Busardo, F. P.

Del Rio, A.

Di Luca, N. M.

Pacifici, R.

Pichini, S.

Tittarelli, R.

English

4461Heroin is the most commonly used opiate with 29.2 million users in 2017 worldwide, which rep-resents a more than twofold increase of the esti-mated global consumption compared to 20081,2. By contrast, only a slight increase from 1.3 to 1.4 million drug users was observed in Europe over the last decade3,4. The recent discovery of illicit heroin laboratories in Bulgaria, Czech Republic, Spain, and the Netherlands and the increase in drug seizures in Europe suggest that a percentage of street heroin is now produced closer to the Eu-ropean drug market5.In Italy, the latest national report on drug abuse to Parliament indicated that the number of high-risk heroin users substantially increased by 35% from 2008, representing approximately 285,000 users in 20186. Concurrently, with the increase of heroin users, a 10% increase in the number of drug-related deaths was reported in 2017, in Italy; in most cases, heroin was involved, either alone or in combination with other psychotropic sub-stances6-9. Different causes have been suggested to explain this increase in heroin-related overdose fatalities: a potential change in adulterants compo-sition10,11, a simultaneous use of new psychoactive substances (NPS) (especially new synthetic opi-oids), the illicit sale of fentanyl or/and analogues as cutting agents or in place of heroin, and a possible increase in heroin purity in street preparations5,12.In this concern, we sought to explore the vari-ability of heroin purity in products seized by the police forces in Italy from 2013 to 2019 and reported by the Italian Early Warning System (IEWS) on classic drugs and new psychoactive substances. The data highlight a fluctuating trend increase in drug purity from 2013 to 2018 with a significant rise in 2019 all over the country, especially in northern regions of Italy (Table I). The average heroin purity was lower than 30% in 2013 (range: 15.0-51.5%), was 33.9% (range: 21.1-59.1%), 32.2% (range: 20.2-48.7%), 33.1% (range: 24.3-49.1%), 35.0% (range: 14.5-51.5%), and 30.7% (range: 13.9-42.4%) from 2014 to 2018, and reached 48% in 2019 (range: 32.2-74.5%) (Figure 1). Between 2013 and 2019, most products were seized in northern regions (86.2%), where-as 9.2% seizures were made in southern Italy and 4.6% in central Italy (Table I). Interestingly, caffeine was the most common adulterant (55.4% cases), followed by methorphan (52.3% cases) and paracetamol (36.9% cases); information on adul-terants was not available in 24% cases. Caffeine and paracetamol13 are indeed the most frequently reported adulterants in street heroin14. It has been suggested that caffeine induces additional syn-ergistic effects when smoked, improving opiate uptake15 and slightly enhancing drug effects16; levamisole has been widely used as an adulter-ant in cocaine seizures for similar reasons17,18. By contrast, paracetamol is used as a cheap and readily available cutting agent since it has a melt-ing point similar to that of heroin. Methorphan, an opium alkaloid, refers to a racemic mixture of two stereoisomers: dextromethorphan, an over-the-counter cough and cold medicine also used as a recreational drug for its dissociative and psy-chedelic effects19, and levomethorphan, a potent narcotic agent of the morphinan family that has never been commercialized. Methorphan use as heroin adulterant has not been reported by other countries, suggesting a specific feature of the Ital-ian drug market20. Generally speaking, only limited informa-tion is currently available on the presence and European Review for Medical and Pharmacological Sciences 2020; 24: 4461-4466R. TITTARELLI1, N.M. DI LUCA1, R. PACIFICI2, S. PICHINI2, A. DEL RIO1, F.P. BUSARDÒ31Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University   of Rome, Rome, Italy. 2National Centre on Addiction and Doping, Istituto Superiore di Sanità, Rome, Italy3Department of Excellence of Biomedical Sciences and Public Health, University “Politecnica delle  Marche” of Ancona, Ancona, ItalyA. Del Rio and F.P. Busardò equally contributed to the paperCorresponding Author: Simona Pichini, MD; e-mail: simona.pichini@iss.itCommentary – Heroin purity and adulteration: an updated snapshot from the Italian Early Warning System4462Year Region Color Purity (%) Other opiates Adulterants  2019, September Puglia Beige 74.5      –      – 2019, June Trentino-Alto Adige Beige 32.9      – Caffeine, paracetamol2019, May Lombardia Beige 50.3      –      –2019, April Puglia Beige 44      – Caffeine, paracetamol2019, March Lazio Beige 51.4      – Paracetamol2019, February Lazio Beige 48.6      –      –2019, January Lombardia Brown 34.5 (*) Methorphan, morphine, Caffeine, paracetamol    6-monoacetylmorphine 2018, November Lombardia Beige 38.8 6-monoacetylmorphine, acetyl codeine      – Veneto Beige 13.9 6-monoacetylmorphine (5.12%), acetyl codeine Caffeine, paracetamol2018, October Trentino-Alto Adige Beige 26.5 Methorphan Caffeine, paracetamol2018, August Veneto Beige 20.5 6-monoacetylmorphine, acetyl codeine Caffeine, paracetamol (10.6%)2018, July Trentino-Alto Adige -- 41.8 Methorphan Caffeine2018, May Trentino-Alto Adige Beige 30.6      – Phenacetin, caffeine, paracetamol2018, April Trentino-Alto Adige Beige 17.7      – Dimenhydrinate, caffeine,       paracetamol2018, March Lazio Beige 41 Methorphan, 6-monoacetylmorphine Caffeine Campania Beige 42.4(*) Methorphan, 6-monoacetylmorphine (4.5%) Caffeine Veneto Beige 23.8 acetyl codeine, 6-monoacetylmorphine (11.7%) Caffeine, paracetamol2018, February Veneto Beige 33.8 Methorphan, codeine, acetyl codeine,  Paracetamol      6-monoacetylmorphine 2017, March-August Veneto Beige/Yellow  51(*) Methorphan Caffeine, paracetamol  ocher 37.5(*)     30(*)     51.5(*)     40(*)     44.5(*)     26(*)     14.5(*)     22(*)     15.5(*)  2017, February Lombardia Beige 51.2 6-monoacetylmorphine (7.7%)  Veneto Beige 50.8 Meconin, acetyl codeine, 6-monoacetylmorphine (8.6%)      –2017, January Trentino-Alto Adige Beige 21 Metorphan, 6-monoacetylmorphine, morphine      –2016, May Trentino-Alto Adige – 24.3(*) Methorphan Caffeine, paracetamol Emilia-Romagna -- 49.1 Methorphan Caffeine Table I. Heroin purity and adulterants in products seized in Italy between 2013 and 2019.Continued4463Year Region Color Purity (%) Other opiates Adulterants  2016, April Trentino-Alto Adige – 25.8 Methorphan Caffeine, paracetamol2015, December Trentino-Alto Adige – 20.2      –      –2015, October Veneto – 30.1      –      –2015, September Trentino-Alto Adige – 32.8      –      –2015, July Lombardia – 48.7      –      –2015, May Piemonte – 36.7      –      –2015, March Veneto – 21.7      –      –2015, January Trentino-Alto Adige – 35.8      –      –2014, September Trentino-Alto Adige – 59.1 Codeine, thebaine, noscapine 2014, March Veneto – 30.1 Acetyl codeine, methorphan Paracetamol, caffeine, mannitol   32.4 Acetyl codeine, methorphan Paracetamol, caffeine, mannitol2014, February Veneto – 21.1 Methorphan Caffeine, paracetamol   47.6 Methorphan Caffeine, mannitol   32.5 Methorphan Caffeine, paracetamol   44.6 Methorphan Caffeine Piemonte – 38.5 Methorphan Caffeine  – 21.4 Methorphan Caffeine, paracetamol Campania – 22.1 Methorphan Caffeine, lidocaine, paracetamol2014, January Piemonte – 24.2 Methorphan Caffeine, lidocaine, paracetamol2013, November Veneto – 47.6 Methorphan Caffeine, paracetamol Trentino-Alto Adige – 51.5 Methorphan, 6-monoacetylmorphine Caffeine Campania – 24.3 Methorphan Caffeine  – 21.8 Methorphan Caffeine Piemonte – 28.1 Methorphan Caffeine  – 29.1 Methorphan Caffeine2013, September Trentino-Alto Adige – 28.9 Methorphan Caffeine  – 36.4 Methorphan Caffeine  – 29.2 Methorphan Caffeine, paracetamol  – 29.6 Methorphan Caffeine, paracetamol Piemonte – 15 Methorphan Lidocaine2013, June Trentino-Alto Adige – 16.3 Methorphan      –  – 31.3 Methorphan      –Table I (continued). Heroin purity and adulterants in products seized in Italy between 2013 and 2019. (*) average purity of heroin seizedR. Tittarelli, N.M. di Luca, R. Pacifici, S. Pichini, A. Del Rio, F.P. Busardò4464concentration of drug adulterants in Italy. There is no standardized protocol to perform complete toxicological analysis of seizures, and concen-trations of adulterants are rarely assessed. Test-ing of adulterants is not required by the judicial authorities and is generally not performed19. The absence of reports on the detection of NPS as heroin adulterants, which has been described in other countries, may be another consequence of this regulatory vacuum21. Additionally, cer-tified standards of the newest NPS are rarely available and detection methodologies are not frequently adapted. For this reason, the IEWS promoted the “NPS-LABVEQ” project in 2019, aiming to improve the performance of labora-tories for developing and validating analytical methodologies to identify NPS in non-biolog-ical and biological matrices22-24. Therefore, IEWS laboratories, including the police forces, have been encouraged to search for distributed NPS in upcoming seizures and in cases of in-toxication and fatalities, including heroin-relat-ed overdoses.The increase in opiate overdoses during the last two years have been improperly attribut-ed to the so-called “yellow” or “cheese” her-oin by the media25. “Yellow” heroin is a street preparation of a black tar with a heroin purity ranging from 2 to 8%, cut with paracetamol and diphenhydramine, an antihistaminic26. It was first described in the United States, where it caused a high number of deaths among teenag-ers in Dallas between 2005 and 200727. In real-ity, only one single seizure of “yellow” heroin, containing a non-established amount of diphen-hydramine, was reported in Italy during the last decade (central region of Umbria in 2018). This seizure was an isolated case and is not responsi-ble for the rise of heroin-related overdose fatali-ties. Local media28 hypothesized that this high-ly deadly heroin could be cut or totally replaced by illicit fentanyl and analogues. This hypoth-esis has not been confirmed by toxicological analyses and it was finally concluded that a continuous rise in heroin purity, demonstrated by the present data, is the probable cause of the rising number of heroin-related overdoses. The diffusion of this higher-purity heroin, in Italy represents a significant public health problem that requires intensive coordination and collaboration between governmental insti-tutions, law enforcement agencies, forensic lab-oratories, and the scientific community to raise awareness on the issue and alert health profes-sionals involved in the care and cure of heroin addicts.Figure 1. Purity of heroin products seized in Italy between 2013 and 2019. Bar are mean values with standard deviations.Commentary – Heroin purity and adulteration: an updated snapshot from the Italian Early Warning System4465Acknowledgement Italian Early Warning System is funded by Presidency of the Ministers Council, Department of Antidrug Policy.Conflict of interestThe authors declare that they have no conflict of in-terests.References  1) United nations office on drUgs and crime (UNODC). World Drug Report 2019, 2019; Available at: https://wdr.unodc.org/wdr2019/prelaunch/WDR19_Book-let_2_DRUG_DEMAND.pdf. 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Commentary - Heroin purity and adulteration: an updated snapshot from the Italian Early Warning System

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Commentary - Heroin purity and adulteration: an updated snapshot from the Italian Early Warning System

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