MSACL 2017 US Abstract

Anodyne by Design; Esoteric Designer Opiates in Pain Management

Gregory Janis (Presenter)
MedTox / Labcorp

Bio: Gregory is the Scientific Director for MedTox Laboratories and a co-discipline director of Mass Spectrometry at Labcorp. He has lead the assay development group at MedTox for over a decade. His main interests are in drugs of abuse and unusual metabolism.

Authorship: Gregory C. Janis, Melissa Goggin
MedTox Laboratories / Labcorp. Saint Paul, MN

Short Abstract Abuse of a multifarious collection of designer opiates has recently emerged. Novel fentanyl analogs, and a variety of esoteric, structurally unique opiate agonists such as U-47700 and IC-26 have been identified as street drugs. It is postulated that opiate seeking individuals within pain management settings may be among the earliest experimenters of this emerging drug class. We devised and validated independent LC-MS/MS screening and confirmation methods targeting 20 designer opiates and their respective metabolites. The methodologies were then employed to survey identified heroin users within pain management programs. A variety of fentanyl analogs were prevalent within this population.

Long Abstract

In an effort to combat opiate abuse, the use of prescribed opiates and opioids in pain management has slowly evolved tighter restrictions. Buprenorphine, tramadol, butorphanol and most notably hydrocodone have all recently moved to more restrictive DEA scheduling. At the same time, abuse resistant formulations have evolved becoming more effective. While these changes have undoubtedly reduced the prevalence of opiate abuse, they have also left a subset of individuals searching for alternatives to satiate addictions or assuage other opiate seeking motivations. Tighter opiate controls have been postulated as contributing to a notable increase in heroin use within the USA over the last several years. Data generated within our laboratory indicates heroin use has doubled, even among those receiving chronic opiate therapies.

However, heroin is not the only powerful black-market opiate available. Multiple classes of designer opiates exist resulting from basic academic research and drug development research, and each compound has the potential for clandestinely applied structural permutations. The elicit evolution of opioids is best exemplified by fentanyl derivatives. The existence of fentanyl analogs are well known with the earliest street derivatives dating back to at least the 1980s, but there is a seemingly continuous appearance of new fentanyl permutations. Structurally unrelated to fentanyl, the isomers U-47700 and AH-7921 are abandoned analgesics drug candidates with little to no similarity to any FDA approved opiate or opioid. IC-26 is a structural isomer of methadone and another abandoned drug candidate. W-18 and W-15 are academic research chemicals which may or may not have activity at opiate receptors, but have been reported to possess analgesic potencies far exceeding that of fentanyl. Almost all of the designer opiates are invisible to routine drug testing methodologies, which could further motivate an individual to seek out designer opiates and thereby conceal their opiate use or opiate supplementation. Each of the esoteric designer opiates possesses its own unique pharmacology and toxicology, but all have at least some reported use by opiate seeking individuals.

While there have been multiple high profile reports of designer opiate use, it is difficult to assess the true prevalence of these drugs. We postulate that the subset of opiate abusing individuals within a pain management setting may be early adopters of designer opiates, and thereby may serve as early indicators of designer opiate trends. Thus, we set out to determine the prevalence of designer opiates in a pain management setting. Pain management samples containing evidence of heroin use were selected for subsequent designer opiate testing. LC-MS/MS screening and independent LC-MS/MS confirmation methods were built targeting parent designer opiates. Documented metabolites and metabolites identified from studies of positive donor samples were additionally targeted. Many metabolites were targeted without the use of certified reference standards and could only be utilized as supporting evidence. The assays monitored for parent drugs and metabolites of the following designer opiates:

Fentanyl, Acetylfentanyl, Carfentanil

Valeryl fentanyl, Acetylfentanyl-4-methylphenethyl,

3-Methylfentanyl, Furanyl fentanyl, Butyryl fentanyl,

IC-26, para-Fluorofentanyl, β-hydroxy-thiofentanyl, Mitragynine, Ocfentanil, para-fluorobutyryl fentanyl,

MT-45, AH-7921, 4-Methoxy butyrylfentanyl, U-47700,

W-18, W-15

A 90 second LC-MS/MS screening procedure targeted a single MRM transition for each compound. A mix of isotopic analogs and structural analogs were utilized as internal standards. An independent conditional confirmation procedure utilized slower chromatography, multiple transitions per analyte, additional targeted metabolites, and additional internal standards verifying and quantifying the presence of the targeted designer opiates. The lower limit of quantitation for targeted parent drugs ranged from 250 to 1000 pg/mL. Both LC-MS/MS screen and confirmation methods were fully validated.

Over a of 3 month period in 2016, 366 samples from suspected heroin users enrolled in chronic pain clinics have been tested for designer opiates. Unsurprising, 40% of the samples contain fentanyl or norfentanyl despite only 7% of those same patients’ attending physicians reported fentanyl being prescribed to the donor. The remaining 93% of positive fentanyl samples may result from alternative fentanyl prescriptions, diverted prescriptions, or from heroin cut with fentanyl. The next most prevalent designer opioid was furanyl fentanyl which was present in 12% of samples. Furanyl fentanyl was determined to be primarily excreted as a dihydroxy metabolite; norfuranyl fentanyl was found only as a minor metabolite. Acetyl fentanyl and fluorofentanyl were each detected in approximately 5% of the samples. Kratom, U-47700 and their respective metabolites were present in just 0.5% of the heroin positive samples. The shared metabolite of remifentanil and carfentanil was identified in approximately 10% of a subset of samples.

Results indicate designer opiate use in pain management patients exists, but their use is not widespread. Use of fentanyl and fentanyl analogs dominate within this population, whereas use of the more esoteric designer opiates exists in this population at a very low frequency.

References & Acknowledgements:

Financial Disclosure

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