There has been a dramatic increase in the observed number of reports on the use of Krokodil (also known as Crocodile, Krok, or Croc) in the last few years. Krokodil use was first reported in Siberia in 2002 and has mostly been described in European countries. This deadly mixture however has made its way into the United States with a few cases reported. It is known as the “drug that eats junkies”, and “Russia’s deadly designer drug”. It is characterized as the “flesh eating” or “flesh rotting” drug. The main active ingredient of Krokodil is desomorphine, a synthetic derivative of morphine. It can be manufactured at home from codeine, along with several other easily available additives, and is significantly cheaper than heroin. Its regular use results in severe damage to the vasculature, muscles, and bones, and in multiorgan failure with a mean survival time of 2 years after its first use. Use of this novel flesh-eating drug has been spreading rapidly across Europe because of its low cost and higher addictive potential. The drug is also called Russian Magic, referring to its potential for short lasting opioid intoxication or, more commonly, to its street name, Krokodil. Krokodil refers both to chlorocodide, a codeine derivate, and to the excessive gross desquamation from gangrenous inflammation at the injection site that resembles scales of a crocodile. The use of desomorphine is prohibited internationally. It is a scheduled I drug under the United States Code Controlled Substance Act.
A 25-year old female presented to the Emergency Department with a week of pain, swelling, and ulceration to her right thigh. She used heroin daily, however due to a recent job loss, she was forced to obtain cheaper homemade heroin substitutes. She reported injecting a homemade drug called “Krokodil” for the past several months. She initially developed blistering of the area, which had progressed to painful necrotic ulcers. On exam, her temperature was 101°F, heart rate 125 beats per minute, blood pressure 115/60 mmHg. Her right anterior thigh was swollen, with erythema and several large necrotic ulcerations. She was admitted to the hospital and treated with intravenous antibiotics and wound care, however left the hospital against medical advice and was lost to follow up.
1) How is Krokodil made?
2) Why is Krokodil more addictive than morphine?
Desomorphine first emerged in the Russian drug scene around 2002-2003 under the term Krokodil. At that time, there was a decreased import of Afghan heroin into local drug markets and a tendency back to the production of homemade drugs. A dramatic increase in the number of addicted individuals was then observed, which is thought to be a result of the easy availability of Krokodil from a simple production process that can be accomplished at home with little cost. Most Krokodil users claim to be former heroin users who switched. In early 2011, 65 million doses of desomorphine were seized in Russia. Currently, there are approximately 100,000 individuals in Russia with a desomorphine addiction, which is likely an underestimate of the true number. Due to his epidemic problem in Russia, as of June 2012, codeine-containing tablets, which are the chemical bases for the home production of desomorphine, became only available in pharmacies. In late 2011, Krokodil use in Germany was reported with devastating dermatologic lesions typical of Krokodil use. Due to the high dependence potential and the toxicity of Krokodil, the mean survival time after first use is reported to be 2 years. At this point, Russia and Ukraine seem to be the countries most affected by Krokodil, however Georgia, Germany, Kazakhstan, Czech Republic, France, Belgium, Sweden, Norway as well as the USA have reported Krokodil use and related injuries. The victims of Krokodil are usually young people between ages 18 and 25, who turn to this drug for economic reasons.
Pathophysiology and Pharmacokinetics
Desomorphine is an opioid analgesic that was first synthesized in the United States in 1932. It was originally synthesized with the intention of creating an alternative to morphine with an improved side effect profile. However desomorphine showed increased dependence potential compared to morphine. It was introduced in Switzerland in 1940 by Hoffman-LaRoche under the trade name of Permonid®, as a post-operative analgesic. It was found to exhibit a faster onset and shorter duration of action than morphine, with less nausea and respiratory depression. It is a potent ?-opioid agonist, with less activity on ?- and ?-receptors. It is almost entirely free from the emetic effects that morphine has. Its chemical structure renders desomorphine more lipophilic than morphine favoring penetration in the brain leading to a higher analgesic potency. It has 8 to 10 times higher analgesic potency, faster onset of action, and shorter half-life compared with morphine, which accounts for its increased addictive potential. Due to this short elimination half-life, patients with desomorphine dependence inject more frequently than those with heroin dependence. The simple and cheap domestic production process involves boiling 80-400mg of codeine with a diluting agent (mostly paint thinner that may contain lead, zinc or ferrous agents), gasoline, hydrochloric acid, iodine, and red phosphorous (which is scraped from the striking surfaces on matchboxes). In this process, desomorphine is generated from codeine (3-methylmorphine) via two intermediate steps (?-chlorocodide and desocodeine). The process takes 10-45 minutes. The final product is a suspension that contains desomorphine as the psychoactive core, along with all other agents involved in the production process. There are various primary substances that can be used for the manufacture of Krokodil, so the chemical composition likely varies between users. The desomorphine content of Krokodil samples may range from traces to 75%. The suspension is used intravenously without using any sort of filter, accounting for the tremendous tissue damage that occurs. Sometimes a weak base, such as cigarette ash or bicarbonate is added after the reaction is complete, however this is insufficient to raise the pH over 3.
Repeated administration of desomorphine can cause physical and psychological dependency, tolerance and a withdrawal syndrome if the substance is no longer used, similar to heroin. Other effects are similar to those of opiates such as miosis, flushing, constipation, urinary retention, nausea, vomiting, sedation and respiratory depression. Specifically with Krokodil, due to the high degree of contamination with various toxic byproducts, injection of Krokodil causes immediate tissue damage to blood vessels, muscle and bone. Multisystem organ dysfunction can occur including thyroid (due to iodine) and cartilage (due to phosphorus). Heavy metal poisoning can also occur with chronic use. Abscess formation, thrombophlebitis, gangrene, necrosis and autoamputation are common occurrences. Skin sloughs off at the injection site, often exposing the bone below. The ill effects of Krokodil are not limited to localized injuries and include pneumonia, sepsis, meningitis, osteomyelitis and osteonecrosis, neurologic injury (such motor and memory impairment), ulceration and tissue damage at sites distant from the injection site, liver injury, renal impairment and death. This is a paucity of information in the medical literature and current information comes mostly from mass media and self reports from “personal drug experience” websites. These complications occur shortly after Krokodil is injected. Present accounts often involve young individuals presenting to Emergency Departments with severe complications. Additionally, practices common to homemade drug production are known to potentiate blood-borne virus transmission such as HIV and hepatitis C. The short duration of action (about 1.5 hours) and less than an hour time required for the home preparation of Krokodil leads its addicts to be trapped in a 24-hour daily cycle of cooking and injecting to avoid withdrawal. High concentrations of iodine in the injected solution disrupt the endocrine system, causing thyroid disorders, while high concentrations of heavy metals cause central nervous system effects such as speech and motor impairment, poor memory and concentration. Jaw osteonecrosis, which is resistant to medical treatment, can develop in the maxillofacial region in users due to red phosphorus contamination.
Because of the high degree of contamination with different toxic chemicals, which vary among users, scientific analysis of the chemical composition is not available. Desomorphine can be detected in blood samples within a couple of hours and in urine samples within 2-3 days after Krokodil administration. Routine testing in the acute clinical setting is not typically available. Diagnosis is therefore based on the history provided by the patient as well as the clinical presentation. Soon after use, patients will present with a physical exam consistent with other opioids ingestions/injection. Although extensive tissue damage is typically described, this can also be seen in patients who develop skin and soft tissue infections from heroin use. In chronic Krokodil users, it may be worthwhile screening for heavy metal poisoning given the contamination during the manufacture process.
In regions where Krokodil use is problematic, poor access to proper health care may exacerbate the described complications. Medical help is reportedly only sought after during the late stages of tissue injury and may end with severe mutilation, amputation and death. If someone seeks care, extensive wound care and IV antibiotics is typically indicated. In many cases, amputation is the only solution. Existing reports have emphasized the high potency of desomorphine and the need for frequent redosing, resulting in binge patterns that can last over days. During these binges, sleep deprivation, poor hygiene, and malnutrition places users at risk for further complications. Variations in potency of desomorphine places users at increased risk of overdose. Treatment must consider not only the local tissue destruction that occurs, but also the distant tissue injury and multi-system organ damage that can occur. In the setting of respiratory depression, naloxone (0.4-2mg IV; repeat every 2-3 minutes until desired effect is achieved) can be administered.
Discussion of case questions
1) The simple and cheap domestic production process involves boiling 80-400mg of codeine with a diluting agent (mostly paint thinner that may contain lead, zinc or ferrous agents), gasoline, hydrochloric acid, iodine, and red phosphorous (which is scraped from the striking surfaces on matchboxes). In this process, desomorphine is generated from codeine (3-methylmorphine) via two intermediate steps (?-chlorocodide and desocodeine). The process takes 10-45 minutes. The final product is a suspension that contains desomorphine as the psychoactive core, along with all other agents involved in the production process.
2) Its chemical structure renders desomorphine more lipophilic than morphine favoring penetration in the brain leading to a higher analgesic potency. It has 8 to 10 times higher analgesic potency, faster onset of action, and shorter half-life compared with morphine, which accounts for its increased addictive potential.
Consultation with a specialist in poison information or with a medical toxicologist can be obtained free of charge by calling the California Poison Control System at 1-800-222-1222.
This issue of CALL US... was written by Alicia Minns, MD,
Published on Sept 5, 2014
CALL US... is published by the California Poison Control System. Editorial Board: Executive Director, Stuart E. Heard, PharmD; CPCS Medical Directors: Timothy E. Albertson, MD, Richard F. Clark, MD, Richard Geller, MD, Kent R. Olson, MD; CPCS Managing Directors: Justin Lewis, PharmD, Thomas E. Kearney, PharmD, Lee Cantrell, PharmD; Editor:Binh T. Ly, MD; Assistant Editor: Alicia Minns, MD.
The California Poison Control System is operated by the School of Pharmacy, University of California, San Francisco (coadmin @calpoison.org)