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Trade names | Permonid |
Other names | Desomorphine, krokodil, dihydrodesoxymorphine, Permonid |
Addiction liability | Very High |
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ECHA InfoCard | 100.006.406 |
Chemical and physical data | |
Formula | C17H21NO2 |
Molar mass | 271.360 g·mol−1 |
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Desomorphine [note 1] is a semi-synthetic opioid commercialized by Roche, with powerful, fast-acting effects, such as sedation and analgesia. [3] [4] [5] [6] It was first discovered and patented by a German team working for Knoll in 1920 [7] but was not generally recognized. It was later synthesized in 1932 by American chemist Lyndon Frederick Small. Small also successfully patented it in 1934 in the United States. [8] Desomorphine was used in Switzerland under the brand name Permonid [9] and was described as having a fast onset and a short duration of action, with relatively little nausea compared to equivalent doses of morphine. Dose for dose it is eight to ten times more potent than morphine. [10]
Desomorphine is a morphine analogue where the 6-hydroxyl group and the 7,8 double bond have been reduced. [8] The traditional synthesis of desomorphine starts from α-chlorocodide, which is itself obtained by treating codeine with thionyl chloride. By catalytic reduction, α-chlorocodide gives dihydrodesoxycodeine, which yields desomorphine on demethylation. [11] [12]
A desomorphine product, usually based on codeine, has been developed as a recreational drug. [13] The product in question is typically a highly impure variant of desomorphine. The scaly sores and necrosis that develop around the injection site has prompted the name krokodil (Russian for crocodile).
Desomorphine was previously used in Switzerland for the treatment of severe pain. While medical usage of desomorphine was terminated in 1981, during the final years leading up to that it was being used to treat a single patient in Bern, Switzerland with a rare illness. [14] : 408–409 While desomorphine was found to be faster acting and more effective than morphine for the rapid relief of severe pain, its shorter duration of action and the relatively more severe respiratory depression produced at equianalgesic doses, as well as a high incidence of other side effects such as hypotension and urinary retention, were felt to outweigh any potential advantages. [15] [16]
Desomorphine abuse in Russia attracted international attention in 2010 due to an increase in clandestine production, presumably due to its relatively simple synthesis from codeine available over the counter. Abuse of homemade desomorphine was first reported in Siberia in 2003 when Russia started a major crackdown on heroin production and trafficking, but has since spread throughout Russia and the neighboring former Soviet republics. [14]
The drug can be made from codeine and iodine derived from over-the-counter medications and red phosphorus from match strikers, [17] in a process similar to the manufacturing of methamphetamine from pseudoephedrine. Like methamphetamine, desomorphine made this way is often contaminated with various agents. The street name in Russia for homemade desomorphine is krokodil (Russian: крокодил, crocodile), possibly related to the chemical name of the precursor α-chlorocodide, or the resemblance of the skin damage caused by the drug to a crocodile's leather. [14] Due to difficulties in procuring heroin, combined with easy and cheap access to over-the-counter pharmacy products containing codeine in Russia, use of krokodil increased until 2012. [18] In 2012 the Russian federal government introduced new restrictions for the sale of codeine-containing medications. This policy change diminished but did not extinguish krokodil use in Russia. [19] It has been estimated that around 100,000 people use krokodil in Russia and around 20,000 in Ukraine. [18] [ needs update ] One death in Poland in December 2011 was also believed to have been caused by krokodil use, and its use has been confirmed among Russian expatriate communities in other European countries. [20] In 2013 two cases of Krokodil use were reported in the United States. [21] A single case of desomorphine use was reported in Spain in 2014, with the drug consumed orally rather than by injection. [22] There are reports of krokodil use in the United Kingdom. [23] [24]
Animal studies comparing pure desomorphine to morphine showed it to have increased toxicity, more potent relief of pain, higher levels of sedation, decreased respiration, and increased digestive activity. [25]
Illicitly produced desomorphine is typically far from pure and often contains large amounts of toxic substances and contaminants as a result of the drug producers neglecting to remove highly toxic reactants and solvents left over from synthesis. This neglect could be due to the producers having a limited understanding of chemistry or as a way to avoid the costs of extracting the toxic material. Injecting any such mixture can cause serious damage to the skin, blood vessels, bone, and muscles, sometimes requiring limb amputation in long-term users. [10] This highly impure product may have received the name of krokodil due to the dire effects of the body which can readily be noticed.
Causes of this damage are associated with iodine, phosphorus and other toxic substances that are present after synthesis. Desomorphine producers would use cheap, readily available but relatively toxic and impure solvents such as battery acid, gasoline or paint thinner during the reaction scheme, without adequately removing them afterwards before distribution. Strong acids and bases such as hydrochloric acid and sodium hydroxide are also employed without measuring the pH of the final solution, and analysis of leftover solutions of "krokodil" in used syringes showed the pH was typically less than 3 (i.e. as acidic as lemon juice).[ citation needed ] Failure to remove insoluble fillers and binding aids from the codeine tablets used as starting material, as well as co-administration with pharmaceuticals such as tropicamide and tianeptine, are also cited as possible contributors to the high toxicity observed in users.
The frequent occurrence of tissue damage and infection among illicit users are what gained the drug its nickname of the flesh-eating drug, or the zombie drug, as homemade versions made under inadequate conditions contain multiple impurities and toxic substances that lead to severe tissue damage and subsequent infection as a direct consequence of use. Gangrene, phlebitis, thrombosis (blood clots), pneumonia, meningitis, septicaemia (blood infection), osteomyelitis (bone infection), liver and kidney damage, brain damage, and HIV/AIDS are common serious adverse health effects observed among users of krokodil. [18] Sometimes, the user will miss the vein when injecting the desomorphine, creating an abscess and causing death of the flesh surrounding the entry-point. [10]
Abuse potential studies of desomorphine in animals had shown that it exhibited limited addiction liability. In monkeys, desomorphine had 10 times the depressant effect of morphine, developed tolerance less rapidly and less completely, and did not lead to the appearance of abstinence symptoms during withdrawal. Studies in rats receiving a daily injection of desomorphine at a constant dose showed that the animals developed tolerance slowly to the depressant effect of desomorphine. [25]
Desomorphine has a molecular weight of 271.35 g/mol and three salts are known: hydrobromide (as in the original Permonid brand; free-base conversion ratio 0.770), hydrochloride (0.881) and sulfate (0.802). [26] Its freebase form is slightly soluble in water (1.425 g/L at 25 °C), although its salts are very water-soluble; its freebase form is also very soluble in most polar organic solvents (like acetone, ethanol and ethyl acetate). [10] Its melting point is 189 °C. [10] It has a pKa of 9.69. [10] Desomorphine comes in four isoforms, A, B, C, and D [27] and the latter two appear to be the more researched and used.
Krokodil is made from codeine mixed with other substances. The codeine is retrieved from over-the-counter medicine and is then mixed with ethanol, gasoline, red phosphorus, iodine, hydrochloric acid and paint thinner. [10] [28] Toxic nitrogen oxide fumes emerge from the drug when heated. [29]
It was first discovered and patented by a German team working for Knoll in 1920. [7] Desomorphine was later synthesised in the U.S. in 1932 and patented on 13 November 1934. [14] In Russia, desomorphine was declared an illegal narcotic analgesic in 1998. However, while codeine-containing drugs generally have been prescription products in Europe, in Russia they were sold freely over the counter until June 2012. [30] The number of users in Russia was estimated to have reached around one million at the peak of the drug's popularity. [31]
In the US, desomorphine is a Schedule 1 controlled substance, indicating that the United States FDA has determined that there are no legal medicinal uses for desomorphine in the United States. It has maintained this status as a controlled substance since 1936. [25] The drug is a Narcotic in Schedule I of the Controlled Substances Act 1970 of the United States as drug number (ACSCN) 9055. It is therefore subject to annual aggregate manufacturing quotas in the United States, and in 2014 the quota for desomorphine was 5 grams. [32] It is produced as a hydrochloride (free base conversion ratio 0.85) and sulphate (0.80). [33]
Media in the U.S. and Canada have brought awareness to desomorphine. There have been incidents reported where desomorphine had supposedly been present within either country, [34] but no incidents have been confirmed by any drug testing or analytical results, and desomorphine use in North America is still considered unconfirmed. [35] [36]
Dextromethorphan, or DXM, a common active ingredient found in many over-the-counter cough suppressant cold medicines, is used as a recreational drug and entheogen for its dissociative effects. Street names include Brownies, Dextro, Drix, Gel, Groove, Lean, Mega-perls, Poor man's ecstasy, Red devils, Robo, Rojo, Rome, Skittles, Sizzurp, Sky and Velvet.
Hydrocodone, also known as dihydrocodeinone, is a semisynthetic opioid used to treat pain and as a cough suppressant. It is taken by mouth. Typically it is dispensed as the combination acetaminophen/hydrocodone or ibuprofen/hydrocodone for pain severe enough to require an opioid and in combination with homatropine methylbromide to relieve cough. It is also available by itself in a long-acting form under the brand name Zohydro ER, among others, to treat severe pain of a prolonged duration. Hydrocodone is a controlled drug: in the United States a Schedule II Controlled Substance.
Morphine, formerly also called morphia, is a strong opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies. It is mainly used as an analgesic. There are numerous methods used to administer morphine: oral; sublingual; via inhalation; injection into a muscle, injection under the skin, or injection into the spinal cord area; transdermal; or via rectal suppository. It acts directly on the central nervous system (CNS) to induce analgesia and alter perception and emotional response to pain. Physical and psychological dependence and tolerance may develop with repeated administration. It can be taken for both acute pain and chronic pain and is frequently used for pain from myocardial infarction, kidney stones, and during labor. Its maximum effect is reached after about 20 minutes when administered intravenously and 60 minutes when administered by mouth, while the duration of its effect is 3–7 hours. Long-acting formulations of morphine are available as MS-Contin, Kadian, and other brand names as well as generically.
Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid agonist used for chronic pain and also for opioid use disorder. It is used to treat chronic pain, and it is also used to treat addiction to heroin or other opioids. Prescribed for daily use, the medicine relieves cravings and removes withdrawal symptoms. Withdrawal management using methadone can be accomplished in less than a month, or it may be done gradually over a longer period of time, or simply maintained for the rest of the patient's life. While a single dose has a rapid effect, maximum effect can take up to five days of use. After long-term use, in people with normal liver function, effects last 8 to 36 hours. Methadone is usually taken by mouth and rarely by injection into a muscle or vein.
Glutethimide is a hypnotic sedative that was introduced by Ciba in 1954 as a safe alternative to barbiturates to treat insomnia. Before long, however, it had become clear that glutethimide was just as likely to cause addiction and caused similar withdrawal symptoms. Doriden was the brand-name version. Current production levels in the United States point to its use only in small-scale research. Manufacturing of the drug was discontinued in the US in 1993 and discontinued in several eastern European countries in 2006.
Hydromorphone, also known as dihydromorphinone, and sold under the brand name Dilaudid among others, is a morphinan opioid used to treat moderate to severe pain. Typically, long-term use is only recommended for pain due to cancer. It may be used by mouth or by injection into a vein, muscle, or under the skin. Effects generally begin within half an hour and last for up to five hours. A 2016 Cochrane review found little difference in benefit between hydromorphone and other opioids for cancer pain.
Opioids are a class of drugs that derive from, or mimic, natural substances found in the opium poppy plant. Opioids work in the brain to produce a variety of effects, including pain relief. As a class of substances, they act on opioid receptors to produce morphine-like effects.
Pethidine, also known as meperidine and sold under the brand name Demerol among others, is a fully synthetic opioid pain medication of the phenylpiperidine class. Synthesized in 1938 as a potential anticholinergic agent by the German chemist Otto Eisleb, its analgesic properties were first recognized by Otto Schaumann while working for IG Farben, in Germany. Pethidine is the prototype of a large family of analgesics including the pethidine 4-phenylpiperidines, the prodines, bemidones and others more distant, including diphenoxylate and analogues.
Ethylmorphine is an opioid analgesic and antitussive.
Nalbuphine, sold under the brand names Nubain among others, is an opioid analgesic which is used in the treatment of pain. It is given by injection into a vein, muscle, or fat.
Lefetamine (Santenol) is a drug which is a stimulant and also an analgesic with effects comparable to codeine.
Drug injection is a method of introducing a drug into the bloodstream via a hollow hypodermic needle, which is pierced through the skin into the body. Intravenous therapy, a form of drug injection, is universally practiced in modernized medical care. As of 2004, there were 13.2 million people worldwide who self-administered injection drugs outside of medical supervision, of which 22% are from developed countries.
Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, Papaver somniferum. It is typically used to treat mild to moderate degrees of pain. Greater benefit may occur when combined with paracetamol (acetaminophen) or a nonsteroidal anti-inflammatory drug (NSAID) such as aspirin or ibuprofen. Evidence does not support its use for acute cough suppression in children. In Europe, it is not recommended as a cough medicine in those under 12 years of age. It is generally taken by mouth. It typically starts working after half an hour, with maximum effect at two hours. Its effects last for about four to six hours. Codeine exhibits abuse potential similar to other opioid medications, including a risk of habituation and overdose.
Heterocodeine (6-methoxymorphine) is an opiate derivative, the 6-methyl ether of morphine, and a structural isomer of codeine; it is called "hetero-" because it is the reverse isomer of codeine. Heterocodeine was first synthesised in 1932 and first patented in 1935. It can be made from morphine by selective methylation. Codeine is the natural mono-methyl ether, but must be metabolized for activity. In contrast the semi-synthetic mono-methyl ether, heterocodeine is a direct agonist. The 6,7,8,14 tetradehydro 3,6 methyl di-ether of morphine is thebaine.
Chloromorphide (α-chloromorphide) is an opiate analog that is a derivative of morphine, where the 6-hydroxy group has been replaced by chlorine. Developed in 1933 in Germany, it has approximately ten times the potency of morphine. It has similar effects to morphine, such as sedation, analgesia, and respiratory depression.
Methyldesorphine is an opioid analgesic. First synthesized in Germany in 1940 and patented in the US in 1952, it has a high potential for abuse as with any potent opioid agonist, and is sometimes found along with desomorphine as a component of the home-made opioid mixture known as "Krokodil" used in Russia and the neighboring former Soviet republics. It is approximately 15 times more potent than morphine as an analgesic but if the 6-7 bond is saturated, the β isomer is some 50 times more potent than morphine.
An equianalgesic chart is a conversion chart that lists equivalent doses of analgesics. Equianalgesic charts are used for calculation of an equivalent dose between different analgesics. Tables of this general type are also available for NSAIDs, benzodiazepines, depressants, stimulants, anticholinergics and others.
Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as well as overdose potential among other possible adverse effects. They have been used recreationally for their anti-anxiety and sedative effects, and are thus controlled in most countries due to the risks associated with such use.
An opiate is an alkaloid substance derived from opium. It differs from the similar term opioid in that the latter is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain. Opiates are alkaloid compounds naturally found in the opium poppy plant Papaver somniferum. The psychoactive compounds found in the opium plant include morphine, codeine, and thebaine. Opiates have long been used for a variety of medical conditions, with evidence of opiate trade and use for pain relief as early as the eighth century AD. Most opiates are considered drugs with moderate to high abuse potential and are listed on various "Substance-Control Schedules" under the Uniform Controlled Substances Act of the United States of America.
Desocodeine is a potent semi-synthetic opioid which is the penultimate intermediate in the manufacture of desomorphine from codeine. Desocodeine is a potent analgesic, being as potent as morphine.It is partially metabolized into desomorphine, among others, after parenteral and oral administration.