er

,

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. . . .

. . . .gical an. . . .. . . .

012, 2013).d in the markets in thename is Krokodil ory green colored, full of

Life Sciences 102 (2014) 8187

Contents lists available at ScienceDirect

Life Scie

j ourna l homepage: www.e lssubstances are being used to substitute or mimic the effects of othercontrolled drugs. Although,many issues concerning their pharmacology

ulcers skin of addicts that emulates that of a crocodile or due to-chlorocodide that is the rst intermediate in the synthetic pathwayand toxicology have been already studied, there is a signicant lack of of desomorphine (Ofce of Alcoholism and Substance Abuse ServicesThe increasing number of new designer drugs or the re-appearanceof older ones (in case that the availability of classic ones is restricted) onthe drug market is a major public health concern today. These

use (United Nations Ofce on Drugs and Crime, 2Desomorphine is an old drug that re-appeare

last decade as a homemade product. Its streetCrocodile (Russian: ) due to the scalIntroduction data on their abuse potential and adverse effects after their recreational Corresponding author at: Department of ForensicMedMedicine, National and Kapodistrian University of AthensAthens, Greece. Tel.: +30 2107462414; fax: +30 210771

E-mail address: pan_nik@hotmail.com (P. Nikolaou).

http://dx.doi.org/10.1016/j.lfs.2014.03.0080024-3205/ 2014 Elsevier Inc. All rights reserved.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

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Conict of interest statement . . . . . . . .References . . . . . . . . . . . . . . . . .Introduction . . . . . . . . . . . .Chemistry . . . . . . . . . . . . .Synthesis of desomorphine . . . . .Clandestine synthesis of krokodil . .Prevalence and use . . . . . . . . .Pharmacology of desomorphine . . .Toxicology of desomorphine . . . . .Toxicology of krokodil . . . . . . .Determination of desomorphine in bioloLegal status . . . . . . . . . . . .Conclusion . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84d expert-forensic samples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85. . . .ContentsDepartment of Forensic Medicine and Toxicology, Faculty of Medicine, National and Kapodistrian University of Athens, Greece

a b s t r a c ta r t i c l e i n f o

Article history:Received 20 January 2014Accepted 5 March 2014Available online 17 March 2014

Keywords:DesomorphineKrokodilCrocodileFlesh-eating drugLegislation

Krokodil is the street name for the semi-synthetic opioid derivative desomorphine. Although an old drug, itre-staged on drug arena during the last decade causing detrimental effects to its users. Despite the fact thatRussia and other former Soviet Republics were the initial plagued countries, krokodil arrived in Europe andUnited States lately, as a substitute of the relative expensive, and inmany cases unavailable, heroin. It can be eas-ily manufactured in home-environment from codeine and causes signicant health problems, even deathsworldwide. The aim of this review is to summarize the current knowledge about this drug, concerning its chem-istry, synthesis, pharmacology and toxicology. Published or reported krokodil related cases, fatalities or intox-ications, as well as self reports from drug users are reviewed. The existing analytical methodologies for thedetermination of desomorphine in biological samples as well as its legal status are also presented.

2014 Elsevier Inc. All rights reserved.Minireview

A Krokodil emerges from the murky watof an old drug

Maria Katselou, Ioannis Papoutsis, Panagiota Nikolaouicine and Toxicology, Faculty of, Mikras Asias 75, Goudi 115 27,6098.s of addiction. Abuse trends

Chara Spiliopoulou, Sotiris Athanaselis

nces

ev ie r .com/ locate / l i fesc ie(OASAS), 2012; Wikipedia and Desomorphine, 2013). The jargonterms Krok or Russian Magic are also used. It is also called drug ofthe poor as it is used by those who cannot afford the more expensiveheroin (Priymak, 2011). Krokodil is characterized as esh eating(Veronese, 2011; Christensen, 2013) or esh rotting drug (Shuster,

2011), as it nally rots the esh, leaving the bone and muscle tissueexposed to infections.

In 2003, krokodil emerged throughout the Russian Federation. Itrepresented a crude desomorphine preparation, produced from codeine(contained in over-the-counter medications) via a process that requireseasily obtainable chemicals and rudimentary laboratory conditions(Grund et al., 2013). The process involved in manufacturing clandes-tinely desomorphine leads to the production of krokodil, a productcontaminated with high concentrations of chemicals, by-products andresiduals, the injection of which results in skin damage, disorders ofthe endocrine, nervous and muscular systems and inammation ofliver and kidneys (Grund et al., 2013; Erowid, 2013). All these healthproblems are added to the ones that appear due to the dependencepotential of desomorphine.

This article reviews all the available information on chemistry, syn-thesis, pharmacology and toxicology of desomorphine, its prevalenceand use as krokodil, as well as the methods for its determination inbiological samples. Emphasis is given on the toxicity of krokodil.Published or reported krokodil related cases, self reports from drugusers and the existing legislation were gathered through a detailedsearch of PubMed and World Wide Web and reviewed.

Synthesis of desomorphine

Desomorphine is not a new drug. It was rst synthesized in 1932 inUSA (Small and Morris, 1933) and patented in 1934 (US patent1980972, 1934). Its traditional synthesis includes the production of-chlorocodide, by reaction of codeine with thionyl chloride, which bycatalytic reduction yields desocodeine (dihydrodesoxycodeine). A nalstep of demethylation leads to desomorphine formation (Fig. 2)(Mosettig et al., 1935; Small et al., 1933; Eddy and Howes, 1935;Rapoport and Bonner, 1951a, 1951b). However, this synthetic proce-dure has low yields and requires tedious reaction conditions. Recently,an optimized process for the synthesis of desomorphine has been de-scribed in the literature achieving higher yield and purity withoutobtaining impurities or by-products. This synthetic method affords thetosylate or mesylate product of codeine which by reduction of the 6-protected-hydroxyl group and hydrogenation (reduction of 7,8 doublebond) over H2/PtO2 gives quantitatively and highly pure desocodeine.Desomorphine is nally obtained after demethylation of desocodeinewith the use of BBr3 in acceptable yield and very high purity. The overallyield of this process is 38% and as no column purication is required atany stage, it can be easily applied in common laboratories (Srimuruganet al., 2012). According to the stoichiometry of the reaction and theestimated mean yield, for the synthesis of 1 mg of desomorphine ap-

traction process can be further repeated, many manufacturers and/orusers proceed directly with the next step that involves the reduction of

82 M. Katselou et al. / Life Sciences 102 (2014) 8187Chemistry

Desomorphine (4,5a-epoxy-17-methylmorphinan-3-ol, dihydro-desoxymorphine) is a morphine analogue where the 6-hydroxylgroup and the 7,8 double bond of morphine have been reduced (USpatent 1980972, 1934). It is an off-white to brown crystalline powderat room temperature, has the molecular formula C17H21NO2, a molecu-larweight of 271.35 g/mol and amelting point of 189 C. It is an organicbase, like morphine and other alkaloids (Fig. 1), the protonated formof which has an estimated pKa value of 9.69. Thus, in physiologicalpH 99.5% is ionized. The ionized form is in equilibrium with thenon-ionized form,which is the form that crosses the bloodbrain barrier.Desomorphine binds to opioid receptors in its ionized form, like allphenanthrene alkaloids (TOXNET, 2013).

Desomorphine, as a free base is slightly soluble in water (1425 mg/Lat 25 C), while its salt forms, which are most commonly injected, arehighly water soluble. It is also soluble in polar organic solvents, such asacetone, ethyl acetate and alcohol (TOXNET, 2013; Drug EnforcementAdministration (DEA) Ofce of Diversion Control, 2013; O' Neil, 2006).Fig. 1. Structures of morphine, codethe extracted codeine with iodine, hydrochloric acid and redproximately 3 mg of a codeine salt (sulfate or phosphate) is required.

Clandestine synthesis of krokodil

Desomorphine can also be clandestinelymanufactured as krokodilfrom codeine via a simple two-step synthetic procedure that can beapplied at homeor in the street since the process requires very little lab-oratory equipment and involves the use of low cost and easily availablechemicals. A rst step involves the extraction of codeine from relativeover-the-counter pharmaceutical products (tablets), which can alsocontain acetaminophen or ephedrine (e.g. Codelac, Sedal-M, CodeVin etc.), with organic solvents (such as gasoline) after the initial ad-dition of a strong base (potassium or sodium hydroxide). Hydrochloricacid is used to acidify the mixture and convert the codeine-base intoits water soluble salt that resides in the aqueous layer. Although the ex-ine, heroin and desomorphine.

omo

83M. Katselou et al. / Life Sciences 102 (2014) 8187phosphorus, through an intermediate reaction (formation of -chlorocodide), to desocodeine which is then demethylated intodesomorphine. This simple one-pot reaction may take up to 45 min(Veronese, 2011; Erowid, 2013) and the nal product is often contami-nated with various toxic and corrosive by-products or residuals. Thus,synthetic analogues of codeine, other drugs such as tropikamide, ephed-rine or acetaminophen (often found in codeine containing prepara-tions), phosphorous, iodine or even heavy metals like lead can befound in the krokodil street samples, as a result of poor synthesis. Allthese substances are considered to be responsible for the most of theundesirable or toxic effects that appear after the repeated injections ofkrokodil which actually is a cocktail of all the above substances;desomorphine, by-products and residuals. The desomorphine contentof krokodil samples may range from traces to 75% (Savchuk et al.,2008).

Prevalence and use

Homemade desomorphine (krokodil) has rst appeared illegallyon the Russian drug market in 2003 in the form of an epidemic. Thiswas connected to an observed tendency back to the production ofhomemade drugs, due to the decreased import of Afghan heroin in thelocal drug markets (Dinga, 2013).

Today, it has been estimated that around 100,000 people usekrokodil in Russia and around 20,000 in Ukraine (Grund et al.,2013). Its use appears to grow among people who inject drugs(PWID) in Kazakhstan, Georgia, Germany, Czech Republic, France,Belgium, Sweden, Norway, as well as in USA (Grund et al., 2013;Skowronek et al., 2012; Harris, 2013a; Piralishvili et al., 2013; Sterling,2013).

The victims of krokodil are usually young people aged between 18and 25, previous users of heroin that come from middle-class back-grounds. They turn to this drug for economic reasons, although some

Fig. 2. Synthesis of desof themalso claim that they are/were not aware ofwhat they use, think-ing of abusing heroin (Nye, 2013). Themain reason for the spread out ofkrokodil is obviously the simplicity and accessibility of its preparation.Indeed, tablets of over-the-counter codeine, which usually contain alsoacetaminophen, could be purchased for a fewdollars and the quantity ofdesomorphine produced could substitute for about 5 times worth ofheroin (Grund et al., 2013; Erowid, 2013; Biesk, 2013; Gaynor, 2013;KyAuna, 2013). Moreover, desomorphine is widely available illicitlyfrom different sources throughout the Internet (Drug EnforcementAdministration (DEA) Ofce of Diversion Control, 2013).

Published reports on the toxicity of krokodil use are currently lim-ited (Hayashi et al., 2013). Information is coming mostly from massmedia and self reports from personal drug experience websites. Thefact that this new epidemic is spreading fast should make peopleworry worldwide. Although USA was supposed to be safe from thisscourge, the Banner and Poison Control Center in Phoenix, Arizona, re-ported in September 2013 the rst instances of use of this drug in theUnited States (Gaynor, 2013; KyAuna, 2013; Moran, 2013; Mukherjee,2013; Winter, 2013). In October 2013, seven cases of krokodil relatedhospitalizations were reported in Illinois (Nye, 2013; Payne, 2013), andsimilar cases were reported in Utah (n=1), Arizona (n=2) and Okla-homa (n = 2). According to newspaper reports, the drug seems to bespreading across the American nation, and is now believed to have hitNew York (Christensen, 2013; Nye, 2013; Biesk, 2013; Payne, 2013;Desomorphine News and Discussion, 20112013; RT Question More,2013). It is now estimated that drug addicts have been using the toxickrokodil cocktail instead of heroin since approximately 2011, whichmeans that the drug has been on the streets of USA for much longerthan originally supposed. However, they claim that they were notinitially aware of what they used, thinking it was regular heroin, butthey continued to use this drug due to its 10-fold lower cost and itsmore intensive action than the former (Nye, 2013; Payne, 2013).

The Oklahoma Bureau of Narcotics announced that two men dieddue to krokodil abuse, as the autopsy results revealed in this region(Nye, 2013). Furthermore, International Medical Center in Murray,Manhattan, was aware of a couple of cases where people have usedthe drug, while a spokesman for the Utah Department of Health men-tioned that he had been informed about two cases tied possible tokrokodil (Winslow, 2013).

It has to be mentioned here that DEA had declared that the agencywas aware of the use of krokodil overseas since 2011 (Nye, 2013), al-though recently a DEA ofcer declared that they had not seen evidenceof the drug surfacing in the USA (Miller, 2013).

Krokodil abuse has also appeared inWestern Europe. In September2013, a British doctor described the presence of a formed crater andexposed bone and tendons in the arm of a 30-year-old male homelessin Gloucester, Gloucestershire, South West England, who apparentlyused krokodil and is now dead (Harris, 2013b). One more case of a fe-male 35-year-old addict has also been reported (Brady and Greig, 2013;Gorgan, 2013). In October 2011, German newspapers reported thatdesomorphine under the name Krok has been found in some regions

rphine from codeine.of Germany, such as Bochum (Dsseldorf) and Frankfurt, mixed withheroin (Belgian Early Warning System on Drugs (BEWSD), 2011;Gleixner, 2011; Opiophile (forum), 20122013). Particularly, four morecases of homeless victims were reported in Bochum (Spiegel Online,2011). Thus, in order to alert citizens about krokodil, the GermanSociety for Addiction Medicine issued a warning on this drug in October2011 (Deutsche Gesellschaft fr Suchtmedizin (DGS), 2011).

A lethal case of a 29-year-old drug addict was reported recently andit was suggested that brain damage could result from the use ofkrokodil. Before the patient's death, a head computed tomography(CT) scan showed massive brain swelling, while autopsy revealed arare encapsulated mass lesion in the frontal right lobe of the brain.The toxicological ndings were negative for desomorphine, while mor-phine, methadone, trimipramine and their metabolites were detected.However, taking into account the absence of prior medical history, au-topsy ndings, like old puncture marks on both arms, and the swelling

84 M. Katselou et al. / Life Sciences 102 (2014) 8187of cervical lymphnodes, aswell as the results of the police investigation,death was attributed to at least the chronic intravenous injection of ille-gal substances, including krokodil and heroin (Hayashi et al., 2013).

Krokodil is promising a cheap high and this is themain cause of itsincreased use as all the above cases show. It has to be emphasized herethat there are signicant limitations when estimating prevalence ofkrokodil use, as there are no good reporting systems at present andthe number of reported cases in other countries than former SovietUnion is limited. In any case, the promise of krokodil for a cheaphigh is always accompanied by a heavy cost for the health of theusers, as the same cases show.

Pharmacology of desomorphine

Desomorphine was rstly introduced in Switzerland in 1940 byHoffman-LaRoche under the trade name of Permonid, as post-operative analgesic (Gahr et al., 2012a). It was found to exhibit a fasteronset and shorter duration of action than morphine, with less nauseaand signicantly less respiratory depression (Himmelsbach, 1939;Casy and Partt, 1986). Desomorphine was available as a hydrobromicsalt and it was withdrawn in 1952 although its production was contin-ued until 1998 (Gahr et al., 2012a).

Results of animal studies showed that desomorphine exhibitedhigher and faster pain-relieving (analgesic) effect, more potent gastro-intestinal mobility and general depression than morphine. This phe-nomenon was attributed to the lack of the alcoholic hydroxyl group indesomorphine and its substitution by hydrogen. This lack makes alsoas a consequence desomorphine to be more toxic and more convulsant(Eddy andHowes, 1935). Its reported effects in animals and its structur-al similarity to morphine suggest that desomorphine is a potent-opioid agonist, with less activity on - and -receptors, including eu-phoria, sedation and analgesia (positive effects). It has the further advan-tage of being almost entirely free from the emetic and other effects ofmorphine on the gastrointestinal tract. The hydrogenation of the 7,8double bond leads to such an increased action. This structural modica-tion in combination with the absence of the 6-hydroxyl group of thecyclohexyl ring, that renders desomorphine more lipophilic thanmorphine and favors its penetration in the brain, possibly explains its10-fold higher analgesic potency thanmorphine and its faster analgesiceffect (Drug Enforcement Administration (DEA) Ofce of DiversionControl, 2013; Eddy and Howes, 1935; Weill and Weiss, 1951; Eddyet al., 1957; Nordal, 1956). It has to be mentioned that althoughdesomorphine has ten times the analgesic power and fteen times thedepression effect of morphine, it has only three times the toxic powerof it (Eddy and Howes, 1935).

Desomorphinewas originally synthesized in order to create a substi-tute to morphine as far as it concerns not only tolerance and addiction,but also its side effects like narcotic action and respiratory depression(Eddy and Howes, 1935; Eddy et al., 1957). However, whendesomorphinewas tested it showed an increased dependence potentialcompared tomorphine (Casy and Partt, 1986; Janssen, 1962). A signif-icant number of clinical human studies veried the analgesic potency ofdesomorphine as well as its dependence potential (Schrch andBrunner, 1957; Eddy and Himmelsbach, 1957; Knaf-Lenz, 1957;Tiffeneau, 1957; Binswanger, 1957; Snyder and Lim, 1957; Drack,1957; Lee, 1957). This increased dependence potential can be explainedby the fact that it shows a faster onset of action and a shorter eliminationhalf-life when compared to morphine (Gahr et al., 2012a; Eddy et al.,1957).

Three independent human studies on the clinical use of desomorphine(Schrch and Brunner, 1957; Drack, 1957; Lee, 1957) reported satisfac-tory relief of pain either in cancer patients (Lee, 1957) or in pre- andpost-operative cases of trauma (Schrch and Brunner, 1957) or acci-dental injury (Drack, 1957). The rst published report of Sch rch andBrunner on the clinical use of desomorphine veried its 5 to 10-fold

higher analgesic potency than morphine that appeared more quickly/earlier and lasted less than the latter. Dizziness and vomiting wereless frequent with desomorphine than with morphine, but respiratorydepression was sometimes greater. Furthermore, its sedative effectand its effect on intestinal peristalsis were less than those of morphine(Schrch and Brunner, 1957). According to a study performed on cancerpatients, 1 mg of desomorphine was equivalent to 10 mg of morphinefor pain relief. The relief per dose also averaged 2 h and 25 min for theformer and 3 h and 7min for the latter (Lee, 1957). Desomorphine pro-duced quiet or light sleep to patients who had suffered an accidental in-jury, but they could respond, speak, co-operate. It also gave completerelief with relaxation for 5 or 6 h without the occurrence of nausea orvomiting (Drack, 1957).

Due to the signicantly shorter half-life than its opioid analoguesand the sharp increase in addiction rates of other opioids, desomorphinewas considered for decades to be a compound with nomedicinal value.Nevertheless, desomorphine due to its strong physical and psychologi-cal dependence potential and the fact that it can lead to an irreversibledestruction of the organism,when used as krokodil, has attracted a re-generated medical interest during the recent years (Drug EnforcementAdministration (DEA) Ofce of Diversion Control, 2013; Gahr et al.,2012a, 2012b).

Toxicology of desomorphine

Repeated administration of desomorphine can cause severe medicalcomplications which include physical and psychological dependency,tolerance and a withdrawal syndrome if the substance is no longertaken, similarly to heroin (Grund et al., 2013; Erowid, 2013). The depen-dence potential of desomorphine was initially described by Eddy et al.(1957) and was veried later by Sargent and May (1970) during theirstudy with monkeys. No further studies have been conducted afterthose concerning the dependence potential or its dependence liabilityof desomorphine compared tomorphine. Other effects of desomorphineare similar to those of opiates, includingmiosis,ushing andparesthesia(neutral effects). Common negative effects are constipation and urinaryretention, nausea and vomiting, as well as more serious medical impli-cations, such as allergic reactions, seizures, and respiratory depressionleading to death (Grund et al., 2013; Erowid, 2013). All the above effectsare expected as they are inherent of an opioid like desomorphine.

Toxicology of krokodil

Desomorphine, in the form of krokodil, is ingested orally or, mostcommonly, injected subcutaneously, intravenously or into the femoralartery as an impure liquid (Shuster, 2011; Drug EnforcementAdministration (DEA) Ofce of Diversion Control, 2013). This liquid isactually a cocktail of unknown composition where desomorphine canrange from traces to 75% (Savchuk et al., 2008). This results in a widevariance of the ingested doses, depending on the purity of the substanceand the user's tolerance (Ofce of Alcoholism and Substance AbuseServices (OASAS), 2012; Erowid, 2013).

Krokodil users experience euphoria just for approximately an hourand a half, while the pharmacological effects of heroin use can last 4 to8 h. The withdrawal symptoms, which are similar to the ones from her-oin, may last up to a month (Erowid, 2013). Thus, the short duration ofaction and the less than an hour time required for the home preparationof krokodil lead its addicts that prepare the drug themselves to betrapped in a 24-h daily cycle of cooking and injecting in order toavoid withdrawal. So, krokodil abuse can be characterized as a full-time job (Christensen, 2013; Shuster, 2011; Walker, 2011). By theend, the addicts are staggered out yellow, exhausted and stinking asthe smell of iodine infuses their clothes (Walker, 2011; Dinis-Oliveraet al., 2012).

The toxicity of by-products and residuals of the manufacturing pro-cess alongwith dirty needles and poor injection technique can lead to a

slew of horric consequences that are not related to the opiate effects of

85M. Katselou et al. / Life Sciences 102 (2014) 8187desomorphine but to the toxic effects of impurities in krokodil (Grundet al., 2013; Gahr et al., 2012a). Indeed, the synthetic method followedfor the production of homemade desomorphine yields an impure,orange-colored liquid contaminated with various toxic and corrosiveby-products or residuals like paint thinner, lighter uid, gasoline, lead,zinc, hydrochloric acid, iodine and/or red phosphorus that are used forits preparation (Erowid, 2013; Thoma and Lehmann, 2011). Since thishomemade cocktail is routinely injected with little or no purication,it can cause immediate skin irritation and ulcers, a discolored (greenish)scale-like appearance, similar to that of a crocodile's, destruction of skinand severe muscle and cartilage tissue damage. Thrombophlebitis canalso appear. The presence of gasoline and hydrochloric acid still in thenally injected liquid solution is considered responsible for thesedamages. Once the skin around the injection site is damaged, the areabecomes a target of gangrene. This leads to skin and muscle decayaround the injection site, and, in time, the skin sloughs off due to therupture of the blood vessels, often exposing the bone below. The sameeffects are also caused by the presence of phosphorus that is usuallyscraped from matchboxes. The damaged tissues are susceptible toinfections that may lead to inammation, abscesses and rotting as thisesh-eating drug kills slowly from the inside out (Christensen, 2013;Grund et al., 2013; Erowid, 2013; TOXNET, 2013; Drug EnforcementAdministration (DEA) Ofce of Diversion Control, 2013; Gahr et al.,2012a; Dinis-Olivera et al., 2012). In most of the cases, extensiveamputation is the only solution.

High concentrations of iodine in the injected solution disrupt the en-docrine system, causing thyroid disorders, while high concentrations ofheavy metals such as iron, zinc, lead and antimony attack the nervoussystem (resulting in speech andmotor skill impairments, affectedmem-ory and concentration) and lead to inammation and shut down of liverand kidneys during chronic use (The Cargo Culte, 2011). Lemon (2013))describes the use of homemade desomorphine as a possible cause ofhallucinations, unlike heroin, although no further information on thesubject is given (Lemon, 2013). Intravenous injection of streetkrokodil can also cause life-threatening blood stream infections,coronary artery burst, septicemia and other systemic damage due to in-fections, such as pneumonia and meningitis (Grund et al., 2013; DrugEnforcement Administration (DEA) Ofce of Diversion Control, 2013).In addition, according to health authorities, hepatitis C and HIV are re-ported in a great percentage of krokodil addicts through the use ofcontaminated needles (Human Rights Watch, 2006; Booth, 2013). Theuse of krokodil leads to a mean survival time of 1 or 2 years, whilethe respective time for heroin could be up to 20 years (DesomorphineNews and Discussion, 20112013). It has to be noticed that manykrokodil abusers die within the rst year of use since it is estimatedthat life expectancy is reduced approximately a year for each dose ofthe drug (Priymak, 2011; Walker, 2011).

Determination of desomorphine in biological andexpert-forensic samples

Desomorphine is an old drug of abuse that has recently attracted at-tention, so, there are only two published studies concerning its analyti-cal determination in biological uids (Savchuk et al., 2008; Su et al.,2011). Desomorphine may be detectable in blood samples within acouple of hours and in urine samples within 23 days after krokodiladministration (Hayashi et al., 2013).

Savchuk et al. determined codeine and synthetic analogues ofcodeine, including desomorphine, in expert-forensic and biologicalsamples by GC/MS, using different derivatization reagents like TFAA,BSTFA and MBTFA. They obtained the respective mass spectra andthey also determined the same substances by liquid-chromatographywith ultraviolet detection (LCUV) or thin-layer chromatography(TLC) techniques (Savchuk et al., 2008). Recently, Su et al. developedan SPDEGCMS (Solid-Phase Dynamic ExtractionGas Chromatogra-

phyMass Spectrometry) method using solgel titania lm coatedneedles for the detection and determination of desocodeine anddesomorphine at trace levels in urine samples. This sensitive methodshowed limit of quantication values (LOQs) ranging from 1.0 to5.0 ng/g and provided a wide range linearity (55000 ppb) (Su et al.,2011).

Legal status

The use of desomorphine is prohibited internationally. It wascontrolled under UN Single Convention on Narcotic Drugs since 1961(Erowid, 2013). It is scheduled as a Schedule I drug under the Title 21United States Code Controlled Substance Act (Title 21 United StatesCode (USC) Controlled Substances Act, 2012). A DEA fact sheet aboutdesomorphine was released in October 2013 (Erowid, 2013; DrugEnforcement Administration (DEA) Ofce of Diversion Control, 2013).In Australia, desomorphine is scheduled as a Schedule II drug underthe Drugs Misuse Regulation 1987 of Queensland (Drugs Misuse Act,1986, 2013). Desomorphine is also controlled as a Class A drug in theUK (Brady and Greig, 2013).

Conclusion

Desomorphine invaded Russia, other former Soviet countries andlater the drug markets of Europe and USA, as krokodil during thelast decade. The advantages of krokodil are that it can be easily pre-pared at home or in the street and is much cheaper than heroin. It is adrug of choice for young and poor people when heroin is unavailableor out of budget. However, its home-environment production, thepoor yield of its chemical synthesis, the resulting impurities and resid-uals, as well as the necessity for its frequent production and injectionare responsible for severe medical complications, even deaths. Inorder to combat the rise of krokodil, governments, police and othernational authorities should focus on measures on how to prevent itsproduction and distribution by making initially its main ingredient,codeine, difcult to be obtained. Whenever, large purchases of over-the-counter medication containing codeine are observed, these should raisesuspicion to authorities for clandestine production of desomorphine. In-tensive awareness campaigns to drug addicts on the possible dangers ofhome produced opioid substitutes could lead to a dramatic harm reduc-tion of the growing use of krokodil, which is currently decimating thelives and health of PWID in Eurasia and USA.

Conict of interest statement

The authors declare that there no conicts of interest.

References

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A Krokodil emerges from the murky waters of addiction. Abuse trends of an old drugIntroductionChemistrySynthesis of desomorphineClandestine synthesis of krokodilPrevalence and usePharmacology of desomorphineToxicology of desomorphineToxicology of krokodilDetermination of desomorphine in biological and expert-forensic samplesLegal statusConclusionConflict of interest statementReferences