The Overdose Crisis

According to the US Centers for Disease Control, using provisional data available for analysis on Sept. 4, 2022, in the 12-month period that ended Dec. 31, 2021 at least 107,521 people in the US are reported to have died from drug overdose and toxins in the supply of banned drugs. Note: Those data are incomplete. The CDC predicts that the final number of overdose deaths in the calendar year 2021 will be 108,886.

The CDC further reports, using provisional data available for analysis on August 16, 2022, that in the 12-month period that ended April 30, 2022, at least 103,664 people in the US are reported to have died from drug overdose and toxins in the supply of banned drugs. These provisional data are incomplete and the CDC predicts that the final number of deaths due to overdose and toxins in the supply of banned drugs in that 12-month period will be 108,174.

(Source: Ahmad FB, Cisewski JA, Rossen LM, Sutton P. Provisional drug overdose death counts. National Center for Health Statistics. 2022.)

Also according to the CDC, a total of 93,655 people died from drug overdose and toxins in the supply of banned drugs in the US in calendar year 2020, an increase from 72,151 in 2019.

Related Chapters for Further Research:

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Page last updated Sept. 15, 2022 by Doug McVay, Editor.

1. Principles of Harm Reduction

"Harm reduction incorporates a spectrum of strategies that includes safer use, managed use, abstinence, meeting people who use drugs 'where they’re at,' and addressing conditions of use along with the use itself. Because harm reduction demands that interventions and policies designed to serve people who use drugs reflect specific individual and community needs, there is no universal definition of or formula for implementing harm reduction.

"However, National Harm Reduction Coalition considers the following principles central to harm reduction practice:

"Accepts, for better or worse, that licit and illicit drug use is part of our world and chooses to work to minimize its harmful effects rather than simply ignore or condemn them

"Understands drug use as a complex, multi-faceted phenomenon that encompasses a continuum of behaviors from severe use to total abstinence, and acknowledges that some ways of using drugs are clearly safer than others

"Establishes quality of individual and community life and well-being — not necessarily cessation of all drug use — as the criteria for successful interventions and policies

"Calls for the non-judgmental, non-coercive provision of services and resources to people who use drugs and the communities in which they live in order to assist them in reducing attendant harm

"Ensures that people who use drugs and those with a history of drug use routinely have a real voice in the creation of programs and policies designed to serve them

"Affirms people who use drugs (PWUD) themselves as the primary agents of reducing the harms of their drug use and seeks to empower PWUD to share information and support each other in strategies which meet their actual conditions of use

"Recognizes that the realities of poverty, class, racism, social isolation, past trauma, sex-based discrimination, and other social inequalities affect both people’s vulnerability to and capacity for effectively dealing with drug-related harm

"Does not attempt to minimize or ignore the real and tragic harm and danger that can be associated with illicit drug use"

National Harm Reduction Coalition. Principles of Harm Reduction. Revised 2020. Last accessed Nov. 2, 2021.

2. Drug Overdose Rates In The US, 2019

"The age-adjusted rate for drug overdose deaths in the United States for 2019 was 21.6 per 100,000 standard population (Figure 1, Table). The five states with the highest rates were West Virginia (52.8), Delaware (48.0), District of Columbia (43.2), Ohio (38.3), and Maryland (38.2). The five states with the lowest rates were Nebraska (8.7), South Dakota (10.5), Texas (10.8), North Dakota (11.4), and Iowa (11.5).

"The age-adjusted drug overdose death rate for the non-Hispanic white population in 2019 (26.2 per 100,000 standard population) was 21.3% higher than the national rate (Figure 2). The rate for the non-Hispanic black population (24.8) was 14.8% higher than the national rate. The rate for the non-Hispanic American Indian or Alaska Native population (30.5) was 41.2% higher than the national rate. The rate for the non-Hispanic Asian population (3.3) was 84.7% lower than the national rate. The rate for the non-Hispanic Native Hawaiian or Other Pacific Islander population (9.5) was 56.0% lower than the national rate. The rate for the Hispanic population (12.7) was 41.2% lower than the national rate."

Miniño AM, Hedegaard H. Drug poisoning mortality, by state and by race and ethnicity: United States, 2019. NCHS Health E-Stats. 2021.

3. Overdose Education and Naloxone Distribution (OEND) Within Syringe Service Programs (SSPs)

"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."

Lambdin, B. H., Bluthenthal, R. N., Wenger, L. D., Wheeler, E., Garner, B., Lakosky, P., & Kral, A. H. (2020). Overdose Education and Naloxone Distribution Within Syringe Service Programs - United States, 2019. MMWR. Morbidity and mortality weekly report, 69(33), 1117–1121. doi.org/10.15585/mmwr.mm6933a2

4. Deaths Attributed To Drug Overdose In The US In 2018

"● In 2018, there were 67,367 drug overdose deaths in the United States, a 4.1% decline from 2017 (70,237 deaths).

"● The age-adjusted rate of drug overdose deaths in 2018 (20.7 per 100,000) was 4.6% lower than in 2017 (21.7).

"● For 14 states and the District of Columbia, the drug overdose death rate was lower in 2018 than in 2017.

"● The rate of drug overdose deaths involving synthetic opioids other than methadone (drugs such as fentanyl, fentanyl analogs, and tramadol) increased by 10%, from 9.0 in 2017 to 9.9 in 2018.

"● From 2012 through 2018, the rate of drug overdose deaths involving cocaine more than tripled (from 1.4 to 4.5) and the rate for deaths involving psychostimulants with abuse potential (drugs such as methamphetamine) increased nearly 5-fold (from 0.8 to 3.9)."

Hedegaard H, Miniño AM, Warner M. Drug overdose deaths in the United States, 1999–2018. NCHS Data Brief, no 356. Hyattsville, MD: National Center for Health Statistics. 2020.

5. Conclusion of National Institutes of Health Report to Congress on Overdose Prevention Centers

"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

National Institutes of Health. Report to Congress: Overdose Prevention Centers. Washington, DC: Dept. of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse. Nov. 2021.

6. Drug Overdose Deaths In 2018 - Demographic Details and Changes from 2017

"During 2018, drug overdoses resulted in 67,367 deaths in the United States, a 4.1% decrease from 2017. Among these drug overdose deaths, 46,802 (69.5%) involved an opioid. From 2017 to 2018, opioid-involved death rates decreased 2.0%, from 14.9 per 100,000 population to 14.6 (Table 1); decreases occurred among females; persons aged 15–34 years and 45–54 years; non-Hispanic whites; and in small metro, micropolitan, and noncore areas; and in the Midwest and South regions. Rates during 2017–2018 increased among persons aged ≥65 years, non-Hispanic blacks, and Hispanics, and in the Northeast and the West regions. Rates decreased in 11 states and DC and increased in three states, with the largest relative (percentage) decrease in Iowa (–30.4%) and the largest absolute decrease (difference in rates) in Ohio (–9.6); the largest relative and absolute increase occurred in Missouri (18.8%, 3.1). The highest opioid-involved death rate in 2018 was in West Virginia (42.4 per 100,000).

"Prescription opioid-involved death rates decreased by 13.5% from 2017 to 2018. Rates decreased in males and females, persons aged 15–64 years, non-Hispanic whites, Hispanics, non-Hispanic American Indian/Alaska Natives, and across all urbanization levels. Prescription opioid–involved death rates remained stable in the Northeast and decreased in the Midwest, South, and the West. Seventeen states experienced declines in prescription opioid–involved death rates, with no states experiencing significant increases. The largest relative decrease occurred in Ohio (–40.5%), whereas the largest absolute decrease occurred in West Virginia (–4.1), which also had the highest prescription opioid-involved death rate in 2018 (13.1 per 100,000).

"Heroin-involved death rates decreased 4.1% from 2017 to 2018; reductions occurred among males and females, persons aged 15–34 years, non-Hispanic whites, and in large central metro and large fringe metro areas (Table 2). Rates decreased in the Midwest and increased in the West. Rates decreased in seven states and DC and increased in three states from 2017 to 2018. The largest relative decrease occurred in Kentucky (50.0%), and the largest absolute decrease occurred in DC (–7.1); the largest relative and absolute increase was in Tennessee (18.8%, 0.9). The highest heroin-involved death rate in 2018 was in Vermont (12.5 per 100,000).

"Death rates involving synthetic opioids increased from 9.0 per 100,000 population in 2017 to 9.9 in 2018 and accounted for 67.0% of opioid-involved deaths in 2018. These rates increased from 2017 to 2018 among males and females, persons aged ≥25 years, non-Hispanic whites, non-Hispanic blacks, Hispanics, non-Hispanic Asian/Pacific Islanders, and in large central metro, large fringe metro, medium metro, and small metro counties. Synthetic opioid–involved death rates increased in the Northeast, South and West and remained stable in the Midwest. Rates increased in 10 states and decreased in two states. The largest relative increase occurred in Arizona (92.5%), and the largest absolute increase occurred in Maryland and Missouri (4.4 per 100,000 in both states); the largest relative and absolute decrease was in Ohio (–20.7%, –6.7). The highest synthetic opioid–involved death rate in 2018 occurred in West Virginia (34.0 per 100,000)."

Wilson N, Kariisa M, Seth P, Smith H IV, Davis NL. Drug and Opioid-Involved Overdose Deaths — United States, 2017–2018. MMWR Morb Mortal Wkly Rep 2020;69:290–297.

7. Deaths in 2017 in the US Attributed to Drug Overdose

"• 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."

Hedegaard H, Miniño AM, Warner M. Drug overdose deaths in the United States, 1999–2017. NCHS Data Brief, no 329. Hyattsville, MD: National Center for Health Statistics. 2018.

8. Drug Overdose Deaths in the US Involving Cocaine and Psychostimulants On the Rise

"Deaths involving cocaine and psychostimulants have increased in the United States in recent years; among 70,237 drug overdose deaths in 2017, nearly a third (23,139 [32.9%]) involved cocaine, psychostimulants, or both. From 2016 to 2017, death rates involving cocaine and psychostimulants each increased by approximately one third, and increases occurred across all demographic groups, Census regions, and in several states. In 2017, nearly three fourths of cocaine-involved and roughly one half of psychostimulant-involved overdose deaths, respectively, involved at least one opioid. After initially peaking in 2006, trends in overall cocaine-involved death rates declined through 2012, when they began to rise again. The 2006–2012 decrease paralleled a decline in cocaine supply coupled with an increase in cost. Similar patterns in death rates involving both cocaine and opioids were observed, with increases for cocaine- and synthetic opioid-involved deaths occurring from 2012 to 2017. From 2010 to 2017, increasing rates of deaths involving psychostimulants occurred and persisted even in the absence of opioids."

Kariisa M, Scholl L, Wilson N, Seth P, Hoots B. Drug Overdose Deaths Involving Cocaine and Psychostimulants with Abuse Potential — United States, 2003–2017. MMWR Morb Mortal Wkly Rep 2019;68:388–395.

9. Impact of safe consumption facilities on individual and community outcomes

"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."

Sarah J. Dow-Fleisner, Arielle Lomness, Lucía Woolgar, Impact of safe consumption facilities on individual and community outcomes: A scoping review of the past decade of research, Emerging Trends in Drugs, Addictions, and Health, Volume 2, 2022, 100046, ISSN 2667-1182, doi.org/10.1016/j.etdah.2022.100046.

10. Drug Poisoning Deaths In The US, 2019

"In 2019, 70,630 deaths from the toxic effects of drug poisoning (drug overdose) occurred in the United States (1), a 4.8% increase compared with 2018 and the highest recorded number in recent history."

Miniño AM, Hedegaard H. Drug poisoning mortality, by state and by race and ethnicity: United States, 2019. NCHS Health E-Stats. Centers for Disease Control, National Center for Health Statistics, 2021.

11. Drug Checking Services

"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]."

Maghsoudi N, Tanguay J, Scarfone K, Rammohan I, Ziegler C, Werb D, et al. Drug checking services for people who use drugs: a systematic review. Addiction. 2021;1–13. doi.org/10.1111/add.15734

12. Injection Drug Use Globally and in North America

"Globally, there are nearly 15.6 million people (aged 15–64) who inject drugs (PWID), with an estimated 2.6 million PWID in North America (Degenhardt et al., 2017). Canada and the United States (US) have both seen significant increases in the rate of injection drug use, as well as a rise in the rate of infections and fatal overdose related to injection drug use (Jacka et al., 2020; Levitt et al., 2020). The risk of fatal overdose significantly increases when people inject drugs alone, and may be prevented with timely intervention (i.e. administration of naloxone, an overdose prevention medication) (Colledge et al., 2019). There is also an increased risk of disease transmission (e.g. HIV, hepatitis) and serious infections associated with injecting drugs, which are often related to using unsterile equipment, injecting in unhygienic settings, or rushed injections (Colledge et al., 2019). The increase in injection drug use and the risks associated with using alone, in unhygienic or unsupervised settings necessitate the need for services that support safe injection practices among PWID."

Sarah J. Dow-Fleisner, Arielle Lomness, Lucía Woolgar, Impact of safe consumption facilities on individual and community outcomes: A scoping review of the past decade of research, Emerging Trends in Drugs, Addictions, and Health, Volume 2, 2022, 100046, ISSN 2667-1182, doi.org/10.1016/j.etdah.2022.100046.

13. Harm Reduction Interventions Aim To Reduce The Negative Effects Of Health Behaviors

"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."

Hawk M, Coulter RWS, Egan JE, et al. Harm reduction principles for healthcare settings. Harm Reduct J. 2017;14(1):70. Published 2017 Oct 24. doi:10.1186/s12954-017-0196-4

14. Unprecedented Increases In Overdose Mortality In First Seven Months Of 2020

"By disaggregating monthly trends, we found that unprecedented increases in overdose mortality occurred during the early months of pandemic in the United States. At the peak, overdose deaths in May 2020 were elevated by nearly 60% compared with the previous year, and the first 7 months of 2020 were overall elevated by 35% compared with the same period for 2019. To put this in perspective, if the final values through December 2020 were to be elevated by a similar margin, we would expect a total of 93,000 to 98,000 deaths to eventually be recorded for the year. Values for the remaining 5 months of 2020 have yet to be seen; however, it is very likely that 2020 will represent the largest year-to-year increase in overdose mortality in recent history for the United States."

Joseph Friedman , Samir Akre , “COVID-19 and the Drug Overdose Crisis: Uncovering the Deadliest Months in the United States, January‒July 2020”, American Journal of Public Health 111, no. 7 (July 1, 2021): pp. 1284-1291.

15. Drug Consumption Services: Effects on Drug Use

"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]."

Maghsoudi N, Tanguay J, Scarfone K, Rammohan I, Ziegler C, Werb D, et al. Drug checking services for people who use drugs: a systematic review. Addiction. 2021;1–13. doi.org/10.1111/add.15734

16. Provision of Safe Smoking Equipment Reduces Negative Health Consequences

"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."

Prangnell, A., Dong, H., Daly, P. et al. Declining rates of health problems associated with crack smoking during the expansion of crack pipe distribution in Vancouver, Canada. BMC Public Health 17, 163 (2017). doi.org/10.1186/s12889-017-4099-9.

17. Clean Pipe Distribution and Reduced Health Concerns

"We observed that the increase in crack pipe distribution services coincided with a corresponding increase in the uptake of crack pipes obtained through health service points only. Further, rates of reporting health problems associated with crack smoking declined significantly after the crack pipe distribution program was implemented. In the multivariable analysis, compared to obtaining crack pipes through other non-health service sources only, obtaining pipes through health service points only was significantly and negatively associated with reporting health problems from smoking crack. These findings suggest that the recent expansion of crack pipe distributions in this setting has likely served to reduce health problems experienced by crack smokers, achieving the desired outcome of the program.

"While crack users are obtaining their safe crack smoking equipment from health service points, they may also be exposed to education around safer smoking techniques and practices, by being in direct contact with service providers in the community. This may also have the benefit of exposing drug users with no connections to health care to available providers in their area [27]. A previous study of an outreach-based crack smoking kit distribution service indicated that unsafe smoking practices such as using Brillo pads and sharing crack paraphernalia remained prevalent, even after the implementation of the service [10], suggesting the importance of placing such service in a continuum of broader health service system and ensuring the availability of smoking kits to reduce risky smoking behaviours."

Prangnell, A., Dong, H., Daly, P. et al. Declining rates of health problems associated with crack smoking during the expansion of crack pipe distribution in Vancouver, Canada. BMC Public Health 17, 163 (2017). doi.org/10.1186/s12889-017-4099-9.

18. Emergency Department Visits and Trends Related to Cocaine, Psychostimulants, and Opioids in the United States, 2008–2018

"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."

Suen, L.W., Davy-Mendez, T., LeSaint, K.T. et al. Emergency department visits and trends related to cocaine, psychostimulants, and opioids in the United States, 2008–2018. BMC Emerg Med 22, 19 (2022). doi.org/10.1186/s12873-022-00573-0.

19. Opioid-Involved Overdose Deaths in the US 2017-2018

"Of the 70,237 drug overdose deaths in the United States in 2017, approximately two thirds (47,600) involved an opioid (1). In recent years, increases in opioid-involved overdose deaths have been driven primarily by deaths involving synthetic opioids other than methadone (hereafter referred to as synthetic opioids) (1). CDC analyzed changes in age-adjusted death rates from 2017 to 2018 involving all opioids and opioid subcategories* by demographic characteristics, county urbanization levels, U.S. Census region, and state. During 2018, a total of 67,367 drug overdose deaths occurred in the United States, a 4.1% decline from 2017; 46,802 (69.5%) involved an opioid (2). From 2017 to 2018, deaths involving all opioids, prescription opioids, and heroin decreased 2%, 13.5%, and 4.1%, respectively. However, deaths involving synthetic opioids increased 10%, likely driven by illicitly manufactured fentanyl (IMF), including fentanyl analogs (1,3)."

Wilson N, Kariisa M, Seth P, Smith H 4th, Davis NL. Drug and Opioid-Involved Overdose Deaths - United States, 2017-2018. MMWR Morb Mortal Wkly Rep. 2020;69(11):290‐297. Centers for Disease Control. Published 2020 Mar 20.

20. Emergency department visits and trends related to cocaine in the US, 2008–2018

"Cocaine-related ED visits were predominately made by individuals who were older, male, and Black. Potential reasons include differences in drug supply, disparities in comorbidities, socioeconomic disadvantage, and other factors related to structural racism that can affect health and healthcare access [41, 42]. Complications from cocaine use are disproportionately higher in Black communities, where rates of cocaine-related deaths are comparable to the rates of opioid-related deaths in white individuals [41]. Yet cocaine-related harms have been understudied in recent years. This is alarming given overdose deaths in Black individuals are rising faster compared to whites [43, 44], and in our study, cocainerelated visits were as likely to result in admission as opioid-related visits. As attention toward the rising epidemic of stimulant-related deaths increases, interventions addressing stimulant use must address racial equity and pay attention to both cocaine and psychostimulant use to avoid further exacerbating racial and economic disparities [45]."

Suen, L.W., Davy-Mendez, T., LeSaint, K.T. et al. Emergency department visits and trends related to cocaine, psychostimulants, and opioids in the United States, 2008–2018. BMC Emerg Med 22, 19 (2022). doi.org/10.1186/s12873-022-00573-0.

21. Data on First Two Months of Operation of First Legally Authorized Supervised Consumption Sites in the US

"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)."

Harocopos A, Gibson BE, Saha N, et al. First 2 Months of Operation at First Publicly Recognized Overdose Prevention Centers in US. JAMA Network Open. 2022;5(7):e2222149. doi:10.1001/jamanetworkopen.2022.22149

22. Misinformation, Stigma, And Criminalization Prevent People From Seeking Help When Needed

"A number of barriers, both social and systemic, prevent people with OUD from accessing the life-saving medications they need. Making headway against the opioid crisis will require addressing barriers related to stigma and discrimination, inadequate professional education, overly stringent regulatory and legal policies, and the fragmented systems of care delivery and financing for OUD.

"The stigmatization of people with OUD is a major barrier to treatment seeking and retention. Social stigma from the general public is largely rooted in the misconception that addiction is simply the result of moral failing or a lack of self-discipline that is worthy of blame, rather than a chronic brain disease that requires medical treatment. Evidence demonstrates that social stigma contributes to public acceptance of discriminatory measures against people with OUD and to the public’s willingness to accept more punitive and less evidence-based policies for confronting the epidemic. Patients with OUD also report stigmatizing attitudes from some professionals within and beyond the health sector, further undercutting access to evidence-based treatment. The medications, particularly the agonist medications, used to treat OUD are also stigmatized. This can manifest in providers’ unwillingness to prescribe medications due to concerns about misuse and diversion and in the public’s mistaken belief that taking medication is “just substituting one drug for another.” Importantly, the rate of diversion is lower than for other prescribed medications, and it declines as the availability of medications to treat OUD increases.

"Despite the mounting crisis, the health care workforce in the United States does not receive adequate, standardized education about OUD and the evidence base for medication-based treatment. This has created a shortage of providers who are knowledgeable, confident, and willing to provide medications to patients. Many rural areas are being overwhelmed by the opioid epidemic and have very few, if any, trained and licensed providers who can prescribe the medications. Misinformation and a lack of knowledge about OUD and its medications are also prevalent across the law enforcement and criminal justice systems."

National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Committee on Medication-Assisted Treatment for Opioid Use Disorder; Mancher M, Leshner AI, editors. Medications for Opioid Use Disorder Save Lives. Washington (DC): National Academies Press (US); March 30, 2019.

23. Drugs Most Frequently Involved in Drug Overdose Deaths in the US 2011–2016

"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."

Hedegaard H, Bastian BA, Trinidad JP, Spencer M, Warner M. Drugs most frequently involved in drug overdose deaths: United States, 2011–2016. National Vital Statistics Reports; vol 67 no 9. Hyattsville, MD: National Center for Health Statistics. 2018.

24. Drugs Most Frequently Mentioned in Overdose Deaths in the US 2011-2016

"The number of drug overdose deaths per year increased 54%, from 41,340 deaths in 2011 to 63,632 deaths in 2016 (Table A). From the literal text analysis, the percentage of drug overdose deaths mentioning at least one specific drug or substance increased from 73% of the deaths in 2011 to 85% of the deaths in 2016. The percentage of drug overdose deaths that mentioned only a drug class but not a specific drug or substance declined from 5.1% of deaths in 2011 to 2.5% in 2016. Review of the literal text for these deaths indicated that the deaths that mentioned only a drug class frequently involved either an opioid or an opiate (ranging from 54% in 2015 to 60% in 2016). The percentage of deaths that did not mention a specific drug or substance or a drug class declined from 22% of drug overdose deaths in 2011 to 13% in 2016."

Hedegaard H, Bastian BA, Trinidad JP, Spencer M, Warner M. Drugs most frequently involved in drug overdose deaths: United States, 2011–2016. National Vital Statistics Reports; vol 67 no 9. Hyattsville, MD: National Center for Health Statistics. 2018.

25. Drugs Most Frequently Involved in Drug Overdose Deaths in the US 2011–2016

"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."

Hedegaard H, Bastian BA, Trinidad JP, Spencer M, Warner M. Drugs most frequently involved in drug overdose deaths: United States, 2011–2016. National Vital Statistics Reports; vol 67 no 9. Hyattsville, MD: National Center for Health Statistics. 2018.

26. Supervised Inhalation Facilities

"Supervised inhalation rooms (SIR) have the potential to minimise the aforementioned barriers to care and harms associated with crack cocaine smoking [12,21]. Modelled after supervised injection facilities, SIRs are regulated environments in which people can smoke pre-obtained drugs with sterile equipment under the supervision of nurses or other trained staff [22]. These facilities aim to reduce high-risk drug use practices and blood-borne infections, increase contact between PWUD and health and social services, and improve public order through reductions in public drug use [23]. To date, SIRs have been implemented in seven countries: Canada, Germany, Luxembourg, Netherlands, Switzerland, Spain and France [24–26]. In contrast with the significant evidence of the health and community benefits of supervised injection sites, rigorous evaluation of the specific outcomes of SIRs is lacking [24,27]. However, it is plausible that many of the demonstrated health benefits associated with supervised injection sites could extend to SIRs, with available evidence suggesting that SIRs have potential to improve public order, connect PWUD with health and social services, and reduce drug-related harms [11,25]."

Cortina, S., Kennedy, M. C., Dong, H., Fairbairn, N., Hayashi, K., Milloy, M. J., & Kerr, T. (2018). Willingness to use an in-hospital supervised inhalation room among people who smoke crack cocaine in Vancouver, Canada. Drug and alcohol review, 37(5), 645–652. doi.org/10.1111/dar.12815

27. Changes in Synthetic Opioid Involvement in Overdose Deaths in the US and Involvement of Other Drugs in Combination

"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)."

Jones CM, Einstein EB, Compton WM. Changes in Synthetic Opioid Involvement in Drug Overdose Deaths in the United States, 2010-2016. JAMA. 2018;319(17):1819–1821.

28. Growth of Fentanyl Related Deaths in the US

"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."

Julie K. O’Donnell, PhD; John Halpin, MD; Christine L. Mattson, PhD; Bruce A. Goldberger, PhD; R. Matthew Gladden, PhD. Deaths Involving Fentanyl, Fentanyl Analogs, and U-47700 — 10 States, July–December 2016. Morbidity and Mortality Weekly Report. Vol. 66. Centers for Disease Control. October 27, 2017.

29. Rhode Island Becomes First State in US to Approve Legal Establishment of Overdose Prevention Sites

"Gov. Dan McKee has signed legislation introduced by Majority Floor Manager John G. Edwards (D-Dist. 70, Tiverton, Portsmouth) and Sen. Joshua Miller (D-Dist. 28, Cranston, Providence) that authorizes a two-year pilot program to prevent drug overdoses through the establishment of harm reduction centers, which are a community-based resource for health screening, disease prevention and recovery assistance where persons may safely consume pre-obtained substances.

"The law (2021-H 5245A, 2021-S 0016B) authorizes facilities where people may safely consume those substances under the supervision of health care professionals. It requires the approval of the city or town council of any municipality where the center would operate."

State of Rhode Island General Assembly. Harm reduction center pilot program to combat overdose deaths becomes law. News Release, July 7, 2021.

30. Quality Data Needed To Inform Efforts For Implementation Of Appropriate Services

"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."

Harm Reduction International (2020). Global State of Harm Reduction 2020. London: Harm Reduction International.

31. New York City Opens First Legally Authorized Safe Consumption Sites In US

On November 30, 2021, the Office of the Mayor of the City of New York announced that "the first publicly recognized Overdose Prevention Center (OPC) services in the nation have commenced in New York City. OPCs are an extension of existing harm reduction services and will be co-located with previously established syringe service providers."

According to the release:
"OPCs, also referred to as supervised consumption sites or facilities, are safe places where people who use drugs can receive medical care and be connected to treatment and social services. OPC services are proven to prevent overdose deaths, and are in use in jurisdictions around the world. There has never been an overdose death in any OPC. A Health Department feasibility study found that OPCs in New York City would save up to 130 lives a year.

"Additionally, OPCs are a benefit to their surrounding communities, reducing public drug use and syringe litter. Other places with OPCs have not seen an increase in crime, even over many years.

"OPCs will be in communities based on health need and depth of program experience. A host of City agencies will run joint operations focused on addressing street conditions across the City, and we will include an increased focus on the areas surrounding the OPCs as they open."

Office of the Mayor of the City of New York, "Mayor de Blasio Announces Nation's First Overdose Prevention Center Services to Open in New York City," City of New York, NY, Nov. 30, 2021.

32. Key Factors Underlying Increasing Rates of Heroin Use and Opioid Overdose in the US

"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"

Wilson M. Compton, M.D., M.P.E., Christopher M. Jones, Pharm.D., M.P.H., and Grant T. Baldwin, Ph.D., M.P.H. Relationship between Nonmedical Prescription-Opioid Use and Heroin Use. N Engl J Med 2016; 374:154-163. January 14, 2016. DOI: 10.1056/NEJMra1508490.

33. Harm Reduction Implementation Needs To Improve

"Harm reduction implementation has worsened since our last report in 2018, after having stalled since 2014. The number of countries where needle and syringe programmes (NSPs) remained level at 86, and the number of countries where opioid agonist therapy (OAT) is available decreased by two to 84. There are also large differences between the regions in terms of harm reduction implementation: while NSPs and OAT are available in most countries in Eurasia, North America and Western Europe, these core harm reduction interventions are severely lacking in the majority of countries in other regions. An unfavourable drug policy environment hinders harm reduction service implementation in many countries across Asia, Latin America and the Caribbean, the Middle East and North Africa (MENA), and sub-Saharan Africa. Several countries have adopted more punitive drug strategies since the Global State of Harm Reduction last reported in 2018, including Bangladesh, Brazil and Sri Lanka.

"Even where harm reduction services are available, there is often insufficient coverage and quality, or a lack of access to these services. Significant geographical gaps and an uneven distribution of services exist even in countries pioneering harm reduction or in countries where harm reduction has been available for decades. Rural communities are particularly underserved in many countries and regions. In addition to the geographical gaps in coverage, there are sub-groups of people who use drugs that experience barriers in access because harm reduction services aren’t tailored to their unique needs. These groups include women who use drugs, men who have sex with men, people who use stimulants and/or non-injecting methods, and people experiencing homelessness."

Harm Reduction International (2020). Global State of Harm Reduction 2020. London: Harm Reduction International.

34. Structural Barriers To Effective Harm Reduction Implementation

"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."

Harm Reduction International (2020). Global State of Harm Reduction 2020. London: Harm Reduction International.

35. Needle And Syringe Service Programs Worldwide

"As of 2020, 86 countries globally have at least one NSP [Needle and Syringe Program], though on the ground this has meant NSP closures and openings in several countries since 2018. Algeria opened NSPs in the Middle East and North Africa region, but in Palestine and Jordan, NSPs stopped completely; in Asia, NSPs closed in Mongolia; in sub-Saharan Africa, NSPs opened in Benin, Nigeria and Sierra Leone, while in Uganda NSPs ceased to operate. Eurasia, North America, Oceania and Western Europe remained the regions where almost all countries with reported injecting drug use implemented NSPs.[1]

"The availability of NSPs, however, does not ensure adequate coverage and accessibility. There is a large disparity in NSP implementation globally. While NSPs in Australia distribute almost 700 syringes per person who injects drugs per year, in Benin in sub-Saharan Africa, only ten syringes are given in a month to a client visiting the programme.2 In Macau, Asia, the number of NSPs has decreased since 2018, and only one NSP is still open. While NSPs are available in the majority of countries in Eurasia, there are several countries where coverage is very limited as services are implemented solely on a volunteer basis.[3,4] New estimates from India suggest that just 35 syringes (down from 250) are distributed per person who injects drugs, despite an increase in the number of NSP sites in the country. Coverage could also vary within a country. In Western Europe, for example, the coverage of NSPs in urban areas is sufficient and there are no major barriers in access, but rural areas have less coverage in many countries (e.g. Austria, Belgium, the Netherlands, Germany and Portugal).[5–9] Rural populations are also underserved in both the United States and Canada, and an uneven geographical distribution of NSPs is a problem in Australia and New Zealand.[10,11]"

Harm Reduction International (2020). Global State of Harm Reduction 2020. London: Harm Reduction International.

36. Association of Dose Tapering With Overdose or Mental Health Crisis Among Patients Prescribed Long-term Opioids

"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."

Agnoli A, Xing G, Tancredi DJ, Magnan E, Jerant A, Fenton JJ. Association of Dose Tapering With Overdose or Mental Health Crisis Among Patients Prescribed Long-term Opioids. JAMA. 2021;326(5):411–419. doi:10.1001/jama.2021.11013

37. Stigma And Discrimination Hinder Access To Harm Reduction Services

"Stigma and discrimination against people who inject drugs continue to exist and hinder service access in all contexts,[12–15] [16] affecting organisations implementing NSPs. In South Africa, for example, one NSP was closed in 2018 due to concerns of insufficient stakeholder consultation and the systems available for waste management.[17] Though the service was reinstated in late June 2020, programme staff have yet to reach the previous cohort of clients that had accessed the service before its closure.[18]

"In addition to geographical gaps and stigmatisation of people who inject drugs, there are groups of people who inject drugs that experience barriers to access. The lack of appropriate, gender-specific programmes for women who use drugs is a recurring issue throughout most regions. Furthermore, the needs of Indigenous people are not appropriately met in Oceania,[10,11] and there are reports of migrants who inject drugs facing barriers to accessing harm reduction services in Western Europe.[6,9,19] NSP provision for people who use stimulants is suboptimal in many regions despite the risks involved. In Western Europe, for example, stimulant injecting has been associated with local HIV outbreaks in five countries in the past five years.[20–22]"

Harm Reduction International (2020). Global State of Harm Reduction 2020. London: Harm Reduction International.

38. Few Stimulant-Specific Harm Reduction Responses Implemented Globally

"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]"

Harm Reduction International (2020). Global State of Harm Reduction 2020. London: Harm Reduction International.

39. Successful Operation of an Unsanctioned Supervised Consumption Site in the US

"In total, there were 10,514 injections and 33 opioid-involved overdoses over 5 years, all of which were reversed by naloxone administered by trained staff (Table 1). No person who overdosed was transferred to an outside medical institution, and there were no deaths. The number of overdoses increased over the years of operation, due partially to the number of injections increasing over the same period of time (Fig. S1 in the Supplementary Appendix). The types of drugs used at the site changed over the 5 years of operation, with a steady increase in the proportion of injections involving the combination of opioids and stimulants, from 5% in 2014 to 60% in 2019 (Fig. S2).

"Although this evaluation was limited to one city and one site that is unsanctioned, and therefore the findings cannot be generalized, our results suggest that implementing sanctioned safe consumption sites in the United States could reduce mortality from opioid-involved overdose. Sanctioning sites could allow persons to link to other medical and social services, including treatment for substance use, and facilitate rigorous evaluation of their implementation and effect on reducing problems such as public injection of drugs and improperly discarded syringes."

Kral, Alex H., Lambdin, Barrot H., Wenger, Lynn D., Davidson, Pete J. Evaluation of an Unsanctioned Safe Consumption Site in the United States. New England Journal of Medicine. July 8, 2020. 10.1056/NEJMc2015435.

40. Involvement of Fentanyl in Overdose Deaths in the US

"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."

Julie K. O’Donnell, PhD; John Halpin, MD; Christine L. Mattson, PhD; Bruce A. Goldberger, PhD; R. Matthew Gladden, PhD. Deaths Involving Fentanyl, Fentanyl Analogs, and U-47700 — 10 States, July–December 2016. Morbidity and Mortality Weekly Report. Vol. 66. Centers for Disease Control. October 27, 2017.

41. Reductions in Opioid Prescribing for People with Severe Pain

"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."

Mark Olfson, Shuai Wang, Melanie M. Wall, and Carlos Blanco. Trends In Opioid Prescribing And Self-Reported Pain Among US Adults. Health Affairs 2020 39:1, 146-154.

42. Pipe Sharing and Disease Risk

"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)."

Ivsins, A., Roth, E., Benoit, C., & Fischer, B. (2013). Crack Pipe Sharing in Context: How Sociostructural Factors Shape Risk Practices among Noninjection Drug Users. Contemporary Drug Problems, 40(4), 481–503. doi.org/10.1177/009145091304000403

43. Rising Levels Of Stimulant Overdose Mortality In The US

"Of the 1,220,143 deaths with involved drugs listed on the death certificate, 130 560 (10.7% of all decedents) were found to have stimulants listed. Among stimulant-involved deaths, 93,689 decedents (71.8%) were men, the median (interquartile range) age was 45 (34-54) years, and 98,635 (75.5%) were White (Table). Of these, 120,803 certificates (92.5%) listed only illicit stimulants, 5544 (4.2%) listed only medical stimulants, and 3524 listed both types (2.7%). Among illicit stimulants, there were 77,013 deaths (61.9%) involving cocaine, 49,602 deaths (39.9%) involving methamphetamine, and 817 deaths (0.7%) involving 3,4-methylenedioxymethamphetamine. Among medical stimulants, there were 8240 deaths (90.9%) involving amphetamine, 295 deaths (0.3%) involving methylphenidate, and 615 deaths (0.7%) involving pseudoephedrine. Among all 3 stimulant groups, the proportion of deaths that also involved opioids was substantial; concomittant use of benzodiazepines and antidepressants was also not uncommon.

"Stimulant mortality has risen rapidly since 2010 (Figure). The mortality rate involving all stimulants rose from 2.913 deaths per 100,000 population in 2010 to 9.690 in 2017. Mortality rates increased among all medical stimulants (ARR, 1.226; 95% CI, 1.202-1.250), amphetamine (ARR, 1.118; 95% CI, 1.082-1.155), cocaine (ARR, 1.234;95% CI, 1.222-1.245), and methamphetamine (ARR, 1.278; 95% CI, 1.261-1.295)."

Black JC, Bau GE, Iwanicki JL, Dart RC. Association of Medical Stimulants With Mortality in the US From 2010 to 2017. JAMA Intern Med. Published online February 01, 2021.

44. Association of Dose Tapering With Overdose or Mental Health Crisis

"In the current study, tapering was associated with absolute differences in rates of overdose or mental health crisis events of approximately 3 to 4 events per 100 person-years compared with nontapering. These findings suggest that adverse events associated with tapering may be relatively common and support HHS recommendations for more gradual dose reductions when feasible and careful monitoring for withdrawal, substance use, and psychological distress.9

"Previous research has examined adverse outcomes associated with discontinuing long-term opioids.10-14 This analysis demonstrated associations between adverse outcomes and a more sensitive indicator of opioid dose reduction (≥15% from baseline). The associations persisted in sensitivity analyses that excluded patients who discontinued opioids during follow-up, suggesting that the observed associations between tapering and overdose and mental health crisis are not entirely explained by events occurring in patients discontinuing opioids. Additionally, all categories of maximum dose reduction velocity demonstrated higher relative rates of outcomes compared with the lowest (<10% per month), suggesting that risks were not confined to patients undergoing rapid tapering.

"Patients undergoing tapering from higher baseline opioid doses had higher associated risk for the study outcomes compared with patients undergoing tapering from lower baseline doses. Due to physiologic opioid tolerance,27 patients receiving higher doses may have heightened intolerance of opioid dose disruption, potentially warranting additional caution in patients tapering from higher doses."

Agnoli A, Xing G, Tancredi DJ, Magnan E, Jerant A, Fenton JJ. Association of Dose Tapering With Overdose or Mental Health Crisis Among Patients Prescribed Long-term Opioids. JAMA. 2021;326(5):411–419. doi:10.1001/jama.2021.11013

45. Opioid Use for Pain Management

"'Opioid' is a generic term for natural or synthetic substances that bind to specific opioid receptors in the central nervous system (CNS), producing an agonist action. Opioids are also called narcotics—a term originally used to refer to any psychoactive substance that induces sleep. Opioids have both analgesic and sleep-inducing effects, but the two effects are distinct from each other.

"Some opioids used for analgesia have both agonist and antagonist actions. Potential for abuse among those with a known history of abuse or addiction may be lower with agonist-antagonists than with pure agonists, but agonist-antagonist drugs have a ceiling effect for analgesia and induce a withdrawal syndrome in patients already physically dependent on opioids.

"In general, acute pain is best treated with short-acting (immediate-release) pure agonist drugs at the lowest effective dosage possible and for a short time; Centers for Disease Control and Prevention (CDC) guidelines recommend 3 to 7 days (1 ). Clinicians should reevaluate patients before re-prescribing opioids for acute pain syndromes. For acute pain, using opioids at higher doses and/or for a longer time increases the risk of needing long-term opioid therapy and of having opioid adverse effects.

"Chronic pain, when treated with opioids, may be treated with long-acting formulations (see tables Opioid Analgesics and Equianalgesic Doses of Opioid Analgesics ). Because of the higher doses in many long-acting formulations, these drugs have a higher risk of serious adverse effects (eg, death due to respiratory depression) in opioid-naive patients.

"Opioid analgesics have proven efficacy in the treatment of acute pain, cancer pain , and pain at the end of life and as part of palliative care . They are sometimes underused in patients with severe acute pain or in patients with pain and a terminal disorder such as cancer, resulting in needless pain and suffering. Reasons for undertreatment include
"Underestimation of the effective dose
"Overestimation of the risk of adverse effects

"Generally, opioids should not be withheld when treating acute, severe pain; however, simultaneous treatment of the condition causing the pain usually limits the duration of severe pain and the need for opioids to a few days or less. Also, opioids should generally not be withheld when treating cancer pain; in such cases, adverse effects can be prevented or managed, and addiction is less of a concern.

"Duration of opioid trials for chronic pain due to disorders other than terminal disorders (eg, cancer) has been short. Thus, there is little evidence to support opioid therapy for long-term management of chronic pain due to nonterminal disorders. Also, serious adverse effects of long-term opioid therapy (eg, opioid use disorder [addiction], overdose, respiratory depression, death) are being increasingly recognized. Thus, in patients with chronic pain due to nonterminal disorders, lower-risk nonopioid therapies should be tried before opioids; these therapies include
"Nonopioid drugs
"Complementary (integrative) medicine techniques (eg, acupuncture, massage, superficial electrical stimulation)
"Cognitive-behavioral techniques
"Interventional therapies (epidural injections, joint injections, nerve blocks, nerve ablation, spinal or peripheral nerve stimulation)

"In patients with chronic pain due to nonterminal disorders, opioid therapy may be considered, but usually only if nonopioid therapy has been unsuccessful. In such cases, opioids are used (often in combination with nonopioid therapies) only when the benefit of pain reduction and functional improvement outweighs the risks of opioid adverse effects and misuse. Obtaining informed consent may help clarify the goals, expectations, and risks of treatment and facilitate education and counseling about misuse.

"Patients receiving long-term (> 3 months) opioid therapy should be regularly assessed for pain control, functional improvement, adverse effects, and signs of misuse. Opioid therapy should be considered a failed treatment and should be tapered and stopped if the following occur:
"Patients have persistent severe pain despite increasing opioid doses.
"Patients do not adhere to the terms of treatment.
"Physical or mental function do not improve.

"Physical dependence (development of withdrawal symptoms when a drug is stopped) should be assumed to exist in all patients treated with opioids for more than a few days. Thus, opioids should be used as briefly as possible, and in dependent patients, the dose should be tapered to control withdrawal symptoms when opioids are no longer necessary. Patients with pain due to an acute, transient disorder (eg, fracture, burn, surgical procedure) should be switched to a nonopioid drug as soon as possible. Dependence is distinct from opioid use disorder (addiction), which, although it does not have a universally accepted definition, typically involves compulsive use and overwhelming involvement with the drug, including craving, loss of control over use, and use despite harm."

James C. Watson, MD, Treatment of Pain, Merck Manual Professional Version, last accessed August 31, 2021.

46. Tighter Prescribing Regulations Drive Illegal Sales

"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."

Martin James, Cunliffe Jack, Décary-Hétu David, Aldridge Judith. Effect of restricting the legal supply of prescription opioids on buying through online illicit marketplaces: interrupted time series analysis. British Medical Journal. 2018; 361:k2270.

47. The Burden of Opioid-Related Mortality in the United States

"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%])."

Gomes T, Tadrous M, Mamdani MM, Paterson JM, Juurlink DN. The Burden of Opioid-Related Mortality in the United States. JAMA Network Open. 2018;1(2):e180217.

48. Polydrug Involvement in Pharmaceutical Overdose Deaths in the US

"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%)."

Christopher M. Jones, PharmD, Karin A. Mack, PhD, and Leonard J. Paulozzi, MD, "Pharmaceutical Overdose Deaths, United States, 2010," Journal of the American Medical Association, February 20, 2013, Vol 309, No. 7, p. 658.

49. Changes Demographics, Number, and Substance Involved in Drug Overdoses in the US 1979-2016

"The overall mortality rate for unintentional drug poisonings in the United States grew exponentially from 1979 through 2016. This exponentially increasing mortality rate has tracked along a remarkably smooth trajectory (log linear R2 = 0.99) for at least 38 years (left panel). By contrast, the trajectories of mortality rates from individual drugs have not tracked along exponential trajectories. Cocaine was a leading cause in 2005–2006, which was overtaken successively by prescription opioids, then heroin, and then synthetic opioids such as fentanyl. The demographic patterns of deaths due to each drug have also shown substantial variability over time. Until 2010, most deaths were in 40- to 50-year old persons, from cocaine and increasingly from prescription drugs. Deaths from heroin and then fentanyl have subsequently predominated, affecting younger persons, ages 20 to 40 (middle panel). Mortality rates for males have exceeded those for females for all drugs. Rates for whites exceeded those for blacks for all opioids, but rates were much greater among blacks for cocaine. Death rates for prescription drugs were greater for rural than urban populations. The geographic patterns of deaths also vary by drug. Prescription opioid deaths are widespread across the United States (right panel), whereas heroin and fentanyl deaths are predominantly located in the northeastern United States and methamphetamine deaths in the southwestern United States. Cocaine deaths tend to be associated with urban centers."

Hawre Jalal, et al. Changing dynamics of the drug overdose epidemic in the United States from 1979 through 2016. Science, Sept. 21, 2018. Vol. 361, Issue 6408, eaau1184. DOI: 10.1126/science.aau1184.

50. Opioid Involvement in Deaths in the US Attributed to Drug Overdose, 2016

According to the US Centers for Disease Control, in 2016, there were 63,632 drug overdose deaths in the United States. The CDC further estimates that of those, 42,249 deaths involved any opioid.

The CDC reports that in 2016, 15,469 deaths involved heroin; 14,487 deaths involved natural and semi-synthetic opioids; 3,373 deaths involved methadone; and 19,413 deaths involved synthetic opioids other than methadone, a category which includes fentanyl. The sum of those numbers is greater than the total opioid involved deaths because, as noted by the CDC, "Deaths involving more than one opioid category (e.g., a death involving both methadone and a natural or semisynthetic opioid such as oxycodone) are counted in both categories."

Hedegaard H, Warner M, Miniño AM. Drug overdose deaths in the United States, 1999–2016. NCHS Data Brief, no 294. Hyattsville, MD: National Center for Health Statistics. 2017.

51. Prescription Opioid Tapering, Overdose Risk, and Suicidality

"In this emulated trial including more than 400 000 episodes of stable long-term opioid therapy, opioid tapering was associated with a small (0.15%) absolute increase in the risk of overdose or suicide events compared with a stable dosage during 11 months of follow-up. We did not identify a difference in the risk of overdose or suicide events between abrupt discontinuation and stable dosage, although the smaller number of episodes categorized as abrupt discontinuation may have reduced precision. The findings were robust to secondary and sensitivity analyses.

"The risk ratio of 1.15 for opioid overdose or suicide events associated with opioid tapering was smaller than in past studies conducted in other populations. This study examined commercially insured individuals receiving a stable long-term opioid dosage without evidence of opioid misuse. A large study of Veterans Health Administration patients estimated adjusted hazard ratios between 1.7 and 6.8 for the association of treatment discontinuation with suicide or overdose among patient subgroups defined by length of prior treatment.17 A study of Oregon Medicaid recipients found adjusted hazard ratios for suicide of 3.6 for discontinuation and 4.5 for tapering.18 A study using the same claims data set and similar definition of long-term opioid therapy as our study identified effect estimates between those in our study and those in prior studies, with an estimated adjusted incidence rate ratio of 1.3 for the association of dose tapering with overdose and 2.4 for the association of dose tapering with suicide attempts.32"

Larochelle MR, Lodi S, Yan S, Clothier BA, Goldsmith ES, Bohnert ASB. Comparative Effectiveness of Opioid Tapering or Abrupt Discontinuation vs No Dosage Change for Opioid Overdose or Suicide for Patients Receiving Stable Long-term Opioid Therapy. JAMA Netw Open. 2022;5(8):e2226523. doi:10.1001/jamanetworkopen.2022.26523

52. Deaths from Drug Overdose in the United States in 2015

"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."

Rudd RA, Seth P, David F, Scholl L. Increases in Drug and Opioid-Involved Overdose Deaths — United States, 2010–2015. MMWR Morb Mortal Wkly Rep 2016;65:1445–1452.

53. Likelihood That Young People with Diagnosed Mental Health Conditions Will be Put on Long Term Opioid Therapy

"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."

Quinn PD, Hur K, Chang Z, et al. Association of Mental Health Conditions and Treatments With Long-term Opioid Analgesic Receipt Among Adolescents. JAMA Pediatr. 2018;172(5):423–430. doi:10.1001/jamapediatrics.2017.5641.

54. Wholesale Price of Heroin in the US and Around the World

All Data For 2016 Unless Otherwise Noted. Prices in US$.

United States:
Black tar heroin ranged in price from $10,000 to $100,000 per kilogram.
South American heroin ranged in price from $10,000 to $100,000 per kilogram
The typical price of Southwest Asian heroin was $50,000 per kilogram.

Mexico:
The typical price of heroin was $35,000 per kilogram.

Colombia:
The typical price of heroin was $5,598 per kilogram.
The typical price of illegal morphine was $3,244 per kilogram.
The typical price of opium was $743 per kilogram.

Hong Kong:
The typical price of heroin was $48,797 per kilogram, ranging from $47,582 to $54,352 per kilogram.

Thailand:
The price of heroin ranged between $7,082 and $9,348 per 700 grams.

Afghanistan:
The typical price of heroin was $2,493 per kilogram.
The typical price of high purity heroin was $3,414 per kilogram.
The typical price of opium was $187 per kilogram, ranging from $171 to $203 per kilogram.

Pakistan:
The typical price of heroin was $2,632 per kilogram, ranging from $2,116 to $3,148 per kilogram.
The typical price of illegal morphine was $887 per kilogram, ranging from $619 to $1,155 per kilogram.
The typical price of opium was $432 per kilogram, ranging from $357 to $508 per kilogram.

Turkey:
The typical price of heroin was from $1,420 to $27,288 per kilogram.

UN Office on Drugs and Crime. Retail and Wholesale Drug Prices (In US$), accessed March 11, 2021.

55. Estimated Economic Impact of Illegal Opioid Use and Opioid-Related Overdose Deaths

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."

"The Underestimated Cost of the Opioid Crisis," Council of Economic Advisers, Executive Office of the President of the United States, November 2017.
Warner M, Trinidad JP, Bastian BA, et al. Drugs most frequently involved in drug overdose deaths: United States, 2010–2014. National vital statistics reports; vol 65 no 10. Hyattsville, MD: National Center for Health Statistics. 2016.

56. Good Samaritan and Naloxone Access Laws Save Lives

"GAO found that 48 jurisdictions (47 states and D.C.) have enacted both Good Samaritan and Naloxone Access laws. Kansas, Texas and Wyoming do not have a Good Samaritan law for drug overdoses but have a Naloxone Access law. The five U.S. territories do not have either type of law. GAO also found that the laws vary. For example, Good Samaritan laws vary in the types of drug offenses that are exempt from prosecution and whether this immunity takes effect before an individual is arrested or charged, or after these events but before trial.

"GAO reviewed 17 studies that provide potential insights into the effectiveness of Good Samaritan laws in reducing overdose deaths or the factors that may contribute to a law’s effectiveness. GAO found that, despite some limitations, the findings collectively suggest a pattern of lower rates of opioid-related overdose deaths among states that have enacted Good Samaritan laws, both compared to death rates prior to a law’s enactment and death rates in states without such laws. In addition, studies found an increased likelihood of individuals calling 911 if they are aware of the laws. However, findings also suggest that awareness of Good Samaritan laws may vary substantially across jurisdictions among both law enforcement officers and the public, which could affect their willingness to call 911."

"Most States Have Good Samaritan Laws and Research Indicates They May Have Positive Effects," US General Accountability Office, March 2021, GAO-21-248.

57. Retail Price of Heroin in the US, Canada, and the UK

Prices Per Gram, 2016

United States:
Black tar heroin: range from $17-$400
South American heroin: range from $45-500

Canada:
Heroin: range from $105.70-$452.80

UK, 2016:
Brown heroin: typical price $67.80, range from $54.20-$81.30
Opium: typical price $13.60, range from $13.60-$20.30

UN Office on Drugs and Crime. Retail and Wholesale Drug Prices (In US$), accessed March 20, 2021.

58. Risk of Heroin Dependence After Onset of Use

"When observed within approximately 1 to 12 months after heroin onset, an estimated 23% to 38% of new heroin users have become dependent on heroin. Rank-order correlation and post hoc exploratory analyses prompt a hypothesis of recently increased odds of becoming dependent on heroin.

"Seeking estimates for comparison, we found 3 published studies on how often heroin dependence was found among people who have used heroin at least once in their lifetime. The National Comorbidity Survey (1990-1992) estimate was 23% dependence rate (with a standard error [SE] of 5%); National Epidemiologic Survey on Alcohol and Related Conditions (2001-2002) estimate (SE) was 28% (4%); and National Epidemiologic Survey on Alcohol and Related Conditions-III (2012-2013) estimate (SE) was 25% (2%).4,6 These 3 values yield a random-effects meta-analysis summary of 26%, with a 95% CI of 22% to 29%, which clearly overlaps this study’s overall finding of 23% to 38% of all participants becoming heroin dependent soon after first heroin use."

Rivera OJS, Havens JR, Parker MA, Anthony JC. Risk of Heroin Dependence in Newly Incident Heroin Users. JAMA Psychiatry. Published online May 30, 2018. doi:10.1001/jamapsychiatry.2018.1214

59. Likelihood That Young People with Diagnosed Mental Health Conditions Will be Put on Long Term Opioid Therapy

"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."

Quinn PD, Hur K, Chang Z, et al. Association of Mental Health Conditions and Treatments With Long-term Opioid Analgesic Receipt Among Adolescents. JAMA Pediatr. 2018;172(5):423–430. doi:10.1001/jamapediatrics.2017.5641.

60. Harm Reduction and Web Outreach Work

"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."

Davitadze, A., Meylakhs, P., Lakhov, A. et al. Harm reduction via online platforms for people who use drugs in Russia: a qualitative analysis of web outreach work. Harm Reduct J 17, 98 (2020). doi.org/10.1186/s12954-020-00452-6.

61. Association of Opioid Overdose Laws with Opioid Use and Mortality

"• Naloxone access laws that ease restrictions on naloxone possession and distribution are associated with a 20% reduction overdose deaths among African-Americans.

"• Good Samaritan laws, providing immunity from prosecution for those calling emergency services, are associated with broad reductions in overdose deaths, reducing overdose deaths by 13% overall.

"• None of these harm reduction measures result in increase in opioid or heroin use.

"• These laws are effective at reducing overdose mortality without creating additional opioid use. Correspondingly, these measures should be considered an important part of the strategy used to address the opioid epidemic."

McClellan, Chandler, Lambdin, Barrot H., et al. Opioid-overdose laws association with opioid use and overdose mortality. Addictive Behaviors. March 19, 2018.

62. Use of Cannabis as a Response to the Overdose Crisis

"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."

Vyas, Marianne Beare et al. The use of cannabis in response to the opioid crisis: A review of the literature. Nursing Outlook, January-February 2018, Volume 66, Issue 1, 56 - 65.

63. Opioid-overdose laws association with opioid use and overdose mortality

"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."

McClellan, C., Lambdin, B. H., Ali, M. M., Mutter, R., Davis, C. S., Wheeler, E., Pemberton, M., & Kral, A. H. (2018). Opioid-overdose laws association with opioid use and overdose mortality. Addictive behaviors, 86, 90–95. doi.org/10.1016/j.addbeh.2018.03.014.

64. Incongruences Between Services Offered By Substance Use Programs and Their Clients

"Findings from our study illustrate that many substance use programs do not fit directly into a binary of “harm reduction” or “treatment.” Most of the participating programs in this study reported offering a spectrum of harm reduction and treatment services. Still, SSPs [Syringe Service Programs] were most likely to offer harm reduction services, MOUD [Medications for Opioid Use Disorder] programs were most likely to offer treatment services, and those characterized as offering both MOUD & SSPs were most likely to offer the broadest services. Program clients also did not fit into the supposed binary of “active drug use” vs. “abstinence.” In fact, of the clients who attended MOUD only programs, nearly three quarters reported using non-prescribed drugs in the past week, and more than half reported injecting drugs in the past week; these rates were similar to those reported by clients who attended combined MOUD & SSP programs. Meanwhile, more than 40% of those who attended SSP only programs reported attending some type of drug treatment service in the past month.

"Our results reveal some important incongruencies between services being offered by substance use programs and characteristics and behaviors reported by clients who attend such programs. For example, while three-quarters of MOUD program clients reported using non-prescribed drugs (one-quarter reported using opioids), only two-thirds of these programs offered overdose education or naloxone distribution and one-third offered fentanyl testing or test strips. This is highly concerning given the high prevalence of fentanyl in both the opioid and non-opioid illicit drug supplies [21] and may partly reflect the presence of policies that criminalize possession of fentanyl test strips in some of the sampled states [22]. Moreover, half of clients who attended MOUD programs without SSP or wound care actively injected drugs. While it is possible that these clients seek safe injection supplies elsewhere, a minority (14%) reported visiting an SSP in the past month.

"There were also discrepancies in services offered by SSPs relative to client-reported service utilization. Of clients recruited from SSPs without MOUD, 22% indicated receiving methadone and 8% reported receiving buprenorphine in the past month. This implies clients are either seeking these medications via other service providers or acquiring them on the street, which has been reported to often be easier than enrolling in formal treatment [9, 23, 24]. Roughly half of MOUD programs offered same-day treatment initiation. Additionally, SSP programs were reaching the highest risk population that with the greatest rates of active drug use. Yet, on average, these programs reported having the smallest number of staff and the least available treatment or social services relative to the other programs types. The limited workforce and services offered may reflect the limited budgets often used to operate these programs. Many harm reduction services operate independently from the medical system and are not eligible for insurance reimbursement. Additionally, programs have been historically banned from accessing federal and local funds for SSPs; programs have had to depend on scarce funds acquired a combination of small grants, individual donations, and charitable foundations [4, 25]. The Biden Administration’s 2021 American Rescue Act was the first federal action to allocate targeted funding toward harm reduction services and SSPs [25, 26]. While this was an important step to potentially help scale up these services, local and national resistance and stigma to these programs remains persistent (highlighted by the recent resistance to federal funding sterile pipes [27]). Continued efforts to combat ongoing stigma and political resistance to these programs are needed [25]."

Krawczyk N, Allen ST, Schneider KE, et al. Intersecting substance use treatment and harm reduction services: exploring the characteristics and service needs of a community-based sample of people who use drugs. Harm Reduct J. 2022;19(1):95. Published 2022 Aug 24. doi:10.1186/s12954-022-00676-8

65. Differences and Similarities Between Harm Reduction Programs and Substance Use Treatment Programs

"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]."

Krawczyk N, Allen ST, Schneider KE, et al. Intersecting substance use treatment and harm reduction services: exploring the characteristics and service needs of a community-based sample of people who use drugs. Harm Reduct J. 2022;19(1):95. Published 2022 Aug 24. doi:10.1186/s12954-022-00676-8

66. Creating A Person-Centered Substance Use Service System That Improves Health And Dignity

"Findings from this study demonstrate that in many ways, existing programs are not adequately meeting the service needs of or catering to the realities of PWUD. Creating a substance use service system that is truly person-centered and successful at improving health and dignity will necessitate moving away from the binary mentality of harm reduction vs. treatment to one which is better tailored to individual clients. This includes offering a continuum of co-located treatment, harm reduction, and social services that can meet individuals where they are. This would help facilitate access to life-saving services and greater socioeconomic stability [28, 29]. This may be particularly important for individuals with multiple vulnerabilities, as well as during emergencies—such as the COVID-19 pandemic—when minimizing travel and co-locating access to multiple health and social services is key [30]. In our study, programs that included both MOUD & SSP offered the greatest range of treatment and harm reduction services, including naloxone distribution, overdose prevention education, same-day treatment initiation, drop-in spaces, peer services/street outreach, and counseling services. However, these programs were the rarest in our sample of providers and remain largely under-resourced and at the periphery of the substance use service system. Moreover, such integrated models have been made possible by the ability to prescribe buprenorphine in non-traditional treatment settings [31]. Methadone, which may be the most effective and desirable MOUD option for some individuals, and used by many participants in our study, is still largely restricted to the opioid treatment program system bound by regulations on staffing, zoning, and hefty requirements for patients such as frequent urine drug screening [32, 33]. While there are some successful models of lower threshold methadone in other countries[34], scaling up methadone to meet needs of PWUD in the USA will require rethinking some of the core federal and state regulations, including expanding methadone availability beyond the opioid treatment program system [35]. It is important to note that most participating clients reported using drugs other than opioids; thus, integrating interventions for stimulant and other drug use should be central to efforts to better align programs with client behaviors."

Krawczyk N, Allen ST, Schneider KE, et al. Intersecting substance use treatment and harm reduction services: exploring the characteristics and service needs of a community-based sample of people who use drugs. Harm Reduct J. 2022;19(1):95. Published 2022 Aug 24. doi:10.1186/s12954-022-00676-8

67. Treatment with Methadone or Buprenorphine Following Nonfatal Overdose Leads to Decreased Mortality

"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."

Larochelle MR, Bernson D, Land T, Stopka TJ, Wang N, Xuan Z, et al. Medication for Opioid Use Disorder After Nonfatal Opioid Overdose and Association With Mortality: A Cohort Study. Annals of Internal Medicine. Epub ahead of print 19 June 2018. doi: 10.7326/M17-3107.

68. Online Harm Reduction Service Provision

"Our analysis of the needs of PWUD [People Who Use Drugs] and services provided to them demonstrates two major functions performed by web outreach workers: 1. They can provide certain services completely online, and 2. They navigate clients within the organization in order to match the needs of the PWUD with a person who can address them. Our research on web outreach work indicates an increasing level of efficiency that comes from online provision of harm reduction services. Instead of traveling to a harm reduction facility, PWUD can contact the organization via an online platform. Furthermore, harm reduction services provided entirely online gain particular relevance amidst the COVID-19 pandemic when offline harm reduction organizations experienced new challenges to providing in-person outreach services.

"Our findings suggest that online harm reduction services provision can be improved in terms of accessibility and efficiency. A challenge for web outreach work, as described by informants, was the inability of workers to communicate with PWUD after hours. One possible solution is to automatize some processes with Telegram bots, as it was done with the cases of OD [Overdoses]. Currently, web outreach workers manually send information to PWUD. If automatized, then PWUD themselves could use a bot to get necessary information at any time of the day. However, not all services can be automatized with a bot; therefore, it may be necessary to employ some workers, who could reply to clients’ requests after hours. This is especially important in emergency situations, such as OD. Another way to develop provision of online harm reduction services is to increase their presence on darknet forums. Greater presence could potentially make online services accessible to more groups of PWUD, who request urgent help after hours and/or who do not use Telegram. Another obstacle in increasing accessibility of online harm reduction services was that some clients refused to continue communication with web outreach workers via the phone. More research is needed to explore the needs that PWUD have in such cases, identify the reasons why certain PWUD refuse to communicate via the phone, and explore how web outreach work can be provided in such instances."

Davitadze, A., Meylakhs, P., Lakhov, A. et al. Harm reduction via online platforms for people who use drugs in Russia: a qualitative analysis of web outreach work. Harm Reduct J 17, 98 (2020). doi.org/10.1186/s12954-020-00452-6.

69. Vivitrol and Risk of Opioid Overdose According To The Manufacturer

"Vulnerability to Opioid Overdose

"After opioid detoxification, patients are likely to have reduced tolerance to opioids. VIVITROL blocks the effects of exogenous opioids for approximately 28 days after administration. However, as the blockade wanes and eventually dissipates completely, patients who have been treated with VIVITROL may respond to lower doses of opioids than previously used, just as they would have shortly after completing detoxification. This could result in potentially life-threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.) if the patient uses previously tolerated doses of opioids. Cases of opioid overdose with fatal outcomes have been reported in patients who used opioids at the end of a dosing interval, after missing a scheduled dose, or after discontinuing treatment.

"Patients should be alerted that they may be more sensitive to opioids, even at lower doses, after VIVITROL treatment is discontinued, especially at the end of a dosing interval (i.e., near the end of the month that VIVITROL was administered), or after a dose of VIVITROL is missed. It is important that patients inform family members and the people closest to the patient of this increased sensitivity to opioids and the risk of overdose [see Patient Counseling Information (17)].

"There is also the possibility that a patient who is treated with VIVITROL could overcome the opioid blockade effect of VIVITROL. Although VIVITROL is a potent antagonist with a prolonged pharmacological effect, the blockade produced by VIVITROL is surmountable. The plasma concentration of exogenous opioids attained immediately following their acute administration may be sufficient to overcome the competitive receptor blockade. This poses a potential risk to individuals who attempt, on their own, to overcome the blockade by administering large amounts of exogenous opioids. Any attempt by a patient to overcome the antagonism by taking opioids is especially dangerous and may lead to life-threatening opioid intoxication or fatal overdose. Patients should be told of the serious consequences of trying to overcome the opioid blockade [see Patient Counseling Information (17)]."

Full Prescribing Information. Vivitrol (Naltrexone for Extended-Release Injectable Suspension). Alkermes. Revised December 2015.

70. Protections Offered by Good Samaritan Laws Vary By Jurisdiction

"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."

"Most States Have Good Samaritan Laws and Research Indicates They May Have Positive Effects," US General Accountability Office, March 2021, GAO-21-248.

71. Medicinal Cannabis as an Alternative to Prescription Opioid Medicines

"The use of MC [Medical Cannabis] as an alternative to POMs [Prescription Opioid Medications] 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 (NIH, 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."

Vyas, Marianne Beare et al. The use of cannabis in response to the opioid crisis: A review of the literature. Nursing Outlook, Volume 66, Issue 1, 56 - 65.
https://www.nursingoutlook.org/...
https://www.nursingoutlook.org/...

72. Types Of Offenses Covered by Good Samaritan Laws

"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."

"Most States Have Good Samaritan Laws and Research Indicates They May Have Positive Effects," US General Accountability Office, March 2021, GAO-21-248.

73. Overdose Risk Based on Prescription Type

"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."

Bohnert ASB, Valenstein M, Bair MJ, et al. Association Between Opioid Prescribing Patterns and Opioid Overdose-Related Deaths. JAMA. 2011;305(13):1315–1321. doi:10.1001/jama.2011.370

74. Factors That May Skew Estimates of Overdose Deaths Attributed to Specific Drugs, Particularly Opioids

"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."

Rudd RA, Seth P, David F, Scholl L. Increases in Drug and Opioid-Involved Overdose Deaths — United States, 2010–2015. MMWR Morb Mortal Wkly Rep 2016;65:1445–1452.

75. Opioid Toxicity or Overdose

"The main toxic effect is decreased respiratory rate and depth, which can progress to apnea. Other complications (eg, pulmonary edema, which usually develops within minutes to a few hours after opioid overdose) and death result primarily from hypoxia. Pupils are miotic. Delirium, hypotension, bradycardia, decreased body temperature, and urinary retention may also occur.

"Normeperidine, a metabolite of meperidine, accumulates with repeated use (including therapeutic); it stimulates the central nervous system and may cause seizure activity.

"Serotonin syndrome occasionally occurs when fentanyl, meperidine, tramadol, methadone, codeine, or oxycodone is taken concomitantly with other drugs that have serotonergic effects (eg, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors). Serotonin syndrome consists of one or more of the following:

"Hypertonia
"Tremor and hyperreflexia
"Spontaneous, inducible, or ocular clonus
"Diaphoresis and autonomic instability
"Agitation
"Temperature > 38° plus ocular or inducible clonus"

Gerald F. O’Malley, DO, and Rika O’Malley, MD, Opioid Toxicity and Withdrawal, in Merck Manual Professional Version, last accessed August 31, 2021.

76. Prescribing Patterns and Opioid Overdose-Related Deaths

"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."

Bohnert ASB, Valenstein M, Bair MJ, et al. Association Between Opioid Prescribing Patterns and Opioid Overdose-Related Deaths. JAMA. 2011;305(13):1315–1321. doi:10.1001/jama.2011.370

77. Heroin Toxicity, Adulterants, and Overdose Potential

"If it is not pure drugs that kill, but impure drugs and the mixture of drugs, then the myth of the heroin overdose can be dangerous. If users had a guaranteed pure supply of heroin which they relied on, there would be little more likelihood of toxic doses than occur with narcotics administered in a hospital.

"But when people take whatever they can off the street, they have no way of knowing how the drug is adulterated. And when they decide to augment heroin's effects, possibly because they do not want to take too much heroin, they may place themselves in the greatest danger."

Peele, Stanton, MD, (1998), The persistent, dangerous myth of heroin overdose. Last accessed August 31, 2021.

78. Lower Opioid Overdose Mortality Rates In States With Medical Cannabis Laws

"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."

Bacchuber, Marcus A., MD; Saloner, Brendan, PhD; Cunningham, Chinazo O., MD, MS; and Barry, Colleen L., PhD, MPP. "Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999-2010." JAMA Intern Med. Published online August 25, 2014.

79. Methamphetamine Overdose

"Tachycardia, arrhythmias, chest pain, hypertension, dizziness, nausea, vomiting, and diarrhea can occur. Central nervous system effects include acute delirium and toxic psychosis. Overdose can also cause stroke (usually hemorrhagic), seizures, muscle rigidity, and hyperthermia (>40° C); all of these effects may precipitate rhabdomyolysis, which can lead to renal failure."

Gerald F. O’Malley, DO, and Rika O’Malley , MD, Amphetamines (Methamphetamines), in Merck Manual Professional Version, last accessed August 31, 2021.

80. Overdose Risk Based on Prescription Type

"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."

Bohnert ASB, Valenstein M, Bair MJ, et al. Association Between Opioid Prescribing Patterns and Opioid Overdose-Related Deaths. JAMA. 2011;305(13):1315–1321. doi:10.1001/jama.2011.370

81. Prescription Opioid Overdose

"Among patients who are prescribed opioids, an estimated 80% are prescribed low doses (<100 mg morphine equivalent dose per day) by a single practitioner (7,8), and these patients account for an estimated 20% of all prescription drug overdoses (Figure 3). Another 10% of patients are prescribed high doses (?100 mg morphine equivalent dose per day) of opioids by single prescribers and account for an estimated 40% of prescription opioid overdoses (9,10). The remaining 10% of patients are of greatest concern. These are patients who seek care from multiple doctors and are prescribed high daily doses, and account for another 40% of opioid overdoses (11). Persons in this third group not only are at high risk for overdose themselves but are likely diverting or providing drugs to others who are using them without prescriptions. In fact, 76% of nonmedical users report getting drugs that had been prescribed to someone else, and only 20% report that they acquired the drug from their own doctor (4). Furthermore, among persons who died of opioid overdoses, a significant proportion did not have a prescription in their records for the opioid that killed them; in West Virginia, Utah, and Ohio, 25%–66% of those who died of pharmaceutical overdoses used opioids originally prescribed to someone else (11–13). These data suggest that prevention of opioid overdose deaths should focus on strategies that target 1) high-dosage medical users and 2) persons who seek care from multiple doctors, receive high doses, and likely are involved in drug diversion."

Centers for Disease Control, CDC Grand Rounds: Prescription Drug Overdoses — a U.S. Epidemic, Morbidity and Mortality Weekly Report, January 13, 2012 / 61(01);10-13

82. Heroin Toxicity and Opiate Overdose

"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."

Zador, Deborah, Sunjic, Sandra, and Darke, Shane, Heroin-related deaths in New South Wales, 1992: toxicological findings and circumstances, The Medical Journal of Australia, 1996; 164 (4): 204-207.

83. Alcohol Overdose

"Symptoms may include:

"Abdominal pain.
"Confusion, slurred speech.
"Internal (stomach and intestinal) bleeding.
"Slowed breathing.
"Stupor (decreased level of alertness), even coma.
"Unsteady walking.
"Vomiting, sometimes bloody.
"Chronic alcohol overuse can lead to additional symptoms and multiple organ failure.

"Home Care
"If you can wake an adult who has had too much alcohol, move the person to a comfortable place to sleep off the effects. Make sure the person will not fall or get hurt.

"Place the person on their side in case they throw up (vomit). DO NOT make the person throw up unless told to do so by a health care professional or Poison Control.

"Check the person frequently to make sure their condition does not get worse.

"If the person is not alert (unconscious) or only somewhat alert (semi-conscious), emergency assistance may be needed. When in doubt, call for medical help."

Ethanol Poisoning, MEDLINEplus Medical Encyclopedia, US National Library of Medicine, last accessed August 31, 2021.

84. Growth in Number of Prescription Drug Overdoses 2004-2009

"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)."

Centers for Disease Control and Prevention, Vital Signs: Overdoses of Prescription Opioid Pain Relievers — United States, 1999–2008, Morbidity and Mortality Weekly Report, November 4, 2011 / 60(43);1487-1492

85. Cannabis Overdose: Toxic Dosage and Mortality Risk

"Tetrahydrocannabinol is a very safe drug. Laboratory animals (rats, mice, dogs, monkeys) can tolerate doses of up to 1,000 mg/kg (milligrams per kilogram). This would be equivalent to a 70 kg person swallowing 70 grams of the drug—about 5,000 times more than is required to produce a high. Despite the widespread illicit use of cannabis there are very few if any instances of people dying from an overdose. In Britain, official government statistics listed five deaths from cannabis in the period 1993-1995 but on closer examination these proved to have been deaths due to inhalation of vomit that could not be directly attributed to cannabis (House of Lords Report, 1998). By comparison with other commonly used recreational drugs these statistics are impressive."

Iversen, Leslie L., PhD, FRS, "The Science of Marijuana" (London, England: Oxford University Press, 2000), p. 178, citing House of Lords, Select Committee on Science and Technology, "Cannabis — The Scientific and Medical Evidence" (London, England: The Stationery Office, Parliament, 1998).

86. Alcohol Overdose

"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."

Gerald F. O’Malley, DO, and Rika O’Malley, MD, Alcohol Toxicity and Withdrawal, in Merck Manual Professional Version, last accessed August 31, 2021.

87. Treatment for Amphetamine Overdose

"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."

Gerald F. O’Malley, DO, and Rika O’Malley , MD, Amphetamines (Methamphetamines), in Merck Manual Professional Version, last accessed August 31, 2021.

88. Overdose Prevention a Priority

"A first priority for prevention must be to reduce the frequency of drug overdoses. We should inform heroin users about the risks of combining heroin with alcohol and other depressant drugs. Not all users will act on such information, but if there are similar behavioral changes to those that occurred with needle-sharing overdose deaths could be substantially reduced. Heroin users should also be discouraged from injecting alone and thereby denying themselves assistance in the event of an overdose."

Wayne D. Hall, PhD, "How can we reduce heroin 'overdose' deaths?" The Medical Journal of Australia (MJA 1996; 164:197).

89. Alcohol Poisoning Deaths in the US

"On average, 6 people died every day from alcohol poisoning in the US from 2010 to 2012. Alcohol poisoning is caused by drinking large quantities of alcohol in a short period of time. Very high levels of alcohol in the body can shutdown critical areas of the brain that control breathing, heart rate, and body temperature, resulting in death. Alcohol poisoning deaths affect people of all ages but are most common among middle-aged adults and men."

"Alcohol Poisoning Deaths: A deadly consequence of binge drinking," CDC Vital Signs, January 2015.

90. Overdose - Opiates

"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."

Zador, Deborah, Sunjic, Sandra, and Darke, Shane, Heroin-related deaths in New South Wales, 1992: toxicological findings and circumstances, The Medical Journal of Australia, 1996; 164 (4): 204-207.

91. Effects of Amphetamine and Methamphetamine Use

"A paranoid psychosis may result from long-term use; rarely, the psychosis is precipitated by a single high dose or by repeated moderate doses. Typical features include delusions of persecution, ideas of reference (notions that everyday occurrences have special meaning or significance personally meant for or directed to the patient), and feelings of omnipotence. Some users experience a prolonged depression, during which suicide is possible. Recovery from even prolonged amphetamine psychosis is usual but is slow. The more florid symptoms fade within a few days or weeks, but some confusion, memory loss, and delusional ideas commonly persist for months."

Gerald F. O’Malley, DO, and Rika O’Malley , MD, Amphetamines (Methamphetamines), in Merck Manual Professional Version, last accessed August 31, 2021.

92. Factors Influencing Methadone-Related Mortality

"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)."

Center for Substance Abuse Treatment, Methadone-Associated Mortality: Report of a National Assessment, May 8-9, 2003. SAMHSA Publication No. 04-3904. Rockville, MD: Center for Substance Abuse Treatment, Substance Abuse and Mental Health Services Administration, 2004.

93. Cocaine Toxicity or Overdose

"An overdose may cause severe anxiety, panic, agitation, aggression, sleeplessness, hallucinations, paranoid delusions, impaired judgment, tremors, seizures, and delirium. Mydriasis and diaphoresis are apparent, and heart rate and blood pressure are increased. Death may result from myocardial infarction or arrhythmias.

"Severe overdose causes a syndrome of acute psychosis (eg, schizophrenic-like symptoms), hypertension, hyperthermia, rhabdomyolysis, coagulopathy, renal failure, and seizures. Patients with extreme clinical toxicity may, on a genetic basis, have decreased (atypical) serum cholinesterase, an enzyme needed for clearance of cocaine.

"Patients who inhale cocaine may develop an acute pulmonary syndrome (crack lung) with fever, hemoptysis, and hypoxia, that may progress to respiratory failure.

"The concurrent use of cocaine and alcohol produces a condensation product, cocaethylene, which has stimulant properties and may contribute to toxicity."

Gerald F. O’Malley, DO, and Rika O’Malley , MD, Cocaine (Crack), in Merck Manual Professional Version, last accessed August 31, 2021.

94. Naloxone As Lifesaving Intervention To Prevent Death By Opioid Overdose

"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"

Burris, Scott; Beletsky, Leo; Castagna, Carolyn; Coyle, Casey; Crowe, Colin; and McLaughlin, Jennie Maura, "Stopping an Invisible Epidemic: Legal Issues in the Provision of Naloxone to Prevent Opioid Overdose," Drexel Law Review, Philadelphia, PA: Earle Mack School of Law, Spring 2009, Vol. 1, Number 2.

95. Benefits from Naloxone Distribution

"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."

Coffin, Phillip O., MD, and Sullivan, Sean D. PhD, "Cost-Effectiveness of Distributing Naloxone to Heroin Users for Lay Overdose Reversal," Annals of Internal Medicine 2013 Jan 1;158(1):1-9. doi: 10.7326/0003-4819-158-1-201301010-00003.

96. Price of Naloxone Has Skyrocketed Since 2006

"We contribute nationally representative evidence to help answer each of these questions, including wholesale pricing data from a proprietary drug sales database spanning January 2006 to February 2017. We find that all formulations of naloxone increased in price since 2006 except for Narcan Nasal Spray. These cumulative increases totaled 2281% for the 0.4 MG single-dose products, 244% for the 2 MG single-dose products, 3797% for the 4 MG multi-dose products, and 469% for the 0.4 MG Evzio auto-injector. We believe that increased demand for naloxone from the opioid epidemic may explain the more gradual price increases for the 0.4 MG single-dose and 4 MG multi-dose products prior to 2012. On the other hand, we believe that the sudden, sustained prices increases occurring for all of the products since 2012 may be the result of a drug shortage for the 0.4 MG single-dose products and the fact that each naloxone product has historically been sold by only a single competitor."

Matthew Rosenberg, Grace Chai, Shekhar Mehta, Andreas Schick, Trends and economic drivers for United States naloxone pricing, January 2006 to February 2017, Addictive Behaviors, 2018, ISSN 0306-4603, doi.org/10.1016/j.addbeh.2018.05.006.

97. Barriers to Naloxone Access

"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."

Burris, Scott; Beletsky, Leo; Castagna, Carolyn; Coyle, Casey; Crowe, Colin; and McLaughlin, Jennie Maura, "Stopping an Invisible Epidemic: Legal Issues in the Provision of Naloxone to Prevent Opioid Overdose," Drexel Law Review, Philadelphia, PA: Earle Mack School of Law, Spring 2009, Vol. 1, Number 2.

98. Rapid Effect of Naloxone

"Heroin is particularly toxic because of high lipid solubility, which allows it to cross the blood–brain barrier within seconds and achieve high brain levels.10
"Naloxone is also lipid soluble and enters the brain rapidly. Reversal of respiratory depression is evident 3–4 minutes after IV and 5–6 minutes after subcutaneous administration.11"

Etherington, Jeremy; Christenson, James; Innes, Grant; Grafstein, Eric; Pennington, Sarah; Spinelli, John J.; Gao, Min; Lahiffe, Brian; Wanger, Karen; Fernandes, Christopher, "Is early discharge safe after naloxone reversal of presumed opioid overdose?" Canadian Journal of Emergency Medicine, Ottawa, ON: Canadian Association of Emergency Physicians, July 2000.

99. Naloxone Availability and Use in the US

"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)."

Coffin, Phillip O., MD, and Sullivan, Sean D. PhD, "Cost-Effectiveness of Distributing Naloxone to Heroin Users for Lay Overdose Reversal," Annals of Internal Medicine 2013 Jan 1;158(1):1-9. doi: 10.7326/0003-4819-158-1-201301010-00003.

100. Need for User Education on Overdose Prevention and Harm Reduction

"Our findings that an ambulance was called while the subject was still alive in only 10% of cases, and that a substantial minority of heroin users died alone, strongly suggest that education campaigns should also emphasise that it is safer to inject heroin in the company of others, and important to call for an ambulance early in the event of an overdose. Consideration should also be given to trialling the distribution of the opioid antagonist naloxone to users to reduce mortality from heroin use."

Zador, Deborah, Sunjic, Sandra, and Darke, Shane, "Heroin-related deaths in New South Wales, 1992: toxicological findings and circumstances," The Medical Journal of Australia, 1996; 164 (4): 204-207.

101. Feasibility of Naloxone Distribution to People Who Use Injection Drugs

"This pilot trial is the first in North America to prospectively evaluate a program of naloxone distribution to IDUs [Injection Drug Users] to prevent heroin overdose death. After an 8-hour training, our study participants' knowledge of heroin overdose prevention and management increased, and they reported successful resuscitations during 20 heroin overdose events. All victims were reported to have been unresponsive, cyanotic, or not breathing, but all survived. These findings suggest that IDUs can be trained to respond to heroin overdose by using CPR and naloxone, as others have reported. Moreover, we found no evidence of increases in drug use or heroin overdose in study participants. These data corroborate the findings of several feasibility studies recommending the prescription and distribution of naloxone to drug users to prevent fatal heroin overdose."

Seal, Karen H., Robert Thawley, Lauren Gee, Joshua Bamberger, Alex H. Kral, Dan Ciccarone, Moher Downing, and Brian R. Edlin, "Naloxone Distribution and Cardiopulmonary Resuscitation Training for Injection Drug Users to Prevent Heroin Overdose Death: A Pilot Intervention Study," Journal of Urban Medicine, New York, NY: New York Academy of Medicine, 2005, Vol. 82, No. 2.

102. Cost-Effectiveness of Naloxone Distribution

"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."

Coffin, Phillip O., MD, and Sullivan, Sean D. PhD, "Cost-Effectiveness of Distributing Naloxone to Heroin Users for Lay Overdose Reversal," Annals of Internal Medicine 2013 Jan 1;158(1):1-9. doi: 10.7326/0003-4819-158-1-201301010-00003.

103. Effectiveness of Naloxone Against Opiate Overdoses

"Treatment with naloxone can reverse respiratory failure within a few minutes (Darke and Hall, 1997; Physician’s Desk Reference, 2000). Naloxone is an opiate antagonist, and is thought to displace heroin at the Mu2 receptors. Physicians and emergency personnel treat patients suspected of heroin overdose by administering an initial dose of naloxone parenterally. While 2 mg are almost always sufficient to revive a patient, additional doses can be administered if the desired improvement does not occur, and smaller doses are often used to minimize the discomfort of sudden heroin withdrawal (Physician’s Desk Reference, 2000). In adults, naloxone has a half-life of between 30 and 81 minutes (Physician’s Desk Reference, 2000). Therefore, repeated administration could be necessary to reverse the effect of particularly large or long-lasting doses of heroin. (Sporer, 1999; Physician’s Desk Reference, 2000). In practice, however, a single 2 mg does is almost always sufficient. If a patient has not taken opioids, naloxone has no pharmacological effect (Darke and Hall, 1997).

"While administration of naloxone may produce acute withdrawal symptoms in patients with heroin dependence (Physician’s Desk Reference, 2000), the drug does not have long-term or life threatening adverse effects when it is administered at therapeutic doses (Strang, et al, 1996). Naloxone has been associated with complications such as seizures and arrhythmia, (Physician’s Desk Reference, 2000) but more recent research suggests that complications are exceedingly rare, that past reports of complications may have been erroneous (Goldfrank and Hoffman, 1995), or that complications occur, if at all, in patients with pre-existing heart disease (Goldfrank and Hoffman, 1995). Naloxone is not addictive, and has no psycho-pharmacological effects."

Burris, Scott; Norland, Joanna; and Edlin, Brian, "Legal Aspects of Providing Naloxone to Heroin Users in the United States," International Journal of Drug Policy, 2001, Vol. 12.

104. Naloxone and Overdose Prevention in the EU

"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)."

European Monitoring Centre for Drugs and Drug Addiction, "Annual report 2012: the state of the drugs problem in Europe," Luxembourg: Publications Office of the European Union, November 2012, Catalog No. TDAC12001ENC, doi:10.2810/64775.

105. Marijuana and Overdose Mortality

An exhaustive search of the literature finds no deaths induced by marijuana. The US Drug Abuse Warning Network (DAWN) records instances of drug mentions in medical examiners' reports, and though marijuana is mentioned, it is usually in combination with alcohol or other drugs. Marijuana alone has not been shown to cause an overdose death.

Federal Drug Abuse Warning Network (DAWN); also see Janet E. Joy, Stanley J. Watson, Jr., and John A. Benson, Jr., "Marijuana and Medicine: Assessing the Science Base," Division of Neuroscience and Behavioral Research, Institute of Medicine (Washington, DC: National Academy Press, 1999); and US Department of Justice, Drug Enforcement Administration, "In the Matter of Marijuana Rescheduling Petition" (Docket #86-22), September 6, 1988, p. 57.

106. Wholesale Price of Heroin in 2010

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.

UN Office on Drugs and Crime, World Drug Report 2012 (United Nations publication, Sales No. E.12.XI.1), Opioids: Retail and wholesale prices by drug type and country (2010 or latest available year)
http://www.unodc.org/unodc/en/...
http://www.unodc.org/documents...

107. Mentions of Kratom in Overdose Deaths in the US

"Data on 27,338 overdose deaths that occurred during July 2016–December 2017 were entered into SUDORS, and 152 (0.56%) of these decedents tested positive for kratom on postmortem toxicology (kratom-positive). Postmortem toxicology testing protocols were not documented and varied among and within states. Kratom was determined to be a cause of death (i.e., kratom-involved) by a medical examiner or coroner for 91 (59.9%) of the 152 kratom-positive decedents, including seven for whom kratom was the only substance to test positive on postmortem toxicology, although the presence of additional substances cannot be ruled out (4).

"In approximately 80% of kratom-positive and kratom-involved deaths in this analysis, the decedents had a history of substance misuse, and approximately 90% had no evidence that they were currently receiving medically supervised treatment for pain. Postmortem toxicology testing detected multiple substances for almost all decedents (Table). Fentanyl and fentanyl analogs were the most frequently identified co-occurring substances; any fentanyl was listed as a cause of death for 65.1% of kratom-positive decedents and 56.0% of kratom-involved decedents. Heroin was the second most frequent substance listed as a cause of death (32.9% of kratom-positive decedents), followed by benzodiazepines (22.4%), prescription opioids (19.7%),** and cocaine (18.4%)."

Olsen EO, O’Donnell J, Mattson CL, Schier JG, Wilson N. Notes from the Field: Unintentional Drug Overdose Deaths with Kratom Detected — 27 States, July 2016–December 2017. MMWR Morb Mortal Wkly Rep 2019;68:326–327.

108. Methadone-Associated Mortality

"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)."

Center for Substance Abuse Treatment, "Methadone-Associated Mortality: Report of a National Assessment, May 8-9, 2003," CSAT Publication No. 28-03, Rockville, MD: Center for Substance Abuse Treatment, Substance Abuse and Mental Health Services Administration, 2004.

109. Medical Cannabis Laws and Opioid Overdose Mortality Rates

"In an analysis of death certificate data from 1999 to 2010, we found that states with medical cannabis laws had lower mean opioid analgesic overdose mortality rates compared with states without such laws. This finding persisted when excluding intentional overdose deaths (ie, suicide), suggesting that medical cannabis laws are associated with lower opioid analgesic overdose mortality among individuals using opioid analgesics for medical indications. Similarly, the association between medical cannabis laws and lower opioid analgesic overdose mortality rates persisted when including all deaths related to heroin, even if no opioid analgesic was present, indicating that lower rates of opioid analgesic overdose mortality were not offset by higher rates of heroin overdose mortality. Although the exact mechanism is unclear, our results suggest a link between medical cannabis laws and lower opioid analgesic overdose mortality."

Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999-2010. JAMA Intern Med. 2014;174(10):1668–1673. doi:10.1001/jamainternmed.2014.4005