Krokodil: Poor Man's Heroin

Desomorphine, also known by its street name krokodil, is an opioid derivative of codeine.It has a sedative and analgesic effect and is highly addictive, like heroin and other opioids. People who inject these toxic agents into their veins can develop extreme skin ulcerations, infections, and gangrene. It produces a discolored (green, grey, black) scale-like skin which resemble like crocodile, hence the street name is given as “krokodil". Krokodil is also called “Russian Magic”, which refers to its short duration of opioid intoxication (euphoria).

Krokodil contain desomorphine which is a synthetic morphine analogue synthesized in the 1930s. Due to illicit, home-based manufacturing it may contain other unknown ingredients. It is typically abused via the intravenous (IV) route. Desomorphine is a schedule I substance in the U.S., meaning it has a high abuse potential with no accepted medical use. 

Discrepancies between online information around purification and making homemade drugs safer, and the synthesis of the same substances in a proper laboratory environment, exist.

Krokodil is synthesized through a very simple chemical process consisting of two successive reactions. The required laboratory equipment is minimal, requires the use of highly toxic substances, but easily available and cheap: strong alkalis, hydrochloric acid, red phosphorus and finally organic solvents such as petrol, ethyl acetate or paint thinner. The starting substance is codeine, derived from antitussive drugs or pain killers, which may also contain paracetamol or ephedrine. Generally, small amounts of this precursor are required, from 80 to 400 mg, and the process lasts about 40-45 minutes.

Two steps are required:
(i) codeine extraction from the drug and
(ii) codeine molecule reduction in what is believed to be desomorphine. This reduction process is known as the Nagai method and is based on a reduction method with hydriodic acid and red phosphorus as reagents, often also used for the synthesis of illegal methamphetamine.

 (i) Codeine extraction: The first step consists in the extraction of the codeine from tablets or syrup. Initially, it is mixed with strong alkalis, such as sodium hydroxide, with a diluent agent that may contain lead, ferric or ferrous and antimony agents, and other organic solvents, while subsequently a strong acid is added, such as hydrochloric acid obtained from batteries or industrial products. Petrol may be used as organic solvent, although some users have reported the use of paint thinners.

(ii) Reduction of desomorphine codeine: Codeine is mixed with iodine, water and red phosphorus in glasses or glass containers or in enamelled pots. The resulting mixture is heated, producing hydriodic acid, a very strong acid which has been used to reduce carbonyl groups, nitriles, halides and alcohols for more than 100 years. The reduction process is carried out using directly hydriodic acid or iodine and red phosphorus which form the acid in situ. Iodine is extracted from medical solutions or used as crystal, while red phosphorus is usually obtained from match heads.

The role of phosphorus is to reconvert the molecular iodine, formed during the reaction, into hydriodic acid. The reaction involves a cyclic oxidation of iodide anions to iodine and the subsequent reduction of iodide to iodine by the red phosphorus which instead is converted into phosphoric or phosphoric acid. This step allows the cleavage of the methoxyl group of codeine to form a hydroxyl group. The solution is ready when the mixture has changed its color and smell. The final product is a caramel-colored solution with an acrid smell that is injected into the vein. However, there are limitations on possible production methods and it is important to assess how secondary reactions can affect final drug performance. Numerous descriptions of Krokodil production are reported in the literature, weak bases such as cigarette ash or bicarbonate are often found after the reaction has been completed. A key question is whether the synthetic way followed actually produces desomorphine. The classical synthesis of desomorphine involves the reaction between codeine and thionyl chloride, leading to the formation of α-chlorocodide, and subsequently a reduction and a final demethylation. However, using gas chromatography, Savchuk and coworkers identify 4 synthetic analogues of desomorphine, such as methyldesomorphine, 3,6-dideoxy-dihydromorphine, morphinan-4,5-epoxy-3-ol, and didehydro desomorphine, as well as traces of codeine and other compounds, with a desomorphine content up to 75%. However, there is a variability in desomorphine concentrations on the basis of the different synthesis processes. Furthermore, it should be noted that codeine formulations almost always contain other ingredients, such as paracetamol, caffeine etc. It is not perfectly known yet how each of these compounds affects the chemical reactions and the final result. The Krokodil psychoactive effects may therefore depend on the type of medicine, chemical substances, reagents available locally and actual reaction used. Further analysis is needed to define the actual drug constituents. Recently, Soares and collaborators (2017) reported a total of 54 detected morphinans, highlighting the fact that these additional morphinans may contribute to the psychotropic effects of krokodil.
 

Krokodil also refers to chlorocodide which is a codeine derivative in the synthetic path to desomorphine. Homemade versions of the drug start with codeine, and can be ‘cooked’ similar to illicit methamphetamine (“meth”) production. Organic solvents such as gasoline, paint thinner, or lighter fluid, iodine, hydrochloric acid, and red phosphorus (from matches) are used in homemade synthesis. These dangerous chemicals are not always fully “cooked” out of the concoction when used to make illicit krokodil. 

According to reports, the drug acts within 2 to 3 minutes and has 10 to 15 times more potential than morphine, and three times toxic. In fact, when the toxic chemicals are removed, what is left is desomorphine, which is a compound very similar to heroin.
After a rapid onset of the drug, the euphoric effects may last less than two hours. Due to the short duration of the “high”, many users inject themselves in a rapid repetition of drug use to avoid withdrawal symptoms that resemble heroin. 

According the the DEA, repeated administration of desomorphine with short intervals in cancer patients with severe pain showed that desomorphine produced a high degree of addiction liability.
Due to the drug’s rapid onset but short duration of action and frequent administration, quick physical dependence may occur. 

Reported health hazards due to krokodil injection use include:

• blood vessel damage (thrombophlebitis)
• open ulcers, gangrene
• skin and soft tissue infections
• need for skin grafts and surgery
• limb amputations
• pneumonia
• blood poisoning (bacteremia)
• meningitis
• rotting gums or tooth loss
• blood-borne virus transmission (such as HIV and HCV due to needle sharing)
• bone infections (osteomyelitis) and osteonecrosis
• speech and motor skills impairment
• memory loss and impaired concentration
• liver and kidney damage
• overdose
• powerful respiratory depressant effect (slowed or stopped breathing)
• death.

Existing reports of the dermatologic sequel of krokodil use describes the development of significant swelling and pain in the areas of IV or subcutaneous injection which is followed by a discolored (greenish-black) scaling and large-scale necrotic ulceration.This ulceration can progress to severe muscle and cartilaginous tissue damage. Subsequent skin and muscle decay causes the skin to slough off,and often exposing the underling bone. Thrombophlebitis and gangrene have also been reported at and around injection sites. With 10 times the potency of morphine, krokodil's extreme analgesic effects may cause users to ignore the severity of these deleterious consequences, which may contribute to the delayed medical attention which is often seen in its users. The described tissue injuries seem to consistently manifest shortly after injection of krokodil, and users report relatively short histories of abusing the drug. 

Krokodil is more associated with gangrenous and necrotic tissue destruction than other intravenously injected illicit substances, including heroin. This finding may be related to the ingredients used to prepare krokodil, but the exact mechanism behind its toxicity still remains unknown. Several reports emphasizes on the lack of purification of this concoction before injection, which seems to be cause for immediate irritation and cutaneous damage. Krokodil contains many ingredients that are known to be toxic to the skin amd body. It has been suggested in the reports that the presence of gasoline and hydrochloric acid in the injected solution induces discolored scaling and ulceration, whereas iodine is responsible to cause severe damage to the muscles and endocrine system. Reports also shows, red phosphorous as a cause for cartilaginous tissue and bone damage. Atypical jaw osteomyelitis and necrosis has been reported in patients who use intravenous narcotic drugs containing red phosphorous. Toxic byproducts present because of improper purification such as iron, zinc, and lead have been associated with neurologic, liver, and kidney impairments. Further,  muscle  and cartilage involvement in come cases lead to amputation of affected limbs. The more severe harm associated to krokodil use may also be because of its relatively short half-life which lead to more frequent administration of the drug. Concomitant intravenous abuse of other medications such as tianeptine (antidepressant) has been reported and may contribute to some of the vascular complications frequently seen in krokodil users.

Case Study:

A 50-year-old man having 16-year history of injection heroin abuse was presented to the emergency department of hospital complaining of ulcerative lesions on his right arm, which he stated had become worse over the past 3 months. He claimed the skin lesions, which involved his entire right arm, had grown “wider and deeper” since he started using the drug “Krokodil.” He further added that he buy the product from four different drug suppliers but did not know how it was prepared.

On presentation, his vital signs were:

• blood pressure, 135/78 mm Hg; 
• heart rate, 92 beats/minute; 
• respiratory rate, 14 breaths/minute; 
• temperature, 98.2˚ F. 
• Oxygen saturation was 100% on room air.

Physical examination of the right arm was notable for broad ulcers that exposed fat tissue and muscle and involved the entire forearm circumferentially. There were no signs of acute infection such as erythema, warmth, or abscess formation. The remainder of the physical examination was unremarkable.
The patient in this case was taken to the operating room for debridement of the right arm. The pathology results of the tissue showed ulceration, abscess, acute and chronic inflamed granulation tissue, fibrosis, and necrosis. A magnetic resonance image of the arm showed no signs of osteomyelitis. A blood sample sent for analysis was negative for desomorphine. The patient was stable after the surgery, and was discharged with follow-up instructions and referral for drug abuse counseling.