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Tramadol is a synthetic opioid analgesic approved in 1995 by the United States Food and Drug Administration (FDA) for moderate to moderately severe pain. Its mechanism of action involves opioid and non-opioid pharmacological activities. Tramadol is a μ-opioid receptor agonist, producing opioid-like effects of analgesia, and respiratory and CNS depression. It also acts as a serotonin and norepinephrine reuptake inhibitor, which can cause excitatory neurological effects. Tramadol is metabolized by CYP2D6 to O-desmethyltramadol, an active metabolite that is more potent and has a longer half-life than the parent drug. Tramadol is approximately equipotent to its structural analog codeine. In 2014, the FDA classified tramadol as a schedule IV controlled substance due to its potential for abuse. Tramadol is available as immediate-release and extended-release tablets. Trade names include ConZip®, Ultram®, Ultracet®, Ryzolt®, and Rybix ODT®.
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Dipyrone is a non-opioid analgesic with antipyretic activity, which was developed by the German company Hoechst AG in 1920 with mass production starting in 1922. It is a pro-drug, which is rapidly metabolized after oral administration to active pyrazolone compounds. Dipyrone is also know under different generic names such as metamizole, noramidopyrine, and others. Dipyrone was sold as an over-the-counter (OTC) analgesic until the 1970s, at which time it was banned in several countries, including the United States, several European nations, Japan, and Australia following reports of users developing agranulocytosis, occasionally resulting in death. The safety of the drug is still controversial, resulting in varying levels of restriction and regulation worldwide. Dipyrone is still available, however, by prescription and OTC in many countries in Europe, South America, and Asia.
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The objective of this report is to provide guidance in developing an appropriate analytical scope of testing for novel psychoactive substances (NPS) in the United States based on current trends and intelligence. This report is based on information available in Q1 2021 and is subject to change along with the drug market.

NPS Discovery and the SOFT Designer Drugs Committee have established the below recommendations for NPS scope based on information from extensive collaborations, partnerships, and initiatives which yield national perspectives. Suggested cut-off concentrations or reporting limits (in ng/mL) are listed for each NPS. These values were categorized (i.e., <1, 1-10, and >10 ng/mL) and determined based on currently available quantitative data and/or comparison to structurally similar NPS within the given sub-class.
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Phenacetin, a pain-relieving and fever-reducing drug, was discovered as an analgesic in 1887. It was one of the first synthetic fever reducers on the market and one of the first non-opioid analgesics without anti-inflammatory properties. Due to its hazardous side effects, including carcinogenic and kidney-damaging properties, the Food and Drug Administration (FDA) ordered its withdrawal from drug markets in 1983. Since being withdrawn phenacetin has become a common adulterant of illicit substances. In a 9-year longitudinal study of cocaine powders in the Netherlands, the percentage of samples containing phenacetin increased from 1.6 to 40.6 with a peak of 48% in 2006. Additionally, phenacetin was the most frequently identified adulterant in the samples.
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4F-MDMB-BICA was first identified in the United States (U.S.) in plant-like material seized by law enforcement in May 2020 and soon after in toxicology casework in July 2020, with concurrent emergence in European countries. 4F-MDMB-BICA is structurally similar to the synthetic cannabinoid 4F-MDMB-BINACA, differing by an indole vs. indazole core, respectively. 4F-MDMB-BICA is an activator of the cannabinoid receptor system and its toxicity can be demonstrated through medicolegal death investigations paired with comprehensive toxicology findings. In the U.S., 4F-MDMB-BICA has been identified in at least 26 toxicology cases associated with postmortem (PM) and driving under the influence of drugs (DUID) investigations. In Europe, 4F-MDMB-BICA has been identified in several countries, including Hungary, the United Kingdom, Belgium, and Slovenia. Eleven deaths were attributed to the use of 4F-MDMB-BICA in Hungary between May and August 2020.
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Metonitazene is a potent synthetic opioid bearing structural resemblance to etonitazene, a synthetic opioid that is nationally and internationally controlled. Metonitazene is dissimilar in structure to other synthetic opioids typically encountered in forensic casework (e.g. fentanyl analogues). Metonitazene and similar analogues (e.g. etonitazene, isotonitazene) were first synthesized and reported in the literature in the 1950s. Pharmacological data suggest that this group of synthetic opioids have potency similar to or greater than fentanyl. Metonitazene was first reported by NPS Discovery after detection in a seized drug powder in July 2020. To date, metonitazene has been identified in eight blood specimens associated with postmortem death investigations in the U.S.
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Fluorofentanyl was identified as early as 2016 in the U.S. and Europe, but overall detections remained low until recent months. Positivity of para-fluorofentanyl began increasing in Q3 2020 and within a few months this fentanyl analogue has been identified in 16 forensic cases. para-Fluorofentanyl is commonly found in combination with fentanyl, but the concentration ratio between these two substances varies (0.003 to 26); para-fluorofentanyl is the primary synthetic opioid in multiple cases. para-Fluorofentanyl is a potent synthetic opioid with reported potency similar to fentanyl.
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Clonazolam (also called clonitazolam) first emerged in the recreational drug supply in 2014 (Europe) and 2016 (United States). Like many NPS, clonazolam was first synthesized during drug development in 1971 but was never approved for therapeutic use. Clonazolam is the triazolo– counterpart to clonazepam (Klonopin, Rivotril). Clonazolam appears in various drug preparations, including powders, tablets (i.e. counterfeit pharmaceuticals), liquids, and blotters. Clonazolam has been linked to adverse events resulting in hospitalization or death and is commonly reported in combination with other drugs and/or NPS, including benzodiazepines and opioids. Trend reports developed by NPS Discovery previously indicated a decline in clonazolam positivity in Q3 2020. However, recent developments show that the positivity of clonazolam is currently increasing based on new data collected after testing for its metabolite.

Assessments of drug prevalence and positivity are contingent on accurate characterization of drug targets within specific samples. These assessments include consideration of the analytical methods used for drug testing and the drug species (e.g. parent drug, metabolite) targeted during method development and/or data processing. Nitro–group–containing benzodiazepines (e.g. clonazolam, clonazepam) are metabolized in the body to amino– counterparts (e.g. 8-aminoclonazolam, 7-aminoclonazepam). Additionally, instability of these drugs can lead to the production of these same amino– species. Therefore, data-mining for 8-aminoclonazolam was conducted on all samples analyzed in 2019 and 2020 to re-evaluate the positivity of clonazolam in our sample populations. The results indicate that the positivity of clonazolam was previously underreported when targeting only the parent drug and 8-aminoclonazolam appears to be a more appropriate biomarker for accurate determination of clonazolam use.
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Xylazine was discovered as an antihypertensive agent in 1962 by Farbenfabriken Bayer in Germany. Due to its hazardous side effects, including sedation, hypotension and bradycardia, it was not approved by the Food and Drug Administration (FDA) for human use. The FDA did however approve it for veterinary use, and it is now used as an animal tranquilizer and a sedative, analgesic and muscle relaxant. It may be sold under the trade names Rompun®, Anased®, Sedazine®, and Chanazine®. Xylazine is not a controlled substance in the United States and only requires a veterinary prescription to obtain. It has emerged as an adulterating agent in many illicit drug products, including cocaine, heroin, fentanyl and combinations of these substances. Xylazine can be used as a drug of abuse alone and as a drug for attempted sexual assault or poisoning. Xylazine is referred to as “Tranq Dope” on the street in the United States or “Anestecia de Caballo” in Puerto Rico. The drug has been implicated as a cause, or contributing cause, of death in several cases both alone and in combination with other drugs.
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MDMB-4en-PINACA was first identified in toxicology casework in the United States in September 2019; however, its emergence dates back earlier to seized drug testing from Europe in June 2018. MDMB-4en-PINACA is structurally similar to the popular synthetic cannabinoid 5F-ADB (5F-MDMB-PINACA), differing by the removal of the fluorine atom and replacement with a terminal alkene. MDMB-4en-PINACA is a potent activator of the cannabinoid receptor system and its toxicity has been demonstrated through medicolegal death investigations paired with comprehensive toxicology findings. In the United States, MDMB-4en-PINACA has been identified in at least 51 toxicology specimens associated with post-mortem (PM) death investigations, driving under the influence of drugs (DUID) investigations, and clinical investigations. Internationally, MDMB-4en-PINACA has been identified on several continents including North America, Europe, Asia, and Oceania.
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