplies such as syringes, supervised consumption of substances, and drug checking using both test strips and more sophisticated technologies. In contrast to the potential for behaviour change from drug checking results, analysis of several cohort studies within Vancouver during the period of increasing fentanyl contamination in late 2016 showed that a majority of PWUD did not change their drug use behaviours nor translate the knowledge of a changing drug supply to an increased risk of overdose (Brar et al., 2020; Moallef et al., 2019). These findings indicate the need for targeted education and harm reduction interventions for those at risk. Distribution of testing supplies provides an opportunity for further engagement. In BC, an expansion of this pilot program, including continuation at sites included in this evaluation, has occurred to distribute fentanyl test strips labelled with instructions for use. Notably, the described positive behaviour changes rely on an individual possessing knowledge around safer ways to use substances, including knowledge around using a small amount (“test dosing”) and using with others or not alone to avoid overdose and allow for naloxone administration. Furthermore, participants identified using at an OPS/SCS as a potential behaviour, which necessitates that these services exist. Our findings around behaviour change in response to a positive fentanyl result underscore the need for comprehensive harm reduction services and education."

"These pilots suggest that community-based drug safety testing can provide, first, engagement with more diverse drug–using communities than event-based testing—in terms of demographics, drugs of choice and risk taking behaviours—and therefore potentially can be more inclusive and impactful across drug–using communities including with marginalised groups. Second, there is the potential benefit of issuing proactive alerts for substances of concern in local drug markets ahead of specific leisure events, as happened with a mis-sold ketamine analogue identified in this study. Third, community testing can benefit from accessing fixed site laboratory facilities (in this case, a university chemistry department) to complement the speed and convenience of mobile laboratories with potentially greater analytical capabilities and trialling of new technological developments.

"These benefits cannot be presumed, however. The community pilots highlighted that service design characteristics and operational variations such as venue, day of week, prior publicity and outreach activities all can influence outcomes. Moving to a neutral central building attracted larger numbers and a greater diversity of service users as well as building trust with new service user groups, with drugs outreach staff further enhancing engagement with more marginalised drug using communities."

"In this nationwide study of commercially insured adolescents, LTOT [Long Term Opioid Therapy] was relatively uncommon. The estimated incidence of LTOT receipt was 3.0 per 1000 adolescents within 3 years of filling an initial opioid prescription. Although adolescents with a wide range of preexisting mental health conditions and treatments were modestly more likely than adolescents without those conditions or treatments to receive an initial opioid, the former had substantially higher rates of subsequent transitioning to LTOT. Associations were strongest for OUD [Opioid Use Disorder], OUD medications, nonbenzodiazepine hypnotics, and other SUDs. The associations were stronger sooner after first opioid receipt for OUD, as well as for anxiety and sleep disorders and their treatments, suggesting that adolescents with these conditions and treatments were more likely to quickly transition into LTOT."

"During 2015, drug overdoses accounted for 52,404 U.S. deaths, including 33,091 (63.1%) that involved an opioid. There has been progress in preventing methadone deaths, and death rates declined by 9.1%. However, rates of deaths involving other opioids, specifically heroin and synthetic opioids other than methadone (likely driven primarily by illicitly manufactured fentanyl) (2,3), increased sharply overall and across many states."

"This term, which we hope can over time be employed as a keyword in the literature, is intended to foreground children under the age of majority and for whom child rights laws apply in harm reduction theory, policy and practice. Child-centred harm reduction draws attention to the specificities of childhood in harm reduction work. Existing theories of harm reduction may need adaptation to the sociology and psychology of childhood, including the interconnected relationship between parent and child, family-centred care, and attention to children’s rights (see Maynard et al., 2019). Some interventions may not be practical, effective or ethical for children (Watson et al., 2015). Research on existing harm reduction services that work with minors – including those that may not strictly be permitted to do so - may place those children or the service at risk. Issues of consent, identity, agency and maturity, as well as the child’s ‘best interests’ may challenge the assumptions and premises upon which ‘low threshold’ harm reduction services are delivered (Barrett, Petersson, & Turner, 2022). Different legal and human rights standards are engaged, from drug laws to family law to child rights. Child protection laws may require duties of reporting that affect harm reduction service provision and research (ibid). In some cases both parent and child can be legal minors, leading to further challenges and complications regarding assessments of best interests. National, regional and international policy frameworks may need renewed scrutiny through a child-centred harm reduction lens (see for example Barrett, 2015).

"The term is not perfect. For example, ‘child’ may conjure the image of only very young children, when the majority of drug use would involve older adolescents. Few seventeen year-olds would refer to themselves as children. However, those under the age of 18 are legal minors in most contexts, and are ‘children’ for the purposes of child rights. Other terms, such as ‘youth harm reduction’ reproduce the problem of age ranges noted above, while ‘adolescent harm reduction’ omits younger children. ‘Adolescence’ can also extend beyond the age of majority. ‘Paediatric harm reduction’ was considered, but implied an overly medical approach.

"The word ‘centred’ is critical. Our view of child-centred harm reduction extends from neonates to adolescents, with all of the challenges and differing capacities and relationships that arise at these stages of development. Centring the child is key and draws our attention also, for example, to dependent children in adult harm reduction work. We believe that ‘child-centred’ focuses on the specificities of childhood in harm reduction and captures a holistic, rights-based, and person-centred approach."

The White House Council of Economic Advisers [CEA] released its analysis of the economic costs of illegal opioid use, related overdoses, and overdose mortality in November 2017. It reported a dramatically higher estimate than previous analyses, largely due to a change in methodology. Previous analyses had used a person's estimated lifetime earnings to place a dollar value on that person's life. According to the CEA, "We diverge from the previous literature by quantifying the costs of opioid-related overdose deaths based on economic valuations of fatality risk reduction, the “value of a statistical life” (VSL)."

The CEA noted that "According to a recent white paper prepared by the U.S. Environmental Protection Agency’s (EPA) Office of Policy for review by the EPA’s Science Advisory Board (U.S. EPA 2016), the EPA’s current guidance calls for using a VSL estimate of $10.1 million (in 2015 dollars), updated from earlier estimates based on inflation, income growth, and assumed income elasticities. Guidance from the U.S. Department of Health and Human Services (HHS) suggests using the range of estimates from Robinson and Hammitt (2016) referenced earlier, ranging from a low of $4.4 million to a high of $14.3 million with a central value of $9.4 million (in 2015 dollars). The central estimates used by these three agencies, DOT, EPA, and HHS, range from a low of $9.4 million (HHS) to a high of $10.1 million (EPA) (in 2015 dollars)."

In addition, the CEA assumed that the number of opioid-related overdoses in the US in 2015 was significantly under-reported. According to its report, "However, recent research has found that opioids are underreported on death certificates. Ruhm (2017) estimates that in 2014, opioid-involved overdose deaths were 24 percent higher than officially reported.⁴ We apply this adjustment to the 2015 data, resulting in an estimated 41,033 overdose deaths involving opioids. We apply this adjustment uniformly over the age distribution of fatalities."

The combination of that assumption with the methodology change resulted in a dramatically higher cost estimate than previous research had shows. According to the CEA, "CEA’s preferred cost estimate of $504.0 billion far exceeds estimates published elsewhere. Table 3 shows the cost estimates from several past studies of the cost of the opioid crisis, along with the ratio of the CEA estimate to each study’s estimate in 2015 dollars. Compared to the recent Florence et al. (2016) study—which estimated the cost of prescription opioid abuse in 2013—CEA’s preferred estimate is more than six times higher, reported in the table’s last column as the ratio of $504.0 billion to $79.9 billion, which is Florence et al.’s estimate adjusted to 2015 dollars. Even CEA’s low total cost estimate of $293.9 billion is 3.7 times higher than Florence et al.’s estimate."

In contrast, the CEA noted that "Among the most recent (and largest) estimates was that produced by Florence et al. (2016), who estimated that prescription opioid overdose, abuse, and dependence in the United States in 2013 cost $78.5 billion. The authors found that 73 percent of this cost was attributed to nonfatal consequences, including healthcare spending, criminal justice costs and lost productivity due to addiction and incarceration. The remaining 27 percent was attributed to fatality costs consisting almost entirely of lost potential earnings." According to the CDC, there were 25,840 deaths in 2013 related to an opioid overdose.

According to the CEA, "We also present cost estimates under three alternative VSL assumptions without age-adjustment: low ($5.4 million), middle ($9.6 million), and high ($13.4 million), values suggested by the U.S. DOT and similar to those used by HHS. For example, our low fatality cost estimate of $221.6 billion is the product of the adjusted number of fatalities, 41,033, and the VSL assumption of $5.4 million. Our fatality cost estimates thus range from a low of $221.6 billion to a high of $549.8 billion."

"Of the 1,000,453 opioid recipients (81.7%) with at least 6 months of follow-up, 51.1% were female, and the median age was 17 years (interquartile range, 16-18 years). Among these adolescents, the estimated cumulative incidence of LTOT [Long Term Opioid Therapy] after first opioid receipt was 1.1 (95% CI, 1.1-1.2) per 1000 recipients within 1 year, 3.0 (95% CI, 2.8-3.1) per 1000 recipients within 3 years, 8.2 (95% CI, 7.8-8.6) per 1000 recipients within 6 years, and 16.1 (95% CI, 14.2-18.0) per 1000 recipients within 10 years. The prevalence of mental health conditions and treatments in this sample is shown in eTable 3 in the Supplement.

"All mental health conditions and treatments were associated with higher rates of transitioning from a first opioid prescription to long-term therapy. Table 2 provides the estimated incidence of LTOT among those with and without mental health conditions and treatments.Adjusted relative increases in the rate of LTOT ranged from a factor of 1.73 for ADHD [Attention-Deficit/Hyperactivity Disorder] (hazard ratio [HR], 1.73; 95% CI, 1.54-1.95) to approximately 4-fold for benzodiazepines (HR, 3.88; 95%CI, 3.39-4.45) and nonopioid SUDs [Substance Use Disorders] (HR, 4.02;95%CI, 3.48-4.65) to 6-fold for non benzodiazepine hypnotics (HR, 6.15; 95%CI, 5.01-7.55) and to nearly 9-fold for OUD [Opioid Use Disorder] (HR, 8.90; 95%CI, 5.85-13.54). In addition, relative to no condition, the number of condition types was also associated with higher LTOT rates (1 condition: HR, 2.21; 95% CI, 2.01-2.43; 2 or more conditions: HR, 4.01; 95% CI, 3.62-4.46).

"Given the strong associations for OUD, we explored other mental health factors and opioid receipt among those with preexisting OUD. These adolescents were more likely than
adolescents without OUD to have other mental health conditions and treatments (eTable 4 in the Supplement). For example, 76.1% of adolescents with OUD had other SUDs, 61.0% had depressive disorders, and 52.6% had received an SSRI [Selective Serotonin Reuptake Inhibitor]. During follow-up, those with preexisting OUD received opioid drugs similar to those received by adolescents without OUD, although the former were more likely to receive certain opioids (eg, oxycodone and tramadol; eTable 5 in the Supplement). Of those with preexisting OUD, 15.5% filled a prescription for OUD medication treatment during follow-up."

"Our research demonstrates that a number of harm reduction-related needs among PWUD [People Who Use Drugs] can be met entirely through web outreach work, while some can only be partially met online. These findings are in line with the existing literature on online platforms bringing new opportunities to harm reduction services provision [18–20]. They also contribute to the growing amount of literature regarding the processes of web outreach work [22, 23] and bring new evidence on how various needs of PWUD are addressed by web outreach services.

"We identified a three-stage process of web outreach work. The process illustrates the benefits that PWUD gain from online harm reduction services provision without face-to-face contact with web outreach workers. An absence of requirement for physical presence of PWUD at a harm reduction organization facilitates greater level of anonymity in comparison with offline harm reduction services provision. In addition, the use of text messages brings greater convenience to PWUD, who do not feel comfortable with discussing drug use-related issues in person. These factors indicate that web outreach work helps to encourage harm reduction behaviors among PWUD who, otherwise, might not seek or have access to brick-and-mortar harm reduction services."

"The opioid epidemic is a public health crisis that is at least partially driven by harms associated with POM [Prescription Opioid Medication] use. States are passing laws allowing use of MC [Medical Cannabis] and patients are using MC, but currently there is little understanding of how this influences POM use or of MC-related harms. This literature review provides preliminary evidence that states with MC laws have experienced reported decreases in POM use, abuse, overdose, and costs. However, existing evidence is limited by significant methodological shortcomings; so, general conclusions are difficult to draw.

"The use of MC as an alternative to POMs for pain management warrants additional empirical attention as a potential harm reduction strategy. NASEM (2017) recommends more clinical trials to elucidate appropriate MC forms, routes of administration, and combination of products for treating pain, but access to MC products to fully evaluate these questions is challenging due to federal regulations. However, the recently funded National Institutes of Health longitudinal study to research the impacts of MC on opioid use is a critical step in the right direction (National Institute of Health, 2017, Williams, 2017). MCs potential as an alternative pain treatment modality to help mitigate the major public health opioid crisis, could be a missed opportunity if data on safety, efficacy, and outcomes are not collected and explored. Health care practitioners, particularly nurses who are charged with ensuring patient comfort, have a vested interest in providing viable alternatives to POMs when appropriate, as part of an integrative approach to pain management, and must advocate for more research to better understand the public health implications and risks and benefits of such alternatives."

"Results
"By 2014, 30 states had a naloxone access and/or Good Samaritan law. States with naloxone access laws or Good Samaritan laws had a 14% (p = 0.033) and 15% (p = 0.050) lower incidence of opioid-overdose mortality, respectively. Both law types exhibit differential association with opioid-overdose mortality by race and age. No significant relationships were observed between any of the examined laws and non-medical opioid use.

"Conclusions
"Laws designed to increase layperson engagement in opioid-overdose reversal were associated with reduced opioid-overdose mortality. We found no evidence that these measures were associated with increased non-medical opioid use."

"While cultural and structural differences continue to divide many substance use treatment and harm reduction services, the needs and goals of people who seek these two services may have always been much less distinctive. For example, many who attend substance use treatment continue to use drugs [5]. Similarly, many who attend harm reduction programs seek to engage in treatment at some points [6]. Indeed, clients of SSPs are approximately five times more likely to engage in treatment and three times more likely to stop using drugs than persons who do not access SSPs [7]. In recent decades, harm reduction and treatment goals have become increasingly blurred with the growing uptake of medications for opioid use disorder (MOUD). In particular, methadone and buprenorphine are used by some with a goal of abstaining from opioid use; for others, MOUD are used to help mitigate withdrawal and overdose risk without abstaining from drug use [8, 9].

"Despite this reality, programs that successfully combine treatment and harm reduction services and principles are often the exception rather than the rule [8, 10, 11]. Yet, the increasing severity of the opioid overdose crisis in North America and the rise in viral and bacterial infections among PWUD [12–14] have led to a recognition of the urgent need to utilize multiple approaches toward the joint goal of reducing drug-related harms [15]. In particular, concerns about the increasingly lethal opioid supply [16] have emphasized the need to use any available evidence-based strategies known to reduce opioid-related overdose mortality. These concerns have encouraged more treatment providers to incorporate harm reduction approaches (e.g., naloxone distribution and overdose education) [17], and harm reduction providers to integrate MOUD as a direct service [18]."

"In the 12 months after a nonfatal overdose, 2040 persons (11%) enrolled in MMT for a median of 5 months (interquartile range, 2 to 9 months), 3022 persons (17%) received buprenorphine for a median of 4 months (interquartile range, 2 to 8 months), and 1099 persons (6%) received naltrexone for a median of 1 month (interquartile range, 1 to 2 months). Among the entire cohort, all-cause mortality was 4.7 deaths (95% CI, 4.4 to 5.0 deaths) per 100 person-years and opioid-related mortality was 2.1 deaths (CI, 1.9 to 2.4 deaths) per 100 person-years. Compared with no MOUD, MMT was associated with decreased all-cause mortality (adjusted hazard ratio [AHR], 0.47 [CI, 0.32 to 0.71]) and opioid-related mortality (AHR, 0.41 [CI, 0.24 to 0.70]). Buprenorphine was associated with decreased all-cause mortality (AHR, 0.63 [CI, 0.46 to 0.87]) and opioid-related mortality (AHR, 0.62 [CI, 0.41 to 0.92]). No associations between naltrexone and all-cause mortality (AHR, 1.44 [CI, 0.84 to 2.46]) or opioid-related mortality (AHR, 1.42 [CI, 0.73 to 2.79]) were identified."

"Our analysis of the characteristics of the 48 Good Samaritan laws found that they differ in the protections they offer to individuals who call for medical assistance for an overdose victim. First, there is variation in whether criminal immunity—an exemption from prosecution—is offered and, if so, for which type of drug offense, such as possessing or delivering drugs in violation of an otherwise applicable drug law. Second, there is variation in when criminal immunity takes effect—the timing can be before an individual would otherwise be arrested and charged as a criminal defendant or after these events but before an individual is prosecuted.

"Finally, because a jurisdiction retains the power to prosecute individuals who do not have criminal immunity, some Good Samaritan laws offer either an affirmative defense at trial or a mitigating factor at sentencing, or both."

"Of the 47 laws that provide criminal immunity to individuals who call for medical assistance, 44 cover drug possession offenses. The other three laws (Iowa’s, South Carolina’s, and Vermont’s) cover both drug possession offenses as well as more serious drug delivery offenses, such as selling, dispensing, or possessing drugs with an intent to sell or dispense.25 The 47 laws vary in the specific drug possession and drug delivery offenses covered by criminal immunity (immunized offenses). At the broadest level, Vermont’s law provides immunity for any drug offense.26 In comparison, the other 46 laws limit immunity to a subset of drug offenses. For example, in regards to immunized drug possession offenses, Alabama’s law limits immunity to misdemeanor drug offenses, such as possession of marijuana for personal use, whereas Illinois’s law includes some felonies, such as possession of less than 3 grams of heroin or morphine.27 In regards to immunized drug delivery offenses, Iowa’s law provides immunity if the drugs were delivered without profit, while South Carolina’s law provides immunity if the drugs were delivered to the overdose victim."

"First, factors related to death investigation might affect rate estimates involving specific drugs. At autopsy, the substances tested for, and circumstances under which tests are performed to determine which drugs are present, might vary by jurisdiction and over time. Second, the percentage of deaths with specific drugs identified on the death certificate varies by jurisdiction and over time. Nationally, 19% (in 2014) and 17% (in 2015) of drug overdose death certificates did not include the specific types of drugs involved. Additionally, the percentage of drug overdose deaths with specific drugs identified on the death certificate varies widely by state, ranging from 47.4% to 99%. Variations in reporting across states prevent comparison of rates between states. Third, improvements in testing and reporting of specific drugs might have contributed to some observed increases in opioid-involved death rates. Fourth, because heroin and morphine are metabolized similarly (9), some heroin deaths might have been misclassified as morphine deaths, resulting in underreporting of heroin deaths. Finally the state-specific analyses of opioid deaths are restricted to 28 states, limiting generalizability."

"There is some evidence that higher prescribed doses increase the risk of drug overdose among individuals treated with opioids for chronic non-cancer pain.⁴ Specifically, the risk of drug-related adverse events is higher among individuals prescribed opioids at doses equal to 50 mg/d or more of morphine. The association of opioid prescribing patterns with risk of over-dose may vary across groups of patients; opioid treatment recommendations for pain are typically specific to particular subgroups such as those with chronic noncancer pain,⁵ cancer-related pain, and substance use disorders.⁶ However, potential subgroup differences in opioid prescribing have not been examined."

"Although the mean annual opioid analgesic overdose mortality rate was lower in states with medical cannabis laws compared with states without such laws, the findings of our secondary analyses deserve further consideration. State-specific characteristics, such as trends in attitudes or health behaviors, may explain variation in medical cannabis laws and opioid analgesic overdose mortality, and we found some evidence that differences in these characteristics contributed to our findings. When including state-specific linear time trends in regression models, which are used to adjust for hard-to-measure confounders that change over time, the association between laws and opioid analgesic overdose mortality weakened. In contrast, we did not find evidence that states that passed medical cannabis laws had different overdose mortality rates in years prior to law passage, providing a temporal link between laws and changes in opioid analgesic overdose mortality. In addition, we did not find evidence that laws were associated with differences in mortality rates for unrelated conditions (heart disease and septicemia), suggesting that differences in opioid analgesic overdose mortality cannot be explained by broader changes in health. In summary, although we found a lower mean annual rate of opioid analgesic mortality in states with medical cannabis laws, a direct causal link cannot be established."

"In alcohol-naïve people, a BAC of 300 to 400 mg/dL (65.1 to 86.8 mmol/L) often causes unconsciousness, and a BAC ≥ 400 mg/dL( 86.8 mmol/L) may be fatal. Sudden death due to respiratory depression or arrhythmias may occur, especially when large quantities are drunk rapidly. This problem is emerging in US colleges but has been known in other countries where it is more common. Other common effects include hypotension and hypoglycemia.

"The effect of a particular BAC varies widely; some chronic drinkers seem unaffected and appear to function normally with a BAC in the 300 to 400 mg/dL (65.1 to 86.8 mmol/L) range, whereas nondrinkers and social drinkers are impaired at a BAC that is inconsequential in chronic drinkers."

"Dunn et al⁴ found that risk of drug-related adverse events among individuals treated for chronic noncancer pain with opioids was increased at opioid doses equivalent to 50 mg/d or more of morphine. Our analyses similarly found that the risk of opioid overdose increased when opioid dose was equivalent to 50 mg/d or more of morphine.

"The present study also extended prior research in several important ways. We used a large, national sample of individuals and focused exclusively on opioid overdose deaths. Because the circumstances that lead to overdose death may vary by the condition for which the opioid is prescribed and substance use disorder status, we conducted analyses for subgroups of patients, including those with cancer, acute pain, and substance use disorders.

"The present study also extended the prior research by exploring a novel risk factor, ie, concurrent prescriptions of regularly scheduled and as-needed opioids. We found that those patients who were simultaneously treated with as-needed and regularly scheduled opioids, a strategy for treating pain exacerbations,^7,8 did not have a statistically significant increased risk of opioid overdose in adjusted models. Recent treatment guidelines have indicated that the long-term safety of this strategy for pain exacerbation has not been established,^5,9 and in the present study we did not find evidence of greater overdose risk associated with this treatment practice after accounting for maximum daily dose and patient characteristics."

"A striking finding from the toxicological data was the relatively small number of subjects in whom morphine only was detected. Most died with more drugs than heroin alone 'on board', with alcohol detected in 45% of subjects and benzodiazepines in just over a quarter. Both of these drugs act as central nervous system depressants and can enhance and prolong the depressant effects of heroin."

"In 2009, 1.2 million emergency department (ED) visits (an increase of 98.4% since 2004) were related to misuse or abuse of pharmaceuticals, compared with 1.0 million ED visits related to use of illicit drugs such as heroin and cocaine ⁽³⁾."

"When significant oral toxicity is recent (eg, < 1 to 2 h), activated charcoal may be given to limit absorption, although this intervention has not been shown to reduce morbidity or mortality. Urinary acidification hastens amphetamine excretion, but it may worsen myoglobin precipitation in the renal tubules and thus is not recommended.

"Benzodiazepines are the preferred initial treatment for CNS excitation, seizures, tachycardia, and hypertension. Lorazepam 2 to 3 mg IV q 5 min titrated to effect may be used. High doses or a continuous infusion may be required. Propofol, with mechanical ventilation, may be required for severe agitation. Hypertension that does not respond to benzodiazepines is treated with nitrates (occasionally nitroprusside or other antihypertensives as needed, depending on the severity of the hypertension. ?-Blockers (eg, metoprolol 2 to 5 mg IV) may be used for severe ventricular arrhythmias or tachycardia.

"Hyperthermia can be life threatening and should be managed aggressively with sedation plus evaporative cooling, ice packs, and maintenance of intravascular volume and urine flow with IV normal saline solution."

"The disadvantage of continuing to describe heroin-related fatalities as 'overdoses' is that it attributes the cause of death solely to heroin and detracts attention from the contribution of other drugs to the cause of death. Heroin users need to be educated about the potentially dangerous practice of concurrent polydrug and heroin use."

"Still, methadone is a potent drug; fatal overdoses have been reported over the years (Baden, 1970; Gardner, 1970; Clark, et al., 1995; Drummer, et al., 1992). As with most other opioids, the primary toxic effect of excessive methadone is respiratory depression and hypoxia, sometimes accompanied by pulmonary edema and/or aspiration pneumonia (White and Irvine, 1999; Harding-Pink, 1993). Among patients in addiction treatment, the largest proportion of methadone-associated deaths have occurred during the drug's induction phase, usually when (1) treatment personnel overestimate a patient's degree of tolerance to opioids, or (2) a patient uses opioids or other central nervous system (CNS) depressant drugs in addition to the prescribed methadone (Karch and Stephens, 2000; Caplehorn, 1998; Harding-Pink, 1991; Davoli, et al., 1993). In fact, when deaths occur during later stages of treatment, other drugs usually are detected at postmortem examination (Appel, et al., 2000). In particular, researchers have called attention to the 'poison cocktail' resulting from the intake of multiple psychotropic drugs (Borron, et al., 2001; Haberman, et al., 1995) such as alcohol, benzodiazepines, and other opioids. When used alone, many of these substances are relatively moderate respiratory depressants; however, when combined with methadone, their additive or synergistic effects can be lethal (Kramer, 2003; Payte and Zweben, 1998).
"It is important to note that postmortem blood concentrations of methadone do not appear to reliably distinguish between individuals who have died from methadone toxicity and those in whom the presence of methadone is purely coincidental (Drummer, 1997; Caplan, et al., 1983)."

"The heart of the challenge is the possibility that things could be different: overdose is a public health problem that can be solved. Unlike many of the other leading causes of death, death from opioid overdose is almost entirely preventable,²¹ and preventable at a low cost.²² Opioids kill by depressing respiration, a slow mode of death that leaves plenty of time for effective medical intervention.²³ Overdose is rapidly reversed by the administration of a safe and inexpensive drug called naloxone. Naloxone strips clean the brain’s opioid receptors and reverses the respiratory depression causing almost immediate withdrawal.²⁴ A growing number of harm reduction organizations in the United States are offering overdose prevention programs that provide injection drug users with resuscitation training and take-home doses of naloxone.²⁵"

"Naloxone distribution to heroin users would be expected to reduce mortality and be cost-effective even under markedly conservative assumptions of use, effectiveness, and cost. Although the absence of randomized trial data on naloxone distribution and reliance on epidemiologic data increase the uncertainty of results, there are few or no scenarios in which naloxone would not be expected to increase QALYs [Quality-Adjusted Life-Years] at a cost much less than the standard threshold for cost-effective health care interventions. Ecological data, in fact, suggest that naloxone distribution may have far greater benefits than those forecast in this model: Reductions in community-level overdose mortality from 37% to 90% have been seen concordant with expanded naloxone distribution in Massachusetts (7), New York City (11), Chicago (10), San Francisco (9, 67, 68), and Scotland (69). Such a result is approached in this model only by maximizing the likelihood of naloxone use or by assuming that naloxone distribution reduces the risk for any overdose. Preliminary data showing that naloxone distribution is associated with empowerment and reduced HIV risk behaviors (70, 71) suggest that future research is needed to test these hypotheses."

"A more prosaic, but no less important, legal barrier to widespread naloxone access is the Food and Drug Administration’s (FDA) classification of naloxone as a prescription drug. This means that public health and harm reduction agencies cannot distribute naloxone like condoms or sterile syringes. Instead, naloxone must be prescribed by a properly licensed health care provider after an individualized evaluation of the patient. Because health care providers have to be involved, naloxone programs must deal with concerns about liability, which among doctors can be powerful even when they are not wellfounded in fact.³¹ The prescription status raises the cost of naloxone distribution and makes it illegal to give naloxone to lay people willing to administer the drug to others suffering an overdose."

"Opioid overdose, a major source of morbidity and mortality worldwide, accounts for half of the mortality among heroin users (1) and is a leading cause of death among adults in the United States (2). Naloxone is a safe, effective, short-acting opioid antagonist for intravenous, intramuscular, subcutaneous, or intranasal administration by medical personnel and—since the late 1990s—laypersons to reverse opioid overdose. (3). Naloxone distribution is endorsed by the American Medical Association, generally integrated into preexisting services, and targeted at anyone at risk for witnessing or having an opioid overdose. Naloxone “kits” are usually wallet-sized packets containing 2 doses of naloxone and other items, including syringes, brochures, simple rescue breathing masks, and brief educational materials about overdose risks and management. As of 2010, a total of 188 U.S. programs distributing naloxone reported training 53,032 persons and recording 10,171 reversals (3)."

"Naloxone distribution was cost-effective in our base-case and all sensitivity analyses, with incremental costs per QALY [Quality-Adjusted Life-Year] gained much less than $50 000 (Table 2 and Appendix Figure 3, available at www.annals.org; see Appendix Table 3, available at www.annals.org, for detailed results of selected analyses). Cost-effectiveness was similar at starting ages of 21, 31, and 41 years; the greater QALY gains of younger persons were roughly matched by higher costs. In scenarios where naloxone administration reduced reliance on EMS, naloxone distribution was cost-saving and dominated (that is, less costly and more effective than) the no-distribution comparison. Cost-effectiveness was somewhat sensitive to the efficacy of lay-administered naloxone and the cost of naloxone but was relatively insensitive to the breadth of naloxone distribution, rates of overdose and other drug-related death, rates of abstinence and relapse, utilities, or the absolute cost of medical services. Naloxone was no longer cost-effective if the relative increase in survival was less than 0.05%, if 1 distributed kit cost more than $4480, or if average emergency care costs (as a proxy for downstream health costs) exceeded $1.1 million. A worst-case scenario, in which the likelihood of an overdose being witnessed, the effectiveness of naloxone, and the likelihood of naloxone being used were minimized and the cost of naloxone was maximized, resulted in an incremental cost of $14,000 per QALY gained. A best-case scenario, in which naloxone distribution reduced the risk for overdose, was dominant."

"In 2011, two thirds of European countries reported that ambulance personnel are trained in naloxone use; in just over half of these countries, naloxone is reported to be one of the standard medications carried in ambulances. Only Italy, Romania and the United Kingdom report the existence of community-based harm-reduction programmes that provide take-home naloxone to opioid users, their family members and carers. Legal barriers remain in place in other European countries, including Estonia, which has the highest drug-related mortality rate among adults (15–64) in the European Union. However, it was demonstrated in the United Kingdom that, with minimal training, healthcare professionals, including drug workers, can increase their knowledge, skills and confidence for managing an opioid overdose and administering naloxone (Mayet at al., 2011)."

In 2010, a kilogram of heroin typically sold for an average wholesale price of $2,527.60 in Pakistan. The 2010 wholesale price for a kilogram of heroin in Afghanistan ranged around $2,266. In Colombia, a kilogram of heroin typically sold for $10,772.3 wholesale in 2010. In the United States in 2010, a kilogram of heroin ranged in price between $33,000-$100,000.

"Three primary scenarios characterize current reports of methadone-associated mortality:

1. "In the context of legitimate patient care, methadone accumulates to harmful serum levels during the first few days of treatment for addiction or pain (that is, the induction period before methadone steady state is achieved or tolerance develops).
2. "Illicitly obtained methadone is used by some individuals who have diminished or no tolerance to opioids and who may use excessive and/or repetitive doses in an attempt to achieve euphoric effects.
3. "Methadone - either licitly administered or illicitly obtained - is used in combination with other CNS depressant agents (such as benzodiazepines, alcohol, or other opioids)."