Heroin (Diacetylmorphine)

"Among people aged 12 or older, the percentage who were past year heroin users increased from 0.2 percent (or 404,000 people) in 2002 to 0.3 percent (or 745,000 people) in 2019 (Figure 14 and 2019 DT 7.2). The percentage of people in 2019 who were past year heroin users was higher than the percentages in most years from 2002 to 2008, but it was similar to the percentages in 2009 to 2018.

"Aged 12 to 17
"Among adolescents aged 12 to 17 in 2019, the estimates of past year heroin use were not reported due to low statistical precision (Figure 14 and 2019 DT 7.5).¹¹ However, the estimate of past year heroin use among adolescents in 2018 was lower than the estimates for most years from 2002 through 2014, but it was similar to the estimates in 2015 to 2017.²⁷ About 0.1 to 0.2 percent of adolescents used heroin in any year from 2002 to 2017.

"Aged 18 to 25
"Among young adults aged 18 to 25 in 2019, 0.3 percent (or 87,000 people) were past year heroin users (Figure 14 and 2019 DT 7.11). The percentage in 2019 was lower than those in 2005 to 2018 (ranging from 0.4 to 0.8 percent), but it was similar to those in 2002 to 2004.

"Aged 26 or Older
"Among adults aged 26 or older, the percentage who were past year heroin users increased from 0.1 percent (or 231,000 people) in 2002 to 0.3 percent (or 658,000 people) in 2019 (Figure 14 and 2019 DT 7.14). These estimates of past year heroin use in 2019 were higher than those in most years from 2002 through 2013, but they were similar to those in 2014 to 2018."

"Over the past 15 years, six RCTs [Randomized Controlled Trials] have been conducted involving more than 1,500 patients, and they provide strong evidence, both individually and collectively, in support of the efficacy of treatment with fully supervised self-administered injectable heroin, when compared with oral MMT, for long-term refractory heroin-dependent individuals. These have been conducted in six countries: Switzerland (Perneger et al., 1998); the Netherlands (van den Brink et al., 2003); Spain (March et al., 2006); Germany (Haasen et al., 2007), Canada (Oviedo-Joekes et al., 2009) and England (Strang et al., 2010).

"Across the trials, major reductions in the continued use of ‘street’ heroin occurred in those receiving SIH [Supervised Injectable Heroin] compared with control groups (most often receiving active MMT). These reductions occasionally included complete cessation of ‘street’ heroin use, although more frequently there was continued but reduced irregular use of ‘street’ heroin, at least through the trial period (ranging from 6 to 12 months). Reductions also occurred, but to a lesser extent, with the use of a range of other drugs, such as cocaine and alcohol. However, the difference between reductions in the SIH group and the various control groups was not as great (compared with major reductions in the use of ‘street’ heroin)."

"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"

"Importantly, our results show that evidence of injection was more prevalent among decedents with xylazine and heroin and/or fentanyl detections. Despite limited literature on the health effects of chronic xylazine use, regular injection of xylazine has been associated with skin ulcers, abscesses and lesions in Puerto Rico.^{2 3} Semistructured interviews with people who use xylazine in Puerto Rico revealed that regular use of xylazine leads to skin ulcers.⁴ As skin ulcers are painful, people may continually inject at the site of the ulcer to alleviate the pain as xylazine is a potent α2-adrenergic agonist that mediates via central α2-receptors, which decreases perception of painful stimuli.¹ People may self-treat the wound by draining or lancing it, which can exacerbate negative outcomes.⁸ While Philadelphia has seen a rise in skin and soft tissue infections relating to injection drug use, it is not yet clear whether or not this is due to increased presence of xylazine in the drug supply.⁹"

"Heroin is an opiate drug that is synthesized from morphine, a naturally occurring substance extracted from the seed pod of the Asian opium poppy plant. Heroin usually appears as a white or brown powder or as a black sticky substance, known as 'black tar heroin.'"

"People who use heroin (PWUH) have increased morbidity and mortality compared to the general population [1]. A syndemic of opioid overdose, human immunodeficiency virus (HIV), hepatitis C virus (HCV), skin and soft tissue infections (SSTI), and infective endocarditis accounts for many of the poor health outcomes among PWUH [2,3,4,5]. Heroin can be consumed in several ways, including injection and smoking [6]. High-risk injection behaviors, including syringe sharing and reuse of non-sterile injection equipment, are established routes of HIV and HCV transmission and increase risk of SSTI and infective endocarditis [7,8,9]. Opioid overdose is a common cause of mortality among PWUH, with higher overdose risk among those who inject [10,11,12].

"Because smoking heroin does not injure the skin or introduce non-sterile equipment into blood or tissue, this method of consumption does not entail the same risk of blood-borne infections or SSTI compared to injection. While similar pharmacological effects can be achieved by smoking or injecting heroin, peak plasma concentrations are 2–4 times lower when heroin is smoked, which may reduce risk of lethal opioid overdose [13, 14]. Programs that encourage PWUH to transition from injecting to smoking heroin may decrease injection frequency and thereby reduce harms associated with heroin use, including risks of infection and overdose [15]. Distribution of smoking equipment may also help PWUH avoid using pipes fashioned from cans or other poor-quality materials that easily crack or overheat, thereby reducing risk of developing burns or cuts on the lips that can serve as sites of infection [16,17,18]. Pipe distribution programs may also reduce pipe sharing, a risk behavior potentially associated with respiratory virus or HCV transmission [17,18,19,20]."

"In this pilot pretest–posttest quasi-experimental study, we saw a lower proportion of SSP clients exclusively inject heroin and a higher proportion of SSP clients consume heroin through both injection and smoking after the implementation of a heroin pipe distribution program. The proportion of SSP clients who reported syringe reuse was also lower following the heroin pipe distribution intervention. We did not observe any difference in self-reported health outcomes associated with drug use between the pre- and post-intervention periods; however, the short follow-up period and small sample size of this pilot study may have contributed to this null finding. Our results suggest heroin pipe distribution may be a novel RTI that can be added to existing SSPs to further reduce harms associated with heroin use. This study also highlights the potential for public health service innovations to be developed by marginalized communities and the importance of placing PWUD in leadership positions in efforts to optimize harm reduction programming.

"Despite the non-randomized design of this pilot study, several findings suggest heroin pipe distribution may have prompted changes in heroin consumption behaviors among PWUH. The proportion of SSP clients who exclusively injected heroin was lower by a quarter, while the proportion who both injected and smoked heroin was higher by over a quarter after heroin pipe distribution began. Twenty-four percent of respondents who used heroin reported heroin pipe distribution had reduced their heroin injection. Higher proportions of SSP clients who received heroin pipes exclusively smoked heroin or both smoked and injected heroin compared to SSP clients who did not receive a heroin pipe. We are unaware of any prior published research investigating heroin pipes as an RTI; however, pre–post-analyses examining foil distribution at SSPs in Europe found similar changes in drug consumption behaviors, with up to 85% of SSP clients having used foil to inhale rather than inject heroin on at least one occasion [23, 28]. Our non-randomized study design cannot control for confounding and prevents firm conclusions as to whether this observed shift from injection to smoking can be attributed to the intervention. Additionally, only 14% of respondents who used heroin completed surveys during both the pre- and post-intervention periods, and thus, outcomes may have been impacted by changes in the SSP client population across time periods. Further experimental research is needed to clarify the causal relationship between heroin pipe distribution and reductions in heroin injection. Study designs that are randomized by individual may be complicated by heroin pipe sharing across intervention and control groups. Cluster randomization may better control for contamination given extensive social networks and resource exchange among PWUD [29]."

"Methadone is a long-acting µ-opioid receptor agonist, introduced in the 1960s, after being developed in Germany at the end of World War II.⁶⁰ It has an onset of action within 30 minutes^61-63 and an average duration of action of 24 to 36 hours. Its oral bioavailability is excellent and approaches 90%. These unique pharmacologic properties ideally lend themselves to once-daily dosing for maintenance therapy, although, when used to treat chronic pain, methadone is generally dosed 3 times daily. When the dosage is judiciously titrated, methadone treated patients generally do not experience euphoria or sedation, nor do they suffer impairment in the ability to perform mental tasks. One of the most important advantages of methadone is that it relieves narcotic craving, which is the primary reason for relapse. Similarly, methadone blocks many of the narcotic effects of heroin,⁶⁴ which helps reinforce abstinence. Once a therapeutic dose is achieved, patients frequently can be maintained for many years with the same dose.⁶⁵

"Methadone hydrochloride is available in 5- and 10-mg tablets as well as a 40-mg dispersible wafer. However, it is most frequently used for maintenance in a 10-mg/mL liquid concentrate. An intravenous solution is also available but has been linked with bradycardia when administered for sedation."

"Multiple studies that have examined why some persons who abuse prescription opioids initiate heroin use indicate that the cost and availability of heroin were primary factors in this process. These reasons were generally consistent across time periods from the late 1990s through 2013.^34-41 Some interviewees made reference to doctors generally being less willing to prescribe opioids as well as to increased attention to the issue by law enforcement, which may have affected the available supply of opioids locally.^38,40"

"There is evidence for the existence of opium poppy in Europe as long ago as 4,200 B.C. and even earlier.^a There are also references towards opium use in ancient Greece, starting around 1,500 B.C. during the Minoan culture, with various references in the 7th century B.C. (Iliad and Odyssey) and during the reign of Alexander the Great (4th century B.C.) whose troops and medical doctors apparently introduced opium to Central Asia and India.^b In Asia, opium was already produced and used by the Sumerians earlier than 3000 B.C, in Mesopotania (today’s Iraq)c from where the know-how was passed on to the Assyrians, the Babylonians, the Egyptians (1,300 B.C.) and other peoples in the region.⁶ China got acquainted to opium via Arab merchants, with dates given in the literature ranging from around 4th⁷ to the 8th century A.D.⁸"

"In our study, there was greater evidence for an association between substance use and chronic pain among inpatients than among MMTP [Methadone Maintenance Treatment Program] patients. Among inpatients, there were significant bivariate relationships between chronic pain and pain as a reason for first using drugs, multiple drug use, and drug craving. In the multivariate analysis, only drug craving remained significantly associated with chronic pain. Not surprisingly, inpatients with pain were significantly more likely than those without pain to attribute the use of alcohol and other illicit drugs, such as cocaine and marijuana, to a need for pain control. These results suggest that chronic pain contributes to illicit drug use behavior among persons who were recently using alcohol and/or cocaine. Inpatients with chronic pain visited physicians and received legitimate pain medications no more frequently than those without pain, raising the possibility that undertreatment or inability to access appropriate medical care may be a factor in the decision to use illicit drugs for pain."

"Among people aged 12 or older in 2022, 0.4 percent (or 1.0 million people) used heroin in the past year (Figures 13 and 18 and Table A.5B). The percentage was highest among adults aged 26 or older (0.4 percent or 991,000 people), followed by young adults aged 18 to 25 (0.2 percent or 55,000 people), then by adolescents aged 12 to 17 (less than 0.05 percent or 3,000 people)."

"Harms of xylazine use in humans are not well documented, but evidence suggests that combined use of xylazine and an opioid such as fentanyl may increase the risk of overdose fatality.¹ Although naloxone, the opioid overdose reversal drug, is not effective against xylazine alone, unintentional fatal overdoses with xylazine detections also had heroin and/or fentanyl detections in Philadelphia, indicating timely administration of naloxone is critical for preventing deaths. Additional treatment for xylazine poisoning may involve supportive care using intubation, ventilation and administration of intravenous fluid.¹

"Of note, as fentanyl has largely replaced the heroin supply in Philadelphia, xylazine has been increasingly found in combination with fentanyl. Some evidence suggests that the combination of xylazine and fentanyl in humans may potentiate the desired effect of sedation and the adverse effects of respiratory depression, bradycardia and hypotension caused by fentanyl alone,¹ comparable to the synergistic effects of combining benzodiazepines with heroin and/or fentanyl.⁷ While benzodiazepines were detected in 97 (58%) of the 168 unintentional overdose deaths with heroin and/or fentanyl detections in Philadelphia in 2010, this decreased to 232 (28%) of the 858 unintentional overdose deaths with heroin and/or fentanyl detections in 2019. This decline may be the result of increasing demand for xylazine among people who use drugs in Philadelphia and/or changes in the illicit drug market as drug seizure data indicate that xylazine is increasing in polydrug samples. Indeed, focus groups with people who use drugs in Philadelphia have suggested that the addition of xylazine to fentanyl “makes you feel like you’re doing dope (heroin) in the old days (before it was replaced by fentanyl)” when the euphoric effects lasted longer."

"Findings from these recent surveys of SSP clients in Seattle showed that goofball use is common, with over half of respondents reporting using heroin and methamphetamine together. Moreover, PWID whose main drug was goofball reported considerable health risks and morbidity, including more frequent injection, femoral and jugular vein injection, public injection, abscesses and skin infections, infected blood clots and blood infections, and endocarditis. They also reported more overdose-related risk including injecting alone and witnessing both opioid and stimulant overdoses. At the same time, the majority of PWID who reported that goofball was their main drug also reported interest in reducing or stopping their drug use. In light of the opioid crisis in the U.S., it is critical for stakeholders to recognize the substantial and growing overlap between opioid and methamphetamine use, acknowledge the contextual factors that may be driving the combined use of these drugs, and develop health interventions accordingly.

"Polysubstance use is a global phenomenon, especially the use of opioids in combination with stimulants, and has been associated with high levels of HIV and other negative health outcomes.^9–11 Prior opioid-stimulant co-use research has mostly focused on speedball. At present, there is limited epidemiologic data on the unique health effects of combined heroin and methamphetamine use. Due to the shorter half-life of heroin relative to methamphetamine,¹² people using goofball may re-dose when the effects of heroin wane but before the effects of methamphetamine have worn off, potentially leading to the unsafe injection behaviors or overdose.

"A very high proportion (82.5%) of people whose main drug was goofball were homeless or unstably housed. This aligns with dramatic increases in homelessness in the Seattle area.¹³ Many other observed associations with goofball use are correlated with homelessness. People living outdoors may use stimulants to counter the depressant effects of opioids to remain more aware of their possessions and surroundings.¹⁴ However, further research is needed to better understand the motivations and causes of the increase in methamphetamine use, particularly among this largely homeless population with high levels of risk and vulnerability."

"Despite a 19 per cent decline in the quantity of opiates seized globally from 2017 to 2018 (calculated on the basis of converting those seizures into heroin equivalents), dropping to 210 tons, that was still the third highest amount ever reported and continued to exceed the quantity of pharmaceutical opioids seized.² The overall decline in the quantity of opiates seized in 2018 was mostly due to a decrease by half in the quantity of morphine seized. The quantity of opium and heroin seized, by contrast, remained rather stable in 2018 (+2 per cent for opium; and -6 per cent for heroin on a year earlier).

"The opiate seized in the largest quantity in 2018 continued to be opium (704 tons), followed by heroin (97 tons) and morphine (43 tons). Expressed in heroin equivalents, however, heroin continued to be seized in larger quantities than opium or morphine. Globally, 47 countries reported opium seizures, 30 countries reported morphine seizures and 103 countries reported heroin seizures in 2018, suggesting that trafficking in heroin continues to be more widespread in geographical terms than trafficking in opium or morphine.

"The quantities of opium and morphine seized continued to be concentrated in just a few countries in 2018, with three countries accounting for 98 per cent of the global quantity of opium seized and 97 per cent of the global quantity of morphine seized. By contrast, seizures of heroin continue to be more widespread, with 54 per cent of the global quantity of heroin seized in 2018 accounted for by the three countries with greatest seizures."

"In the Seattle area, the increase in methamphetamine use has paralleled an increase in methamphetamine-involved deaths, many of which also involved opioids.³⁵ Although we did not find that people who primarily use goofball were more likely than others to experience an opioid overdose or stimulant overdose/overamp, several behaviors associated with overdose were higher in this group including more frequent injection and injecting alone. Moreover, people who primarily use goofball were the most likely to witness opioid and stimulant overdoses, highlighting the critical importance of engaging this group in overdose prevention services. Fortunately, naloxone possession was also highest in this group, suggesting that these efforts have been successful."

"The role of co-use of heroin and methamphetamine in overdose requires greater exploration. Intentional co-use of heroin and methamphetamine is increasing in the US, whether in simultaneous injection as a ‘goofball’, sequential injection or other combined modes, including smoking and snorting. Supply changes have played a part in widespread distribution of ‘ice’ or ‘cream’, a more potent and lower price Mexican-sourced methamphetamine supplanting the domestic product [10, 16].

"‘Goofball’ was originally a term for barbiturate-type drugs with the earliest mention in the literature as heroin-methamphetamine injection in 2005 [17]. Heroin and methamphetamine co-use (referred to in some locations as a goofball and in others as a speedball, which historically has been a combination of heroin and cocaine) is spreading in locations as varied as Seattle, Washington; San Diego, California; Denver, Colorado; and Dayton, Ohio [18,19,20,21]. Qualitative research has found many people who use drugs (PWUD) believe methamphetamine can prevent or reverse opioid-related overdoses [20] and reduce withdrawal severity [22]. A study in Vancouver, Canada, found that practitioners used goofballs bi-directionally, both to enhance the individual effects of opioids and methamphetamine and to control for each drug’s negative effects [23]. However, knowledge about forms of co-use of methamphetamine and heroin, particularly from recent years, is needed to understand rising mortality among people using methamphetamine."

"Motives for using methamphetamine with heroin/fentanyl can be conceptualized as forming three thematic categories: ‘intrinsic use’, representing the inherent pleasure of the combination or self-medication of particular conditions; ‘opioid assisting use’ in which methamphetamine helped manage existing heroin/fentanyl use and ‘reluctant or indifferent use’. All 30 individuals had some experience using methamphetamine, whether separately or combined with heroin.

"We heard about and witnessed several ways that people used the two drugs, including simultaneous or alternating injections along a temporal spectrum. Daily order of dosing was another important and varied aspect of goofball use, with participants’ strategies dependent upon time of day, activity level, social situations and other factors. Most participants prioritized heroin over methamphetamine due to managing both opioid withdrawal and limited financial resources. Participants generally used the term ‘heroin’ to describe heroin, heroin adulterated with fentanyls and fentanyls without heroin; this language is reproduced in this paper to incorporate both drugs. Participants used the term ‘speedball’ to indicate co-injection of heroin and methamphetamine simultaneously, and generally did not use this term to refer to use separated in either time or mode of use (snorting, smoking). Ratios of heroin to methamphetamine within a speedball varied significantly among participants based on opioid tolerance, social situations and personal preference.

"The co-use of heroin and methamphetamine, known locally as a ‘speedball’, a term used elsewhere to describe a cocktail of heroin and cocaine, gained popularity among our sample within the last several years, and was virtually unknown before approximately 2015. This was despite the earlier presence of domestically produced ‘shake and bake’Footnote1 methamphetamine in the local drug culture, albeit recently less widely available than the newer ice. Heroin was also a latecomer to the area, with evidence suggesting that the local market developed from 2012 onwards [35]. Among participants where the order of drug progression was clear, all had initiated their opioid use with prescription opioid pills, but had transitioned to heroin after the pills became prohibitively expensive and more difficult to obtain."

"Polysubstance use may increase the risk of opioid overdose [36, 37] but although studies have found associations between overdose and combined use of heroin with other sedatives [38], the literature on overdose risk from heroin-stimulant combinations is limited [19, 39]. Goofball use has been associated with larger networks of PWID [19], which while potentially protective against overdose, may increase the likelihood of sharing injection equipment and contribute to transmission of bloodborne infections. Additionally, participants reported using methamphetamine to alter their sleep schedules or that methamphetamine use kept them awake for days, and the impact of sleep disturbances on susceptibility to opioid overdose needs additional study.

"Consistent with other studies [20], several respondents strongly believed in the ability of methamphetamine to prevent and reverse opioid overdose. Set against this are statistical data that show greater frequency of overdose among individuals co-using methamphetamine and heroin compared to people solely using heroin [19, 40] and rising numbers of deaths involving combinations of fentanyl and methamphetamine [41]. Increased mortality from co-use of these substances could represent greater co-use of methamphetamine overall or escalating fentanyl saturation of the opioid market but does not explain the lay belief in the possible protective effects of methamphetamine against opioid overdose.

"A potential explanation arises from recent mouse-model data which shows a bi-directional effect of amphetamine on fentanyl-depressed respiration depending on amphetamine dosage. Lower amphetamine doses depressed respiration after fentanyl, increasing the likelihood of overdose but higher amphetamine doses elevated respiration [42]. If applicable to humans, this finding may help to explain the apparent contradiction of methamphetamine both increasing and reducing the risks of fatal overdose and could lead to the development of important harm reduction strategies. However, more specific research on this drug interaction in humans is needed to understand this causal pathway.

"The importance of dosage and drug sequence when using methamphetamine to mitigate adverse respiratory effects of opioids, fentanyl in particular, requires further study. Order of use may not be evident in post-mortem toxicology and the interaction of these drug mechanisms over time needs further exploration. Amidst rising amphetamine-related hospitalizations [43, 44], research should also consider other specific morbidity risks posed by co-use of opioids and methamphetamine, including how non-injection modes of use (i.e. smoking, snorting [45]) may impact morbidity and mortality (e.g. by reducing HIV/HCV or overdose risks)."

"Methamphetamine use is increasing in the wake of the opioid crisis in the United States (U.S.). Increases in the use of this highly addictive stimulant have been documented in the health literature^1,2 as well as in the national media.³ In Denver, Colorado, and Seattle, Washington, the increase in methamphetamine use has predominantly involved a growing proportion of people who inject drugs (PWID) using both methamphetamine and heroin, either separately or in a single injection commonly known as a goofball.^1,2 (Goofball can also be smoked.) Data from San Diego, California, and Tijuana, Baja California, Mexico have also demonstrated high levels of co-injection of methamphetamine and heroin.⁴

"Although existing literature provides some insight into the characteristics and circumstances of people who inject goofball, the available data remain very limited. We previously published an analysis of data from syringe services program (SSP) clients in the Seattle area between 2009 and 2017, and found that people who used goofball were significantly more likely than other PWID to be young, homeless, inject daily, and self-report an opioid overdose.² Additional data on specific injection behaviors, other health outcomes, and interest in treatment among people who inject goofball are needed to understand how to most effectively implement harm reduction and substance use treatment efforts. In addition, it is important to focus on people whose primary drug is goofball to determine how the needs of this potentially high acuity group may differ from people predominantly using other drugs."

"Prior to the widespread availability of xylazine in the Philadelphia drug supply, it was often mentioned in passing by residents of the majority Puerto Rican neighborhood where our fieldwork was based as a powerfully psychoactive additive ‘“back on the Island”.’ Xylazine was occasionally detected in fatal overdoses in Philadelphia as early as 2006 (Wong et al., 2008), but it was not common knowledge among PWID. Significantly, however, many of our long-term informants recently immigrating/returning from Puerto Rico spoke with a mix of intrigue and apprehension about the psychoactive effects and health risks of 'anastesia de caballo [horse tranquilizer]'."

"At least a decade after Xylazine became a fixture in Puerto Rico, it entered the street opioid supply in Philadelphia as a more prevalent additive in the mid-2010s. The shift was noted by PWID, as well as harm reductionists and city public health officials (Johnson et al., 2021). PWID began to describe xylazine – often referred to as tranq – as a known element of specific ‘stamps’ or brands of opioid products in the illicit retail market. Opioid formulations containing xylazine, (e.g.,'tranq dope') became largely sought-after, as the addition of xylazine was reported to improve the euphoria and prolong the duration of fentanyl injections, in particular, solving 'the problem' of the 'short legs' of the otherwise euphoric effects of illicitly manufactured fentanyl."

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

"Total global opium production jumped by 65 per cent from 2016 to 2017, to 10,500 tons, easily the highest estimate recorded by UNODC since it started estimating global opium production at the beginning of the twenty-first century.

"A marked increase in opium poppy cultivation and a gradual increase in opium poppy yields in Afghanistan resulted in opium production in the country reaching 9,000 tons in 2017, an increase of 87 per cent from the previous year. Among the drivers of that increase were political instability, lack of government control and reduced economic opportunities for rural communities, which may have left the rural population vulnerable to the influence of groups involved in the drug trade.

"The surge in opium poppy cultivation in Afghanistan meant that the total area under opium poppy cultivation worldwide increased by 37 per cent from 2016 to 2017, to almost 420,000 ha. More than 75 per cent of that area is in Afghanistan.

"Overall seizures of opiates rose by almost 50 per cent from 2015 to 2016. The quantity of heroin seized globally reached a record high of 91 tons i 2016. Most opiates were seized near the manufacturing hubs in Afghanistan."

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.

"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."

"People who use heroin over the long term may develop:

"insomnia

"collapsed veins for people who inject the drug

"damaged tissue inside the nose for people who sniff or snort it

"infection of the heart lining and valves

"abscesses (swollen tissue filled with pus)

"constipation and stomach cramping

"liver and kidney disease

"lung complications, including pneumonia

"mental disorders such as depression and antisocial personality disorder

"sexual dysfunction for men

"irregular menstrual cycles for women

"Other Potential Effects

"Heroin often contains additives, such as sugar, starch, or powdered milk, that can clog blood vessels leading to the lungs, liver, kidneys, or brain, causing
permanent damage. Also, sharing drug injection equipment and having impaired judgment from drug use can increase the risk of contracting infectious diseases such as HIV and hepatitis (see "Injection Drug Use, HIV, and Hepatitis")."

"Pain was very prevalent in representative samples of 2 distinct populations with chemical dependency, and chronic severe pain was experienced by a substantial minority of both groups. Methadone patients differed from patients recently admitted to a residential treatment center in numerous ways and had a significantly higher prevalence of chronic pain (37% vs. 24%). Although comparisons with other studies of pain epidemiology are difficult to make because of methodological differences, the prevalence of chronic pain in these samples is in the upper range reported in surveys of the general population. The prevalence of chronic pain in these chemically dependent patients also compares with that in surveys of cancer patients undergoing active therapy, approximately a third of whom have pain severe enough to warrant opioid therapy."

"The majority of drug deaths in an Australian study, conducted by the National Alcohol and Drug Research Centre, involved heroin in combination with either alcohol (40 percent) or tranquilizers (30 percent)."

"There can be no doubt, however, that fatal opioid overdose, long a chronic health problem in the United States, is now a rapidly growing one.⁷¹ National surveillance data suggest that almost 83,000 Americans died from this form of overdose between 1999 to 2005, with over 16,000 fatalities in 2005 alone.⁷² Opioid overdose death has seen a sharp increase over the last decade, especially in the category of overdose from prescription medications.⁷³ Because of gaps in the surveillance system, the actual figure is likely to be substantially higher."

"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"

"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."

"The withdrawal syndrome usually includes symptoms and signs of CNS hyperactivity. Onset and duration of the syndrome depend on the specific drug and its half-life. Symptoms may appear as early as 4 h after the last dose of heroin, peak within 48 to 72 h, and subside after about a week. Anxiety and a craving for the drug are followed by increased resting respiratory rate (> 16 breaths/min), usually with diaphoresis, yawning, lacrimation, rhinorrhea, mydriasis, and stomach cramps. Later, piloerection (gooseflesh), tremors, muscle twitching, tachycardia, hypertension, fever and chills, anorexia, nausea, vomiting, and diarrhea may develop. Opioid withdrawal does not cause fever, seizures, or altered mental status. Although it may be distressingly symptomatic, opioid withdrawal is not fatal.
"The withdrawal syndrome in people who were taking methadone (which has a long half-life) develops more slowly and may be less acutely severe than heroin withdrawal, although users may describe it as worse. Even after the withdrawal syndrome remits, lethargy, malaise, anxiety, and disturbed sleep may persist up to several months. Drug craving may persist for years."

"Sixteen of 19 CEWG area representatives reported stable or increasing heroin indicators for the 2013 reporting period, compared with 2012. Indicators, including mainly mortality, primary treatment admissions, and some law enforcement indicators, were observed as increasing in Atlanta, Baltimore City and Maryland, Boston, Cincinnati, Denver/Colorado, Maine, Minneapolis/St. Paul, New York City, San Francisco, Seattle, South Florida/Miami-Dade and Broward Counties, and Texas. Heroin levels were described as high relative to other drugs and indicators as relatively stable by area representatives from Chicago, Detroit, St. Louis, and San Diego. Heroin indicators were reported by area representatives as mixed (with some indicators decreasing, some stable, and some increasing) in two CEWG areas — Los Angeles and Phoenix. Trends for heroin were unclear in Philadelphia in this reporting period, according to the area representative. None of the 19 CEWG area representatives reported declining indicators for heroin for 2013."

"The prevalence of heroin use is extremely difficult to estimate despite the fact that harm to society associated with heroin marketing and use is substantial. A disproportionate number of heroin users are part of the nonsampled populations in general prevalence surveys (persons with no fixed address, prison inmates, etc.) Also, heroin users are believed to represent less than one half of one percent of our total population, making heroin usage a relatively rare event. Sample surveys are not sensitive enough to measure rare events reliable. Data from the National Household Survey on Drug Abuse (which is considered to produce conservative estimates), indicated that 1.9 percent of blacks, 1.6 percent of Hispanics, and 1.4 percent of whites had ever tried heroin. As will be noted later in this report, the data available from hospital emergency rooms and from drug abuse treatment programs indicated that heroin use is a more serious problem among blacks than whites and Hispanics."

"The total quantity of heroin seized globally reached a record high in 2016, while the quantities of opium and morphine seized reached the second highest level ever reported. The largest quantities of opiates seized were of opium (658 tons), followed by seizures of heroin (91 tons) and morphine (65 tons). Overall seizures of opiates, expressed in heroin equivalents, increased by almost 50 per cent from 2015 to 2016, of which the quantity of heroin seized exceeded that of opium and morphine.

"As most seizures of opiates are made in, or close to, the main opium production areas, Asia, which is responsible for more than 90 per cent of global illicit opium production, accounted for 86 per cent of the total quantity of heroin and morphine seized in 2016. This is primarily a reflection of the increasing concentration of opium production in Afghanistan and the consequent increase in seizures by neighbouring countries.

"Similarly to the distribution of heroin and morphine seizures, overall, 90 per cent of the total quantity of opiates (including opium), expressed in heroin equivalent, was seized in Asia, the vast majority in the Near and Middle East/South-West Asia (83 per cent), while 6 per cent was seized in East and South- East Asia."

"By far the highest prevalence of HIV among PWID [People Who Inject Drugs] is in South-West Asia and in Eastern and South-Eastern Europe, with rates that are, respectively, 2.4 and 1.9 times the global average. Together, those two subregions account for 49 per cent of the total number of PWID worldwide living with HIV. Although the prevalence of HIV among PWID in East and South-East Asia is below the global average, 24 per cent of the global total of PWID living with HIV reside in that subregion. An estimated 53 per cent of PWID living with HIV worldwide in 2016 (662,000 people) resided in just three countries (China, Pakistan and the Russian Federation), which is disproportionately large compared with the percentage of the world’s PWID living in those three countries (35 per cent)."

"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."

"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."

"A few key conclusions and discussion points regarding the state and future of HAT (heroin-assisted treatment) can be offered based on the above review of completed or ongoing studies.

"First, although the basic goal of the different HAT studies is similar, each of the studies is distinct in key aspects, thus limiting direct comparisons and meta-analyses.⁴⁰ Although this might be a desirable goal for science, it should be noted that heroin addiction and its consequences occur in distinct real-life environments (including unique cultural and system factors), and interventions need to be devised, measured, and evaluated within these to have authentic relevance for policy and practice.^33,41

"Second, the discussed studies above have demonstrated in several different contexts that the implementation of HAT is feasible, effective, and safe as a therapeutic intervention.^21,24,26,30 This should not be seen as a conclusion that could be taken for granted because many observers expected disastrous consequences from the provision of medical heroin prescription.

"Third, even within the contexts of relevant methodological constraints, e.g., the Swiss study relying purely on prospective observational data, and most of the other RCTs comparing HAT outcomes against a control intervention (MMT), which participants have previously either rejected by choice or proven to be ineffective, ^32,42 the reviewed HAT studies have demonstrated rather robust and consistently positive therapeutic outcomes on the various indicators chosen for a population of high-risk heroin addicts for whom currently no effective alternative therapies are available. Clearly, this demonstrated effectiveness is at this point limited to short-term outcomes, and long-term examinations ought to follow (albeit Swiss follow-up data present initial positive evidence in this regard).⁴³ It may very well emerge that HAT's main long-term benefit does not materialize through life-long maintenance, but by stabilizing and readying many of its patients for other simpler therapeutic interventions or even abstinence.

"Fourth, also given the current expansion and diversification of alternative oral opioid maintenance therapies (e.g., buprenorphine and morphine) and considering the complex logistics (on both providers and patients_ ends), high costs, and sociopolitical controversy around (especially injection) HAT, the most sensible role of HAT is likely that of an exceptional 'last resort' option for heroin addicts who cannot be effectively attracted into or treated in other available therapeutic interventions.^44,45 Granted the above, the primary emerging challenge for science—rather than conducting new and more HAT effectiveness studies—is to provide evidence-based guidelines on how to effectively match existing heroin addict profiles and needs with existing treatment options. This challenge has recently been complicated—in at least some jurisdictions—with the increasing diversification of heroin into poly-opioid (e.g., prescription) use profiles.⁴⁶

"Finally, after extensive HAT research efforts over the past decade, the principal onus of action has shifted from the scientific to the political arena in the jurisdictions under study.^12,18 Despite the overall positive results of completed HAT trials undoubtedly justifying some role of HAT in the addiction treatment landscape, authorities in only two countries, Switzerland and the Netherlands, have decisively acted on this issue.³⁴"

"Diacetylmorphine was found to be a dominant strategy over methadone maintenance treatment in each time horizon studied (Table 2). Over a lifetime horizon, people in the methadone cohort lived 14.54 years on average following entry into the model, spending 8.79 years (60% of their remaining life) in treatment and 5.52 years in relapse. They accumulated 7.46 discounted QALYs and generated a societal cost of $1.14 million. People in the diacetylmorphine cohort lived 15.45 years on average, spending 10.41 years (67% of their remaining life) in treatment (2.34 years of which was in post-diacetylmorphine methadone treatment) and 4.05 years in relapse. They accumulated 7.92 discounted QALYs and generated a societal cost of $1.10 million. Based on these findings in the baseline model, over a lifetime horizon the provision of diacetylmorphine in the hypothetical cohort provided greater incremental health benefits and reduced the total costs to society compared with methadone maintenance treatment."

"More than 60 per cent of drug treatment demand in Asia and Europe relate to opiates that are, especially heroin, the most deadly drugs. Deaths due to overdose are, in any single year, as high as 5,000-8,000 in Europe, and several times this amount in the Russian Federation alone."

Heroin
"• Heroin was reported as the primary substance of abuse for 26 percent of TEDS admissions aged 12 and older in 2015 [Table 1.1b].

"• Sixty-seven percent of primary heroin admissions were non-Hispanic White (41 percent were males and 26 percent were females). Non-Hispanic Blacks made up 14 percent (9 percent were males and 5 percent were females). Admissions of Puerto Rican origin made up 7 percent of primary heroin admissions (6 percent were males and 1 percent were females) [Table 2.3b]. See Chapter 3 for additional data on heroin admissions.

"• Injection was reported as the usual route of administration by 68 percent of primary heroin admissions; inhalation was reported by 25 percent. Daily heroin use was reported by 63 percent of primary heroin admissions [Table 2.4b].

"• Twenty-two percent of primary heroin admissions had no prior treatment episode, and 25 percent had been in treatment five or more times previously [Table 2.5b].

"• Primary heroin admissions were less likely than all admissions combined to be referred to treatment by the court/criminal justice system (14 vs. 30 percent) and more likely to be self or individually referred (61 vs. 41 percent) [Table 2.6b].

"• Medication-assisted opioid therapy was planned for 37 percent of heroin admissions [Table 2.7b].

"• Only 17 percent of primary heroin admissions aged 16 and older were employed (vs. 25 percent of all admissions that age); 45 percent were not in labor force (vs. 39 percent of all admissions that age) [Table 2.8b].

"• Sixty-one percent of primary heroin admissions reported abuse of additional substances. Marijuana/hashish was reported by 18 percent, alcohol by 14 percent, and non-smoked cocaine by 13 percent [Table 3.8].

Opiates Other than Heroin
"• Opiates other than heroin were reported as the primary substance of abuse for 8 percent of TEDS admissions aged 12 and older in 2015 [Table 1.1b]. These drugs include methadone, buprenorphine, codeine, hydrocodone, hydromorphone, meperidine, morphine, opium, oxycodone, pentazocine, propoxyphene, tramadol, and any other drug with morphine-like effects.

"• Admissions for primary opiates other than heroin were more likely than all admissions combined to be aged 20 to 39 (74 vs. 58 percent) [Table 2.1b].

"• Non-Hispanic Whites made up approximately 82 percent of admissions for primary opiates other than heroin (43 percent were males and 39 percent were females) [Table 2.3b].

"• The usual route of administration most frequently reported by admissions of primary opiates other than heroin was oral (61 percent); next were inhalation (18 percent) and injection (16 percent) [Table 2.4b].

"• Admissions for primary opiates other than heroin were more likely than all admissions combined to report first use after age 18 (66 vs. 39 percent) [Table 2.5b].

"• Medication-assisted opioid therapy was planned for 31 percent of admissions for primary opiates other than heroin [Table 2.7b].

"• Fifty-eight percent of admissions for primary opiates other than heroin reported abuse of other substances. The most commonly reported secondary substances of abuse were marijuana/hashish (22 percent), alcohol (16 percent), and tranquilizers (12 percent) [Table 3.8]."

"During the course of treatment, many treatment seekers stopped using the drugs that they reported using at entry to the study. Lower rates of drug use were recorded at each follow-up. Furthermore, those that continued to use tended to use less. Most of the changes observed occurred by first follow-up. For most forms of drug use, no particular treatment modality was more associated with cessation than any other and the route into treatment (CJS or non-CJS) did not influence drug-use outcomes.

"The proportion using each drug reduced significantly between baseline and follow-up (Figure 5). Most of this change occurred by first follow-up; indeed use of some drug types increased marginally, and levels of abstinence from all drugs decreased between first and second follow-up.

"The proportion of treatment seekers using heroin, crack, cocaine, amphetamine or benzodiazepines decreased between baseline and follow-up by around 50 per cent; the proportion using non-prescribed methadone or other opiates such as morphine, decreased by considerably more; but the proportion using cannabis or alcohol decreased by considerably less.The proportion who reported each drug to be causing problems fell substantially for all drug types, suggesting that continued use was often, in the client’s view, non-problematic."

"The total area under opium poppy cultivation worldwide is estimated to have increased by some 37 per cent to almost 420,000 ha from 2016 to 2017, primarily reflecting an increase in the cultivation of opium poppy in Afghanistan. With 328,000 ha under opium poppy cultivation, Afghanistan accounted for more than three quarters of the estimated global area under illicit opium poppy cultivation in 2017, a record level.

"By contrast, opium poppy cultivation in Myanmar, the country with the world’s second largest area under opium poppy cultivation (accounting for 10 per cent of the global estimated area in 2017), declined over the period 2015–2017 by some 25 per cent to 41,000 ha, the lowest level since 2010.

"Global opium production increased by 65 per cent to 10,500 tons in 2017, the highest level since UNODC started estimating global opium production on an annual basis at the beginning of the twenty-first century.¹ The surge in global production primarily reflects an 87 per cent increase in opium production in Afghanistan to a record high of 9,000 tons, equivalent to 86 per cent of estimated global opium production in 2017. The increase in production in Afghanistan was not only due to an increase in the area under poppy cultivation but also to improving opium yields. There is no single reason for the massive increase in opium poppy cultivation in Afghanistan in 2017 as the drivers are multiple, complex and geographically diverse, and many elements continue to influence farmers’ decisions regarding opium poppy cultivation. A combination of events may have exacerbated rule-of-law challenges, such as political instability, corruption, a lack of government control and security. The shift in strategy by the Afghan Government — focusing its efforts on countering anti-government elements in densely populated areas — may have made the rural population more vulnerable to the influence of anti-government elements. A reduction in the engagement of the international aid community may also have hindered socioeconomic development opportunities in rural areas.²

"As a result of the massive increase in opium production in 2017, opium prices fell in Afghanistan by 47 per cent from December 2016 to December 2017. However, the price of high-quality Afghan heroin decreased by just 7 per cent over the same period, which may be an indication that heroin manufacture to date has increased far less than opium production.³ Of the 10,500 tons of opium produced worldwide in 2017, it is estimated that some 1,100–1,400 tons remained unprocessed for consumption as opium, while the rest was processed into heroin, resulting in an estimate of between 700 and 1,050 tons of heroin manufactured worldwide (expressed at export purity), 550–900 tons of which were manufactured in Afghanistan."

"Afghanistan maintained its position as the lead producer and cultivator of opium globally. With a global total of over 236,000 hectares under cultivation, illicit cultivation of opium poppy reached peak levels in 2012, surpassing the 10-year high recorded in 2007. This was mainly the result of increases in Afghanistan and Myanmar (the two main producers). A preliminary assessment of opium poppy cultivation trends in Afghanistan in 2013 revealed that such cultivation is likely to increase in the main opium growing regions, which would be the third consecutive increase since 2010.⁶² Mexico remained the largest grower of opium poppy in the Americas. An overview of global potential production of opium and manufacture of heroin, as well as country data on opium poppy cultivation and eradication and opium production can be found in Annex II.
"The fluctuations which characterized opium production in Afghanistan in recent years, also affected Europe, the main market for opiates. Heroin use decreased in Western and Central Europe, which can be ascribed to a change in the structure of the market, which has seen decreased supply, increased law enforcement activity and an ageing user population, combined with an increase in the availability of treatment. However, the same does not apply to the non-medical use of prescription opioids."

"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"

"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."

"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"

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

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

"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."

"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."

"Ninety-three percent of police respondents had attended a serious opioid overdose (defined in the survey) in their career, with 64 % having attended one in the past year. While 77 % of officers felt it was important they were at the scene of an overdose to protect medical personnel, a minority, 34 %, indicated it was important they were present for the purpose of enforcing laws. Arrest during the last overdose officers encountered was rare, with only 1 % of overdose victims and 1 % of bystanders being arrested. In cases in which no arrest was made, 25 % reported confiscating drugs or paraphernalia.

"The majority, 62 %, indicated the law would not change their behavior at a future overdose because they would not have arrested anyone at the scene of an overdose anyway. Smaller proportions indicated they would be less likely to arrest (14 %), did not know what they would do (20 %), or would continue to arrest people at the scene of an overdose (4 %)."

"Among heroin users, research indicates fear of police response as the most common barrier to not calling 911 during overdoses.^12,13 In a Baltimore study, 37 % of injection drug users who did not call 911 during an overdose endorsed concerns about police as the most important reason they did not call.¹³ Several states have enacted laws, commonly called Good Samaritan laws, to encourage calling 911 during overdoses on controlled substances; these laws are in part modeled on college campus alcohol Good Samaritan policies.¹⁴ Overdose Good Samaritan laws had been adopted in ten states as of the end of 2012, but they have not yet been evaluated.¹⁵ Generally, the laws include provisions that provide immunity from criminal prosecution for drug possession to overdose victims and to those who seek medical aid. Eight states have passed laws that ease access to take-home-naloxone by allowing the prescription of naloxone (an opioid antagonist or antidote) to persons at risk for having or witnessing an overdose, enabling bystanders to quickly respond in the event of an overdose.^3,15 Previous research suggests that police are sometimes under-informed, and often ambivalent to public health laws, especially those based in a risk reduction framework.^16,17"

"Similar evidence of the drug war’s failure is provided by US drug surveillance data. For example, from 1981 to 2011, the budget of the US Office of National Drug Control Policy increased by more than 600 percent (inflation-adjusted). However, despite increasing annual multibillion dollar investments in drug control, US government data suggest an approximate inflation- and purity-adjusted decrease in heroin price of 80 percent, and a greater than 900 percent increase in heroin purity between 1981 and 2002, clearly indicating that expenditures on interventions to reduce the supply of heroin into the United States were unsuccessful."

"We do think that the expansion in the world supply of heroin, particularly in the 1990s, had the effect of dramatically raising the purity of heroin available on the streets, thus allowing for new means of ingestion. The advent of new forms of heroin, rather than any change in respondents’ beliefs about the dangers associated with injecting heroin, very likely contributed to the fairly sharp increase in heroin use in the 1990s. Evidence from this study, showing that a significant portion of the self-reported heroin users in recent years are using by means other than injection, lends credibility to this interpretation. The dramatic decline in LSD use in the early to mid-2000s is also not explainable by means of concurrent changes in perceived risk or disapproval; but availability did decline sharply during this period and very likely played a key role in reducing the use of that drug."

"Acute intoxication is characterized by euphoria and drowsiness. Mast cell effects (eg, flushing, itching) are common, particularly with morphine. GI [gastro-intestinal] effects include nausea, vomiting, decreased bowel sounds, and constipation."

"Tolerance develops quickly, with escalating dose requirements. Tolerance to the various effects of opioids frequently develops unevenly. Heroin users, for example, may become relatively tolerant to the drug's euphoric and respiratory depression effects but continue to have constricted pupils and constipation.
"A minor withdrawal syndrome may occur after only several days' use. Severity of the syndrome increases with the size of the opioid dose and the duration of dependence.
"Long-term effects of the opioids themselves are minimal; even decades of methadone use appear to be well tolerated physiologically, although some long-term opioid users experience chronic constipation, excessive sweating, peripheral edema, drowsiness, and decreased libido. However, many long-term users who inject opioids have adverse effects from contaminants (eg, talc) and adulterants (eg, nonprescription stimulant drugs) and cardiac, pulmonary, and hepatic damage due to infections such as HIV infection and hepatitis B or C, which are spread by needle sharing and nonsterile injection techniques (see Drug Use and Dependence: Injection Drug Use)."

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.

"Unlike alcohol or tobacco, heroin causes no ongoing toxicity to the tissues or organs of the body. Apart from causing some constipation, it appears to have no side effects in most who take it. When administered safely, its use may be consistent with a long and productive life. The principal harm comes from the risk of overdose, problems with injecting, drug impurities and adverse legal or financial consequences."

"In the last three to five years an increasing number of reports suggest that people who inject drugs (PWID) in Russia, Ukraine and other countries are no longer using poppies or raw opium as their starting material, but turning to over-the-counter medications that contain codeine (e.g. Solpadeine, Codterpin or Codelac). Codeine is reportedly converted into desomorphine (UNODC, 2012; Gahr et al., 2012a, 2012b, 2012c; Skowronek, Celinski, & Chowaniec, 2012). The drug is called Russian Magic, referring to its potential for short lasting opioid intoxication or, more common, to its street name, krokodil. Krokodil refers both to chlorocodide, a codeine derivate, and to the excessive harms reported, such as the scale-like and discolored (green, black) skin of its users, resulting from large area skin infections and ulcers. At this point, Russia and Ukraine seem to be the countries most affected by the use of krokodil, but Georgia (Piralishvili, Gamkrelidze, Nikolaishvili, & Chavchanidze, 2013) and Kazakhstan (Ibragimov & Latypov, 2012; Yusopov et al., 2012) have reported krokodil use and related injuries as well."

"In considering the drug krokodil, two aspects are of importance, its pharmacology and its chemistry. The short half-life, limited high after the impact effect and, in particular the need for frequent administration may narrow the attention of users on the (circular) process of acquiring, preparing and administering the drug, leaving little time for matters other than avoiding withdrawal and chasing high, as reported in several popular magazines (e.g. Shuster, 2011; Walker, 2011). However, when the layers of bootleg chemistry and attribution are peeled off, what’s left is an opioid analogue (or several ones) that, besides the variations in half-life, behaves pharmacologically not very different than heroin or Hanka (Haemmig, 2011). There are various paths to synthesize desomorphine from codeine, but the chemical process most commonly reported to be used by PWID in Russia and Ukraine is very similar to that of home-produced methamphetamine or Vint (Grund, Zábransky, Irwin, & Heimer, 2009; Zábransky, 2007) – a rudimentary version of a simple chemical reduction. The illicit production of krokodil reportedly involves the processing of codeine into the opiate analogue desomorphine (UNODC, 2012; Gahr et al., 2012a, 2012b, 2012c; Skowronek et al., 2012). Desomorphine (Dihydrodesoxymorphine-D or PermonidTM ) is an opiate analogue first synthesized by Small in 1932 (Small, Yuen, & Eilers, 1933). The analgesic effect of desomorphine is about ten times greater than that of morphine (and thus stronger than heroin), whereas its toxicity exceeds that of morphine by about three times (Weill & Weiss, 1951). The drug’s onset is described as very rapid but its action is of short duration, which may lead to rapid physical dependence and frequent administration."

"In recent years, harm reduction and drug treatment services from Russia, Ukraine, Georgia and Kazakhstan began reporting severe health consequences associated with krokodil injecting. Although serious localized and systemic harms have previously been associated with injecting homemade opiates and stimulants in the region (Grund, 2002; Volik, 2008), the harms associated with krokodil injecting are extreme and unprecedented. The most common complications of krokodil appear to be serious venous damage and skin and soft tissue infections, rapidly followed by necrosis and gangrene (Gahr et al., 2012a, 2012b, 2012c; Skowronek et al., 2012). Our research further identified an impressive, undoubtedly incomplete, list of injuries and symptoms (Table 1), reported in the media (e.g. Shuster, 2011; Walker, 2011) and identified in YouTube clips and photographs on the internet. Importantly, this list includes several parts of the body that are not typically used as sites for injecting drugs. This suggests that the ill effects of krokodil are not limited to localized injuries, but spread throughout the body (Shuster, 2011; UNODC, 2012), with neurological, endocrine and organ damage associated with chemicals and heavy metals common to krokodil production (Lisitsyn, 2010).
"It is important to note that the described harms seem to become manifest relatively shortly after krokodil injecting is initiated. Present accounts of krokodil related harms often concern young people presenting in emergency rooms and surgeries with extreme and advanced complications. According to NGOs that work with people who inject krokodil, these young people have relatively short histories of using the drug. Mortality rates among young krokodil users are reportedly high (Akhmedova, 2012; Shuster, 2011; Walker, 2011), with official reports associating krokodil use with half of all drug-related deaths in at least two Oblasts (Walker, 2011)."

"The estimated number of PWID in Russia was close to 2 million in 2008 (Mathers et al., 2008). 2.3% of the Russian population uses opioids annually and 1.4% heroin, compared to an annual prevalence of 0.4% opioid use in Western and Central Europe (UNODC, 2012). While actual epidemiological data is not available, a number of academic and media reports suggest that 5% or more of Russian drug users (approximately 100,000 PWID) may be injecting krokodil (Walker, 2011), while 'various official estimates' place the numbers of Russian PWID using krokodil as high as one million (Shuster, 2011). Epidemiological data is critical to evaluating claims that the use of krokodil is reaching epidemic proportions in Russia (Walker, 2011), and potentially, the Ukraine. There are an estimated 290,000 to 375,000 PWID in Ukraine (Mathers et al., 2008). A recent national survey found that 7% of PWID have used krokodil in 2011 (Balakireva, 2012), suggesting that around 20,000 PWID in Ukraine may have used krokodil that year. Balakireva and colleagues furthermore found statistically significant differences in krokodil use between the cities in the study, with most krokodil use reported in Uzhhorod (35.6%), Simferopol (26.9%), Kyiv (21.7%), Chernivtsi (15.5%) and Donetsk (12.6%). Estimates from other countries are not available. Outside of the former Soviet region, krokodil has been reported in Germany (Der Spiegel, 2011) and in Tromsø in northern Norway (Lindblad, 2012)."

"In sum, these observations suggest that the relatively limited availability of black market opiates and stimulants and the relative ease of harvesting legal precursors to powerful analogues from the countryside and pharmacies inspired and sustained a Soviet-style homemade drug culture in the Eastern European region that remains radically different from those observed in countries where narco-traffickers dominate the production and distribution of drugs (Booth, Kennedy, Brewster, & Semerik, 2003; Grund et al., 2009; Grund, 2005; Subata & Tsukanov, 1999; Zábransky, 2007).
"The physical and logistical exigencies of home production; its locus in networks of drug injecting friends and the high degree of cooperative action involved (in foraging for, producing and using the drugs); the multiple roles and ambiguous status of injecting paraphernalia; the routine occurrence of well-known risk behaviours (e.g. syringe sharing, frontloading) and those currently less well understood, such as the slapdash nature of the bootleg drug synthesis and its unpredictable outcomes in terms of actual drug product, purity and pollution— indeed all of these factors contribute to and interact within the vastly complex high risk environment of home drug production in the region."

"In Russia and many other post-Soviet countries, the old ideology lingers on in narcological institutes, out of sync with modern public and mental health concepts (Grund et al., 2009). Many narcologists continue to view addiction as criminal or moral deviance and not as a disease. Narcological dispensaries continue to share information with law enforcement (Mendelevich, 2011). The threat of removal of child custody rights may impede women’s access to health care in particular (Shields, 2009). Stigma and discrimination, hostile treatment and lack of confidentiality are persistent in the treatment of PWID and must be viewed as important barriers to timely seeking medical care (Beardsley & Latypov, 2012; Mendelevich, 2011; Wolfe et al., 2010). PWID have therefore strong incentives to avoid narcological facilities and, by association, other state health services. In their personal 'hierarchy of risk,' seeking help for significant health problems is subordinated by the need to stay under the radar of the authorities (Connors, 1992). Several of the YouTube clips on the internet furthermore document not only the gravity of harms among krokodil users, but also poor and inhumane treatment of those hospitalized with krokodil related injuries. In one video a man’s leg is sawn off under the knee with a lint saw in what seems not to be a surgical unit, but perhaps a common hospital ward. The man sits wide-awake in an ordinary wheelchair and holds his leg himself above a bucket, which was lined with a garbage bag just before. These videos and case reports (Asaeva et al., 2011; Daria Ocheret, personal communication, 2012; Sarah Evans, personal communication, 2012) suggest that the care provided to those with krokodil related injuries may be (grossly) substandard, sometimes exacerbated by improper diagnosis and faulty clinical decisions."

Possible federal sentences for heroin possession include:
Amount: 1 kilogram or more of a mixture or substance containing a detectable amount of heroin.
Sentence: Not less than 10 years or more than life. No person sentenced under this subparagraph shall be eligible for parole during the term of imprisonment.
Amount: 100 grams or more of a mixture or substance containing a detectable amount of heroin.
Sentence: Not less than 5 years and not more than 40 years. No person sentenced under this subparagraph shall be eligible for parole during the term of imprisonment.

"• Vigorous and effective leadership is needed within the Office of National Drug Control Policy (ONDCP) (and related Federal and State agencies) to inform the public that dependence is a medical disorder that can be effectively treated with significant benefits for the patient and society.

"• Society must make a commitment to offering effective treatment for opiate dependence to all who need it.

"• The panel calls attention to the need for opiate-dependent persons under legal supervision to have access to MMT [methadone maintenance treatment]. The ONDCP and the U.S. Department of Justice should implement this recommendation.

"• The panel recommends improved training of physicians and other health care professionals in diagnosis and treatment of opiate dependence. For example, we encourage the National Institute on Drug Abuse and other agencies to provide funds to improve training for diagnosis and treatment of opiate dependence in medical schools.

"• The panel recommends that unnecessary regulation of MMT and all long-acting agonist treatment programs be reduced.

"• Funding for MMT should be increased.

"• We advocate MMT as a benefit in public and private insurance programs, with parity of coverage for all medical and mental disorders.

"• We recommend targeting opiate-dependent pregnant women for MMT.

"• MMT must be culturally sensitive to enhance a favorable outcome for participating African American and Hispanic persons.

"• Patients, underrepresented minorities, and consumers should be included in bodies charged with policy development guiding opiate dependence treatment.

"• We recommend expanding the availability of opiate agonist treatment in those States and programs where this treatment option is currently unavailable."

"The German model project for heroin-assisted treatment of opioid dependent patients is so far the largest randomised control group study that investigated the effects of heroin treatment. This fact alone lends particular importance to the results in the (meanwhile worldwide) discussion of effects and benefits of heroin treatment. For the group of so-called most severely dependent patients, heroin treatment proves to be superior to the goals of methadone maintenance based on pharmacological maintenance treatment. This result should not be left without consequences. In accordance with the research results from other countries, it has to be investigated to what extent heroin-assisted treatment can be integrated into the regular treatment offers for severely ill i.v. opioid addicts."

"Naloxone distribution programs in the US are ongoing in Chicago, Baltimore, San Francisco, New Mexico and New York City. Additional community-based organizations interested in minimizing the adverse consequences of drug use in several cities in the US, including Los Angeles, Providence, Pittsburgh and Boston, are in the process of planning and developing naloxone administration programs for drug users."