FACT SHEET Ocfentanil May 2017 For more information, please contact: Dr. P. Blanckaert Coordinator Belgian Early Warning System Drugs Scientific Institute of Public Health National Focal Point on Drugs Jyliette Wytsmanstraat 14 B-1050 Brussels, Belgium Tel : 02/642 5408 [email protected] Science at the service of Public health, Food chain safety and Environment. The information in this message is exclusively meant for the EWS-network, and was sent to you, as a member of this network, in a confidential way. Therefore the information in this message may not be copied, transferred or made public without the prior permission of the WIV-ISP. The WIV-ISP takes responsibility for the editing of a press release, if considered as necessary in the framework of its mission. The information contained in this document is also available on the BEWSD-website (with corresponding pdf-files and analytical data). This part of the website is not accessible for the general public. A login can be requested by contacting [email protected]. © Scientific Institute of Public Health, Brussels 2011 This report may not be reproduced, published or distributed without the consent of the ISP | WIV. A. General information Recent death cases in Belgium Substance: Ocfentanil (mixture with caffeine and paracetamol) Discovered in vicinity of deceased victim Date of death: May 2017 Product type: powder Region: Ghent Substance: Ocfentanil (mixture with caffeine and paracetamol) Date of collection: March 2015 Date of analysis: April 2015 Product type: powder Color: brown Region: Dendermonde Created April 2015 Updated May 2017 Type Narcotic Drugs Group Opioids Name Ocfentanil (A-3217) Nature of substance Ocfentanil is a potent synthetic opioid substance structurally related to fentanyl. Compound with a methoxy group instead of a methylgroup, and a fluorine atom placed on the benzene ring. When studied as a supplement to general anaesthesia, researchers concluded that ocfentanil had a similar mode of action to fentanyl and 3 micrograms of ocfentanil was approximately equivalent to 5 micrograms of fentanyl. Systematic chemical name N-(2-fluorophenyl)-2-methoxy-N-[1-(2-phenylethyl)piperidin-4-yl]acetamide Other names / B. Alerts Alerts Belgium: fatal intoxication linked to the consumption (sniffing) of Ocfentanil, March 2015. Reported by Eurofins forensic lab. A brown powder was found in the house of the victim, containing caffeine, paracetamol and Ocfentanil. Post-mortem blood analysis contained Ocfentanil. The sample was purchased with the use of bitcoins on the internet (darknet?). Reports to EMCDDA Belgium: On 8 April 2015, the Belgian NFP reported the analysis of this sample of Ocfentanil, found during the house-search of a victim of fatal intoxication. The Netherlands: On 24 October 2013, the Dutch FP reported a seizure of white powder seized by the police in September 2013. It was a component of a paracetamol caffeine mixture sold at the drug market as synthetic heroin. Estonia: On 3 March 2017 the Estonian FP reported a seizure of 1,01g white powder seized on 23.04.2016 by the Customs at Tallinn. Post delivery from Netherlands. Sweden: On 29 September 2016 the Swedish FP reported a seizure of 0,97 g and 1,18 g brown pieces (similar to haschish), seized on 14.01.2016 by the Customs at Stockholm. Containing also Paracetamol, coffeine. The substance has been analytically confirmed by GC-MS and TLC at The Swedish Customs Laboratory. France: On 24 June 2016 the French FP reported 3 intoxications that occurred on 31.10.2015. Denmark: On 23 June 2016 the Danish FP reported a seizure of 1g brown powder seized on 22.05.2016 by the Customs at Copenhagen International postoffice. Containing also Caffeine, paracetamol, mannitol. Sent from the Netherlands to Denmark. Packed in a zip bag between several layers of white paper and in a white envelope. Germany: On 29 January 2016 the German FP reported a death case that ocurred on 12.03.2015. Sweden: On 18 December 2015 the Swedish FP reported a seizure of 0.9 g brown powder seized on 2015-11-25 by the Customs at Stockholm. The substance was identified by the Swedish National Forensic Centre (NFC) using GC-MS, LC-HRMS and NMR. Spain: On 2 October 2015 the Spanish FP reported that on June 3rd , 2015, a few milligrams sample of OCFENTANYL was collected by Energy Control´s Drug Checking Service from a user in Madrid (Autonomous Community of Madrid). Sample consisted of a white-coloured powder. Product was sold as heroin on the Internet (160 €/gram). User bought it in March 2015. C. Pictures Powder found in the 2015 case, Belgium. Powder collected and analysed by Wedinos, UK Seizure of brown pieces, Sweden, January 2016 D. Clinical information / Use & Risks Usage Ocfentanil (INN) is an opioid analgesic that is an analogue of fentanyl was developed in the early 1990s. It is similar to fentanyl in effects, producing strong analgesia and sedation, but is slightly more potent. Side effects of fentanyl analogues are similar to those of fentanyl, and include itching, nausea and potentially serious respiratory depression which can be life-threatening. Belgian case of 2015 reported administration through sniffing. Ocfentanil is a potent synthetic opioid structurally related to fentanyl. It was developed as one of a series of potent naloxone-reversible opioids in an attempt to obtain an opioid that had better therapeutic indices in terms of cardiovascular effects and respiratory depression as compared to fentanyl. Study of the analgesic activity of ocfentanil using the mouse hot plate test gave an ED50 of 0.007 mg/kg compared to 0.018 mg/kg for fentanyl; ocfentanil being approximately 2.5 times as potent as fentanyl in this test. In human volunteers ocfentanil induces effective analgesia at 1 μg/kg, while in doses up to 3 μg/kg, analgesia and respiratory depression occurred in a dose-dependent manner. While a further study suggests that ocfentanil may be as effective as morphine in post-operative relief. Ocfentanil was also studied as a supplement to general anaesthesia, in which the researchers concluded that it appears to be similar in action to fentanyl, with 3 μg/kg of ocfentanil approximately equivalent to 5 μg/kg of fentanyl. Modes and scope of the established or expected use Epidemiology What is the availability of ocfentanil on the drug market? It appears that ocfentanil is not being openly sold on the surface web by means of web pages advertising the substance. Reports to the EMCDDA suggest availability of ocfentanil on the dark net. The total amount of ocfentanil seized reported to the EMCDDA between 2014 – 2016 does not exceed 200 grams. The last reported seizure occurred in May 2016. The apparent low amounts of ocfentanil seized should be interpreted in the context of its potency as an analgesic. Fentanyl and its derivatives have been linked with the recent surge in overdose deaths in the USA and Canada. Misuse of fentanyl has also been reported in Estonia as one of the major causes of drug-related deaths. It should also be noted that ocfentanil has been controlled in China since October 2015. Who is using ocfentanil and why? The available data suggests that ocfentanil can be unknowingly used by those seeking heroin; data also suggests that those on opioid substitution programs (such as methadone clinics) and psychonauts may actively seek ocfentanil. Health risks Pharmacology and toxicology The available data suggests that ocfentanil is a potent opioid similar in structure to fentanyl, the effects of which are reversed by naloxone. It is not specified in the literature which opioid receptors ocfentanil is active at, but it does result in typical fentanyl adverse effects with its ability to cause respiratory depression, bradycardia and hypotension. In mouse hot plate test, ocfentanil produced an ED50 of 7.7 µg/kg compared with fentanyl at 18 µg/kg and morphine at 10100 µg/kg in vivo. Based on the results of this test, ocfentanil is roughly 2.5 times as potent as fentanyl and 1,300 times more potent than morphine. A study by Fletcher and co-workers reported that a 3 µg/Kg dose of ocfentanil produced an equivalent level of analgesia to 5 µg/kg of fentanyl in humans. They do state however, that it was impossible to determine an exact potency relationship from their study and it is important to be aware that differences in the sensitivity and pharmacodynamics of opioids occur when comparing information from in vivo to humans. It has been reported that ocfentanil has a greater therapeutic index (TI) than fentanyl. The therapeutic index is a ratio that quantifies the ‘safety’ margin of a compound. A large therapeutic index results in a greater safety margin between the therapeutic dose and toxic effects. A small therapeutic index results in the opposite and a smaller window between the therapeutic dose and toxic effects. In the tail-flick test (conscious freely moving rat), the TI for respiratory depression of ocfentanil was 7.80 and 5.00 for fentanyl. Whilst in the hot plate test this was 5.90 for ocfentanil and 2.50 for fentanyl. This shows that in the hot plate test that ocfentanil has double the therapeutic index of fentanyl and 1.3 times greater in the tail-flick test. Leslie and co-workers have also reported that the therapeutic index of ocfentanil was consistently greater than that of fentanyl. Although the therapeutic index is higher for ocfentanil, it cannot be considered ‘safe’ due to its higher potency relative to morphine and fentanyl. Self-reported effects Limited data is available on the subjective effects of ocfentanil. Two users who submitted samples to drug checking services reported “distinct, short-acting opioid- like effects”.