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Toxicology Rounds

Toxicology Rounds

Designer Opiates 10,000x Stronger than Morphine

Gussow, Leon MD

Author Information
Emergency Medicine News: May 2016 - Volume 38 - Issue 5 - p 6
doi: 10.1097/01.EEM.0000483174.20233.4a
    Fake oxycodone pills containing fentanyl seized by the Royal Canadian Mounted Police.

    Police in Alberta, Canada, seized a cache of green pills this past August that were manufactured to look like 80 mg OxyContin tablets but contained fentanyl as the active ingredient. This was disturbing because fentanyl is an extremely powerful synthetic opiate 50 to 100 times more potent than morphine. At least 145 people had reportedly died of fentanyl overdose last year in Alberta alone, a marked increase over the fatality rate in 2014. In fact, the Alberta Law Enforcement Response Teams (ALERT) went on record citing the emergence of fentanyl as the biggest drug trend of 2015. The policing units prioritized fentanyl investigations, which led to the seizure of 21,000 pills in 2015.

    Authorities were even more alarmed when results of forensic tests on the alleged OxyContin came back, showing that some of them contained a previously little-known research chemical called W-18, a mu-receptor opioid agonist 100 times more potent than fentanyl. For those doing the math at home, that makes it 10,000 times more potent than morphine.

    Chemist Edward Knaus and his colleagues at the University of Alberta first synthesized W-18 in 1981 when they were looking to develop nonaddictive analgesics. It is the most potent of the 32 W compounds with opiate-like activity that the group devised. The first 19 chemicals in the series are pure mu-receptor agonists, and would be expected to have typical opiate effects like sedation and respiratory depression. W-20 through W-32 are opiate agonists-antagonists.

    Compounds in the W series have never been used as pharmaceuticals, and virtually no animal or clinical studies have investigated their effects or reversibility. We do not know if naloxone would reliably reverse respiratory depression caused by W-18, or if so what dose of the antidote would be required. Toxicologists usually teach that additional doses are not be effective if a patient presents with an apparent opiate toxidrome and does not respond to a total naloxone dose of 10 mg. It is certainly possible that W-18 is so potent that more than 10 mg of naloxone might be required if it works at all.

    Another Designer Opioid

    W-18 is not the only designer opioid that has surfaced in recent months. The Fort Worth, TX, Star-Telegram reported in March that two people ended up in the hospital after snorting a white powder they thought was cocaine. Tests revealed the powder was actually U-47700, a short-acting opioid analgesic developed by the pharmaceutical company Upjohn in the 1970s but never put on the market. This drug is about seven to eight times as potent as morphine, according to animal testing, and has been associated with deaths in Europe. One of the Texas patients was admitted to the intensive care unit after being found cyanotic with agonal respirations. Like W-18, the pharmacology and toxicology of U-47700 has not been well studied.

    A mu-receptor agonist called AH-7921 showed up in biological samples from a New York racing horse this past November. This drug, approximately as potent as morphine, was discovered in the 1970s by a British pharmaceutical company. It has been detected as a component of illegal designer drugs in Japan. (Forensic Toxicology 2013;31[2]:223.)

    Helander, et al., published a case series of nine patients with laboratory-proven exposure to MT-45, a synthetic opioid analgesic invented by a Japanese drug company in the 1970s. (Clin Toxicol 2014;52[8]:901.) Five of the cases involved multiple drugs, but four patients tested positive for MT-45 alone. Several patients seemed to respond to relatively small doses of naloxone. Interestingly, three patients experienced hearing impairment, which is a rare but well-documented adverse effect of other opioids such as oxymorphone and hydrocodone.

    We've seen this before. Synthetic cannabinoids first appeared in the United States about six years ago labeled with names such as Spice and K2, which were sold legally as incense, potpourri, and pond cleaner. Analysis revealed these products were, in fact, compounds originally developed for use in studying the body's cannabinoid receptors. Old scientific papers described these agents — JWH-018, AM-2201, XLR-11, and the rest — and gave recipes for manufacturing them. Illicit underground chemists, many believed to be working in Asia, scoured the literature to find psychoactive molecules that would be easy and cheap to make but were not yet widely banned. As one compound was outlawed in a specific jurisdiction, distributors were ready with slightly different structure not covered by an existing law.

    This same thing is now happening with designer opiates. The detection of W-18 in the pills seized in Alberta is no doubt just the tip of the iceberg because tests for W-18 are rarely performed, and even when attempted, are technically challenging. Most authorities believe that many designer opioids originate in China. It is not reasonable to believe that illicit W-18 from abroad made its way into only one batch of faux OxyContin. In fact, South Florida's Sun-Sentinel reported in March that a Broward County man, sentenced for smuggling fentanyl from China, also had more than 2.5 pounds of W-18 in his possession. (

    Pending further study and reports, the take-home lesson is to suspect exposure to a designer opioid in a patient with the opiate toxidrome who tests negative for the usual suspect narcotics. (Table.) Treatment should focus on good supportive care with airway protection and respiratory assist. Naloxone may or may not be effective. Doses higher than the usual 10 mg maximum may be required to reverse respiratory depression, but at that point the wiser intervention might involve an endotracheal tube and mechanical ventilation.

    Opiate Toxidrome

    • Coma/altered mental status
    • Pinpoint pupils
    • Respiratory depression
    • Bradycardia
    • Hypotension
    • Hypothermia
    • Decreased peristalsis
    • Hyporeflexia

    Adapted from Goldfrank's Toxicologic Emergencies (10th edition), New York: McGraw-Hill; 2015.

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