1.1. Identification of the agent

1.1.3. Opium composition and forms

(a) Opium composition

Opium has a complex chemical composition consisting of sugars, proteins, fats, water, meconic acid, plant wax, latex, gum, ammonia, sulfuric and lactic acids, and at least 25 alkaloids (Fig. 1.2) (Pushpangadan et al., 2012; Labanca et al., 2018). The composition of opium is further discussed in Section 4.1. The alkaloids are categorized into two main chemical classes: phenanthrenes and benzylisoquinolines (Yaksh & Wallace, 2018). The types and percentages of these alkaloids differ widely in different poppy cultivars. Also, differences in seed yield per plant and latex yield per plant have been reported (Solanki et al., 2017; Labanca et al., 2018). The principal phenanthrenes are morphine, codeine, and thebaine (Yaksh & Wallace, 2018). Morphine is the most abundant phenanthrene in opium. The metabolites of thebaine, an intermediate of morphine biosynthesis in poppy plants, include thebaol and oripavine (WHO, 2006; Megutnishvili et al., 2018).

Fig. 1.2

Schematic view of the composition of raw opium.

The principal benzylisoquinolines are papaverine and noscapine (Frick et al., 2005; Beaudoin & Facchini, 2014; Labanca et al., 2018; Yaksh & Wallace, 2018).

(b) Composition of different forms of opium

The main forms of opium are raw or crude opium, opium dross, refined opium, and other derivatives.

(i) Raw or crude opium

Raw or crude opium is the unprocessed dried latex of the poppy seedpod and is a dark and sticky substance (Fig. 1.3; Khademi et al., 2012). Alkaloids are major components of crude opium. Among all alkaloids, the most abundant is morphine (10–12% of crude opium by weight). The other alkaloids – including thebaine, codeine, papaverine, noscapine, narcotine, and narceine (UNODC, 1953a; Labanca et al., 2018), together with morphine – make up about 25% of the weight of crude opium, as shown in Table 1.1. Sterols such as cycloartenol and β-sitosterol (Malaveille et al., 1982) are also present in raw opium. [The Working Group noted that the expression of the morphine content of opium as a percentage depends in part on the moisture content.] After the opium has been collected, the moisture content is usually ~30%. Commercial opium usually has a moisture content of ~10–15%. Opium that is apparently dry still retains considerable moisture (~6%) (UNODC, 1953a). Raw opium is often adulterated with other substances, for example, starch (37%) and strontium sulfate were reported in Mexican opium (Sodi Pallares & Meyran Garcia, 1954); arsenic in Indian opium (Datta & Kaul, 1977; Narang et al., 1987); and arsenic and strychnine in Sri Lankan opium (Wijesekera et al., 1988). More recently, traded opium in Iran has been shown to be contaminated with heavy metals such as lead, chromium, cadmium, and thallium, and bacteria such as Clostridium tetani, Enterobacter cloacae, and Pantoea agglomerans (Ghaderi & Afshari, 2016; Aghababaei et al., 2018; Ghane et al., 2018).

Fig. 1.3

Dried latex obtained from the opium poppy.

Table 1.1

Alkaloid content of raw, prepared, and dross illicit opium from south-eastern Asia: analysis after initial drying (weight %).

(ii) Opium dross

Dross is produced by scraping away the tarry residues that accumulate on the inside walls of the opium pipe as a result of incomplete combustion of raw opium. The dross is black, dry, and granular (Meysamie et al., 2009). Each gram of opium yields 0.3 g of dross (Siassi & Fozouni, 1980). The summary content of the five main alkaloids in opium dross is less than their summary content in raw opium (see Table 1.1). This pyrolysed opium (Meysamie et al., 2009), unlike raw opium, contains primary aromatic amines, heterocyclic (nitrogen-containing) aromatic compounds, and polycyclic aromatic hydrocarbons.

(iii) Refined opium or opium sap

Refined opium or opium sap is the (minimally) refined product of opium and is prepared by boiling opium dross with or without raw opium in water for several hours. The solution is then filtered, insoluble parts are separated, and the excess water is left to evaporate. The final product is brown, sticky, and shiny (Kalant, 1997; Meysamie et al., 2009; Khademi et al., 2012; Nikfarjam et al., 2016). The summary alkaloid content in minimally refined opium is about the same as in raw opium (see Table 1.1).

(iv) Other opium derivatives

Other opium derivatives include the pure alkaloids like morphine and codeine; semisynthetic opiates like heroin, compact-heroin, and buprenorphine; and crystal and synthetic opioids like fentanyl, methadone, and pethidine. This group of opium derivative drugs is outside of the scope of this monograph (see Section 1.1.1, Introduction to the agent).

1.2. Methods of measurement, detection, and analysis

1.3. Production

1.3.1. Legal production

As described in Section 1.4.1, legal opium production occurs in a few countries, as prescribed by international protocols. Such cultivation (e.g. Fig. 1.4) is used to produce the global supply of more highly processed forms of opium, such as opium tincture and morphine. India was the main producer and only licit exporter of raw opium in 2017, accounting for 432.5 tonnes (47.5 tonnes in morphine equivalent) or 98.4% of total global licit production. It was followed by China, which produced 6.4 tonnes (0.7 tonnes in morphine equivalent) and where poppy straws (dried seedpod capsules) have replaced opium as the main raw material used in the manufacture of alkaloids since 2000. The Democratic People’s Republic of Korea also produced smaller amounts of opium in 2017, but exclusively for domestic consumption and use. Japan produces very small amounts for scientific purposes only (INCB, 2019). [The Working Group noted that there are large annual variations; for example, Australia was the largest producer in 2016, with 180 tonnes, followed by France, Turkey, Spain, Hungary, and India, in descending order (INCB, 2017). Most substances resulting from licit opium production are outside of the scope of this monograph (e.g. morphine and codeine). However, as noted above, opium tincture and opium syrup are within the scope of this monograph.]

Fig. 1.4

Poppy field in Tasmania, Australia.

1.3.3. Harvesting of opium

Opium is harvested, about 2 weeks after the petals fall, in two phases: the incision of the capsule and the collection of the latex. Opium harvesting is labour-intensive (Ray et al., 2006) and poppies are still processed manually in many producer countries. The incision of the capsule requires a high level of skill: the latex is found between the epicarp and the mesocarp, and the juice channels are cut so that they run upwards from below (Fig. 1.5). A great many channels must be made, but the wall of the capsule must not be cut right through or the latex will run down inside and be lost (UNODC, 1953b). The immature seedpods (fruits) of the opium poppy are scratched and incisions are made by a special lancet called (in Afghanistan) a nushtar or nishtar. A nishtar carries three or four blades, 3 mm apart, and is scored upward along the seedpod. Incisions are made at sunrise or sunset, and it takes from 8 to 14 hours for the latex to exude and solidify (UNODC, 1953b). Incisions are made three or four times, 2–3 days apart. Each time, the sticky brown resin (latex) is scraped off the following morning with a blunt-bladed instrument and collected (Fig. 1.6). The latex is dehydrated by air-drying, boiling, or heating. In the legal processing of opium, scratching the pods is not done and the dried capsules (poppy straws) are processed to extract alkaloids (Ray et al., 2006).

Fig. 1.5

Poppy capsule with opium latex (“poppy tears”) flowing from the immature seedpod.

Fig. 1.6

Harvesting of raw opium from the poppy seedpod in the field.

1.4. Use and consumption

1.4.1. Opium history and description

(a) History

Opium use has been reported from several centuries BCE from several areas in the world, mainly around Mesopotamia (UNODC, 2008). The medicinal and adverse effects of opium were well described by Avicenna, the famous Persian physician, in his textbook “The Canon of Medicine” in the early 11th century CE (Heydari et al., 2013). Avicenna described analgesic, hypnotic, antitussive, gastrointestinal, and cognitive medicinal effects, listed adverse effects such as respiratory depression, neuromuscular disturbances, and sexual dysfunction, and explained the potential toxicity of opium. Opium was used for headache, joint pain, earache, toothache, labour, and kidney and urinary bladder pain. Other indications for use included insomnia, severe cough, severe diarrhoea, and high libido. Opium was applied as oral, topical, rectal, and intranasal treatments. Forms such as syrups, tablets, smoke, and ear drops were popular (Heydari et al., 2013). From the Middle East, opium use spread to Europe, China, and India between the 11th and 15th centuries (Aragón-Poce et al., 2002), and later to the USA and Australia.

In the 17th century, the habit of opium smoking, linked to the spread of tobacco smoking, presented greater addiction potential than when the opium was ingested, which was the traditional means of consuming the drug (UNODC, 2008). After the Opium Wars of the mid-19th century, China fully legalized the importation of opium (UNODC, 2008). According to official Chinese figures, about 3.5% of the total population of China and 25% population of adult men smoked opium in 1906 (UNODC, 2008). In the USA, about 0.18% of the adult population and up to 10% of people in the medical profession were addicted to opium in 1907–1908 (UNODC, 2008). In some other countries (e.g. Iran, Viet Nam, Laos, Cambodia, Thailand, Myanmar, Indonesia, the Philippines, India, Canada), the proportions of opium users among the total populations were estimated to vary between 0.1% and 2.9% in 1907–1908 (UNODC, 2008).

(b) Historical regulation

In Iran, royal orders for the restriction of opium use were documented as many as 400 years ago (Razzaghi et al., 2000). In China, the importation and sale of opium were banned for the first time in 1729 (UNODC, 2008). Bans on some aspects of opium use were initiated early in the 20th century in several countries, including New Zealand, Australia, and Canada (New Zealand Legal Information Institute, 1901; Australasian Legal Information Institute, 1908; Canadian Senate Special Committee on Illegal Drugs, 2002). An International Opium Convention came into force in 1928 and was eventually signed and ratified by 56 countries, which agreed to prohibit the manufacture, import, sale, distribution, export, and use of narcotic drugs, except for medical and scientific purposes (UNODC, 2008).

In 1953, an Opium Protocol was proposed, in which only seven countries – Bulgaria, Greece, India, Iran, Turkey, the former Soviet Union, and the former Serbia and Montenegro – would be authorized to produce opium for export, and opium use was limited exclusively to medical and scientific needs (UNODC, 1953c). The Protocol did not receive enough international ratifications to bring it into force until 1963, and it was superseded by the 1961 Single Convention, which came into force in 1964 (Senate of Canada, 2001) (see Section 1.5).

(c) Opium consumption and description of its forms

Globally, an estimated 1100–1500 tonnes of opium are consumed each year [76% of which is consumed in Asia] (UNODC, 2009, 2020). Annually, an estimated 450 tonnes of opium are consumed in Iran (42% of total global opium consumption) (UNODC, 2010), making this country the world’s largest per capita consumer of opium (Dolan et al., 2011). After Iran, the next highest consumption occurs in Afghanistan and Pakistan, with an estimated 80 tonnes of opium (7% of the globally consumed opium) consumed annually in each of these two countries (UNODC, 2009). Among individual opium users, historical average daily doses have varied between 0.5 and 2.6 g in India and between 3.8 and 15 g in China (UNODC, 2008). In recent epidemiological (case–control) studies, the median daily consumption quantity among control groups who used opium was less than 2 g (Khademi et al., 2012; Mohebbi et al., 2021), and in a recent survey of 8696 daily opium users the mean daily dose was 3 g (Rafiei et al., 2019); these data are further described in Section 1.4.2(c) and Section 2. [The Working Group noted that few published data were found on the quantities of daily opium consumption in Iran and other countries.]

There are two main methods of consuming opium; ingestion (sometimes referred to as “eating” in the literature) and smoking (Khademi et al., 2012). Opium can be ingested through chewing, drinking, and swallowing (UNODC, 1953d). Opium can be chewed or eaten raw, dried, or after boiling or heating, and with or without being combined with substances including spices, amber, aloes, cochineal, musk, saffron, sugar, or rice (UNODC, 1953d; Westermeyer & Neider, 1982). Opium can also be ingested by pounding and mixing it with liquids – including water, tea, or wine – and then drinking (Fig. 1.7; UNODC, 1953d, 2014; Fernandez & Libby, 1998). In rural north-western India, opium is traditionally consumed in the form of nuggets or powder. In contrast to the powder, which is usually smoked, the nuggets are dissolved in water, filtered, and then the extract is drunk (Ray et al., 2006). Finally, some individuals ingest opium by swallowing it in the crude form in which it is sold or as a pill (Richards, 1877; UNODC, 1953d). Liquids for oral use include opium tincture, opium wine, and opium syrup (Ray et al., 2006; Heydari et al., 2013). Opium tincture, also known as laudanum, is an antidiarrhoeal prescription drug. As a solution sold as oral drops, it is authorized in 17 European Union Member States (EMA, 2020). Opium tincture usually contains 10 mg/mL morphine and 19–33% ethanol (Drugs.com, 2019b; EMC, 2020). It is also used for the management of opium withdrawal in adults (Rahimi-Movaghar et al., 2018) and neonates (Ghazanfarpour at al., 2019) and for maintenance therapy in the treatment of opioid addiction (Jittiwutikarn et al., 2004), and has, in this context, also been referred to as opium syrup (Dahmardehei & Rafaiee, 2012). Opium wine is a solution of opium in aromatized sherry or diluted alcohol and has the same strength as ordinary laudanum (Merriam-Webster, 2020).

Fig. 1.7

Preparing opium tea.

In ancient times, opium was usually taken orally (Swift et al., 1997; Heydari et al., 2013); however, after the introduction of the tobacco pipe during the 17th century, smoking opium became a popular method of opium consumption, particularly in China (Swift et al., 1997). Opium smoking (Fig. 1.8) remains a common and preferred method of consuming opium in many countries, including Afghanistan and Iran (UNODC, 2014; Sheikh et al., 2020), which could be due to the pleasurable effects of opium being achieved more rapidly by smoking opium than ingesting it (Westermeyer, 1978). Raw opium and opium dross can be ingested, or smoked with special devices (an opium pipe, called a vafoor in Persian), after direct heating with burning charcoal or sometimes with a hot metal rod (Siassi & Fozouni, 1980; Khademi et al., 2012; Rafiei et al., 2019). Opium is placed in a pipe, the head of the pipe is heated with charcoal, and then the smoke from the heated opium is inhaled through the pipe. Refined opium can be ingested or smoked by indirect heating using a special type of opium pipe. When the refined opium is heated indirectly, the user inhales the opium vapour, not its smoke (Khademi et al., 2012).

Fig. 1.8

A man smokes opium using a traditional tobacco pipe, Lao People’s Democratic Republic.

1.4.2. Prevalence, levels, and trends

(a) Global patterns

While the estimated global number of opiate users has increased from 15–21 million in 2007 to 30 million in 2019 (UNODC, 2009, 2016, 2020), the proportion of opiate users who used opium in 2007 is unknown. In 2008, there were an estimated 4.1 million opium users (UNODC, 2010). Currently, there are approximately 5 million regular users of opium worldwide (Rahimi-Movaghar et al., 2018), 80% of whom reside in Asia (UNODC, 2010). In opium-cultivating countries and some of their neighbours, opium is more commonly used than other opiates (UNODC, 2019b).

(b) Afghanistan

In Afghanistan, a significant increase in the use of opium was observed between 2005 and 2015 (Afghanistan Ministry of Counter Narcotics, 2015). The 2005 drug-use survey estimated that there were ~150 000 regular opium users (0.6% of the total population) in the country (UNODC, Afghanistan Ministry of Counter Narcotics and Afghanistan Ministry of Public Health, 2005); by 2009, this number had increased to 230 000 (UNODC, Afghanistan Ministry of Counter Narcotics and Afghanistan Ministry of Public Health, 2009).

In 2015, the countrywide national drug-use survey – involving 2757 randomly selected households in 11 urban centres and 52 rural villages – sampled 10 549 people, including 2711 men, 3723 women, and 4110 children (The Colombo Plan Secretariat, 2015). Biological specimens (hair, urine, and/or saliva) from 8.5% of the adults (10.3% of men and 6.7% of women) and 6% of the children tested positive for opioids. No more than 9% of children with positive results were estimated to be active users; it was estimated that 46–48% of positive results derived from adult administration and 44–45% from environmental exposure. Parents may give opium to their children to calm them down or to numb their hunger (Afghanistan Ministry of Counter Narcotics, 2013). The survey confirmed that opioids are the most common illicit drug used in Afghanistan (Afghanistan Ministry of Counter Narcotics, 2015). Similar findings were reported in a study conducted in Afghanistan between 2010 and 2012, which included 2187 randomly selected urban households representing 19 025 household members in 11 provinces. In addition to self-reported questionnaires and interviews on past and current drug use among members of their household, hair, urine, and saliva samples from 5236 people in the households were obtained and tested for metabolites of 13 drugs (Cottler et al., 2014). Not all these individuals may have been opium users. Passive opium smoke exposure in Afghan homes was assessed using hair samples, revealing high concentrations of opium products and drug metabolites in the systems of family members of opium users, including women and children (Goldberger et al., 2010).

(c) India

In India, according to a national survey conducted in 2018, 0.52% of the population, or ~1.1 million people, had used opium in the last 12 months (Ambekar et al., 2019); these results are similar to those reported in a national survey conducted in 2002 (Ray, 2004). However, there are areas with higher levels of opium use. In several provinces, it has been reported that 4.8–6.6% of individuals aged 15 years or older are current opium users (Chaturvedi et al., 2003, 2013; Chaturvedi & Mahanta, 2004). In India, ingestion of opium is more common than opium smoking. In rural areas of India, raw opium is consumed in nugget form; the nugget is dissolved in water, filtered, and then the extract is drunk (Ray et al., 2006). Among opioid-dependent patients, 27% in one state and 33% in another were found to be using opium (Gupta et al., 2019).

(d) Islamic Republic of Iran

In Iran, opium has been the most widely used illicit drug for decades. Opium use is seen across different age groups, socioeconomic classes, and regions (see Section 1.4.3). In 2001, a national survey on drug use showed that 5.5% of the adult population were current opium users and 1.5% were opium-dependent (Iranian Ministry of Health, 2002). Ten years later, the 2011 national household survey showed that opium was the main illicit drug used and led to substance-use disorders (Rahimi-Movaghar et al., 2014; Amin‐Esmaeili et al., 2016). Of the population aged 15–64 years, 4.4% and 2.3% were reported to have used raw opium (teriak) and minimally refined opium (shireh), respectively, in the last 12 months, and 1.2% and 0.3% had used them daily in the last 12 months. Opium had been used in the last 12 months by 7.9% and 0.8% of men and women, respectively, which represents [2 300 000] people in the adult population. Two surveys of a rural population showed that daily raw opium and shireh use by people aged 12 years and above increased from 5% and 1.3% in 2000 to 15.7% and 9% in 2012, respectively (Ziaaddini et al., 2013). In two studies that assessed weekly use of opium in the population aged 40–75 years, 17% of respondents in Gonbad in 2006 and 8.4% in Valashahr in 2016 were opium ever-users. Both studies included urban and rural areas (Pourshams et al., 2010; Gandomkar et al., 2017). Opium use is also frequent among high school and university students (Rahimi-Movaghar et al., 2006; Menati et al., 2016). Opium is one of the most common substances for which individuals seek treatment for drug dependency (Jafari et al., 2010; Akbari et al., 2019; Rafiei et al., 2019). There are regional differences in the extent of opium use in Iran (Amin-Esmaeili et al., 2016; Alizadeh et al., 2020; Naghibzadeh-Tahami et al., 2020; Sheikh et al., 2020). In the Golestan Cohort Study (GCS), which was conducted in the north-east of Iran, the median cumulative amount of opium used among the cohort population was 21 nokhod-years [about 4.2 gram-years] (a nokhod is the standard unit of opium supply and is approximately equivalent to 0.2 g) (Sheikh et al., 2020), while in another study conducted in Kerman Province in the south-east of Iran, the median cumulative amount of opium used among the control group was 87.5 gram-years (Naghibzadeh-Tahami et al., 2020).

Comparison of the results of four national studies on drug users from 1998 to 2018 (Razzaghi et al., 2000; Narenjiha et al., 2005, 2009; Rafiei et al., 2019) shows that traditional use of opium has remained the main form of illicit drug use. In the fourth national study on drug users carried out in 2018 (n = 20 175) (Rafiei et al., 2019), daily use of opium (raw opium, opium dross, and/or shireh) was reported by 37.5% of participants (“drug abusers” recruited from 16 outpatient and inpatient centres, drop‐in centres, shelter, prisons, and homes). Moreover, 67.1% of participants reported opium to be their dominant drug of use at the time of the interview. For those who reported daily use of opium, 85% of opium consumed was raw opium; 25% and 5% reported daily use of shireh and opium dross, respectively.

In Iran, the most common method of opium consumption is smoking (90.9%), followed by oral ingestion (8.8%). Smoking of sukhteh and shireh is reported to be the dominant route of use by three quarters of participants in the survey described above. The other one quarter reported ingestion as the dominant route of sukhteh and shireh use (Rafiei et al., 2019).

(e) Pakistan

In Pakistan, opium consumption has decreased over recent decades. A national survey conducted in 2013 estimated that there were 320 000 regular opium users in the previous year (0.3% of the population aged 15–64 years). In Pakistan-administered Kashmir, 0.4% of the population was using opium regularly, and the highest proportion of opium users (1%) was in the province of Balochistan (UNODC and Government of Pakistan, 2013). Opium users were mostly married, slightly older (mostly aged 40–54 years), and were more likely to live in rural areas than were heroin users. Also, 84% of opium users versus about 60% of heroin users lived in a home (rather than a park, road, shrine, or other location). Many of the opium users had also used heroin and cannabis (UNODC and Government of Pakistan, 2013).

(f) Other countries

In China, the proportion of people consuming opium is small. In 2000, a national survey on drug use showed that ~0.14% of individuals aged 15 years and older had used opium in the previous 12 months, which showed a decreasing trend compared with surveys conducted in 1993 and 1996 (Hao et al., 2004). In China, opium is consumed mainly by smoking (Ray et al., 2006).

In 2018, there were 43 511 registered drug users [including more than 3100 registered opium users] in central Asia, excluding Turkmenistan (for which no data were available) (INCB, 2020). In addition, opium use has been reported in a small percentage of the population in Sri Lanka (Sri Lanka National Dangerous Drugs Control Board, 2018), Algeria (Abdennouri, 2014), Viet Nam (Thao et al., 2006), and the Democratic People’s Republic of Korea (Yun & Kim, 2015). Recent data on the extent and pattern of opium use in these countries and for other parts of the world are lacking. Although most of the data on opium use come from southern and south-western Asia, the high number of countries all around the world that produce opium (either legally or illegally), the many countries that report opium seizures annually, and reported cases of opium poisoning (both in adults and in children) in other countries (Martínez & Ballesteros, 2019), suggest that opium use exists to a greater or lesser degree in many areas of the world. Fig. 1.9 indicates countries with reports of opium use during the past 20 years. Fig. 1.10 illustrates countries with reported opium seizures in 2018.

Fig. 1.9

Countries with reports of opium use during the past 20 years, according to United Nations Office on Drugs and Crime reports, country reports, and published studies.

Fig. 1.10

Seizures of opium, 2018.

(g) Exposure to lead and other adulterants and contaminants as part of opium exposure

In the present monograph, contaminants and adulterants of opium are considered integral parts of the complex mixture to which opium users are exposed. Several studies have indicated the presence of different levels of lead contamination in tested opium samples (Aghaee-Afshar et al., 2008; Aghababaei et al., 2018; Akhgari et al., 2018; Rahimi et al., 2020). Some other studies have shown higher concentrations of lead in the blood of opium users than in non-users (Salehi et al., 2009; Amiri & Amini, 2012; Khatibi-Moghadam et al., 2016; Nemati et al., 2016; Ahmadinejad et al., 2019). Although all these reports originate from Iran, there is huge variation in the reported lead concentrations measured in opium samples, with values ranging from 1.88 ± 0.35 μg/g (Aghaee-Afshar et al., 2008) to 138.10 ± 75.01 μg/g (Aghababaei et al., 2018). Similarly, there is significant variation in reported mean blood lead concentrations among opium users (Alinejad et al., 2018; Soltaninejad & Shadnia, 2018), with major differences between opium users in different provinces of Iran (Amiri & Amini, 2012; Khatibi-Moghadam et al., 2016; Soltaninejad & Shadnia, 2018). The exact source of this contamination is not clear; however, water and soil contamination of opium poppy cultivation farms (Salamon & Fejer, 2011; Chizzola, 2012; Moghaddam et al., 2020), the use of inappropriate methods and equipment in opium production, and adulteration of opium with lead to increase its weight to raise profits are among the suggested mechanisms (Aghababaei et al., 2018; Akhgari et al., 2018; Alinejad et al., 2018; Zamani et al., 2020).

There are also reports from some countries that show other types of adulterants in opium, including arsenic (between 25 µg/100 g and 29 mg/100 g) in India and Sri Lanka (Datta & Kaul, 1977; Wijesekera et al., 1988), strontium sulfate in Mexico (Sodi Pallares & Meyran Garcia, 1954), strychnine in Sri Lanka (Wijesekera et al., 1988), and chromium in Iran (Aghababaei et al., 2018).

1.5. Regulation and legislation

The first international conference to discuss the global narcotics problem was the Opium Commission in Shanghai in 1909 (UNODC, 2008). Subsequent international conferences were held in 1924–25 and 1953 to prohibit the manufacture, import, sale, distribution, export, and use of narcotic drugs, except for medical and scientific purposes (UNODC, 2008). More information on international regulations before 1961 is presented in Section 1.4.1.

The current Single Convention on Narcotic Drugs (UNODC, 1961), which came into force in 1964 and was subsequently ratified by 190 countries (INCB, 2020), aims to prohibit the production and supply of named narcotic drugs and prevent drug abuse by coordinated international action (United Nations Treaty Collection, 1975). This Convention includes opium in Schedule I of international control. Parties to the Convention are committed to limit the possession, use, trade, distribution, import, export, manufacture, and production of opium exclusively to medical and scientific purposes. Morphine and thebaine, the main alkaloids that can be purified from opium, are also listed independently in Schedule I. Preparations of opium or morphine containing not more than 0.2% morphine are included in Schedule III of the Convention.

After endorsement of the Single Convention, countries individually developed national legislation to regulate access to the internationally controlled substances. Differences in substance classifications in these national laws may slightly affect the status of opium. For example, the UK has placed opium in class A of its three classes (UK Government, 2019), Canada in Schedule I of its six classes (Minister of Justice Canada, 2019), the USA in Schedule II of its five classes of controlled substances (DEA, 2020b), and Iran in class II of its two classes for illicit substances (Drug Control Law, 2010). However, all countries can prosecute individuals for illegal production, trafficking, and distribution of opium, and most countries can prosecute for possession of opium.

Global licit production of opium was about 30 000 tonnes in 1907–1908 before the international commitment to limit opium production to medical and scientific purposes (UNODC, 2004, 2008). Global illicit opium production decreased by about 25% between 2017 and 2019 (UNODC, 2020). The reduction might reflect the effectiveness of control measures in restricting the production and availability of opium and other opiates for use. Nevertheless, the continuing production of opium and the high number of users reflect partial effectiveness of the international conventions and national laws.

1.6. Quality of exposure assessment in key epidemiological studies of cancer and mechanistic studies in humans

Epidemiological studies have used various exposure assessment methods to investigate the association between opium and cancer incidence. Optimal exposure assessment should consider:

•

the type of epidemiological study

•

the source of the opium exposure data, such as from a validated and structured interview, a clinical interview, or from patients’ records, etc.

•

a clear definition of opium use

•

the age or date of first use of opium

•

the average daily dose of opium (intensity)

•

the duration of exposure in months or years

•

the cumulative exposure (intensity multiplied by duration)

•

the temporality of the exposure (when it occurred relative to the study end-point)

•

the type(s) of opium consumed (raw, dross, or minimally refined; see Section 1.1.2)

•

the mode of consumption (smoking or ingestion).

The intensity, modes, and type of opium use may change between data collection at baseline and at the time of end of follow-up, which is particularly important for cancers with long latency. The manner of data collection should minimize the potential for under-reporting of opium, which can occur because of its illicit nature. Where possible, the accuracy of the exposure ascertainment should be checked (see Section 1.2). However, opium metabolites in urine can only indicate recent exposure to opium (Abnet et al., 2004). Furthermore, as outlined in Sections 1.1.3(b), 1.4.2(g), and 1.6.2, the opium product may be adulterated or contaminated by potentially carcinogenic impurities [the Working Group noted that the extent of and components of adulteration have varied by time and geographical area, which makes exposure assessment difficult].

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