Detection of NPS in Buprenorphine Samples

Clinical Update
March 2024

Detection of NPS in Buprenorphine Samples

Aegis recently conducted a retrospective analysis of patient samples from individuals who were prescribed buprenorphine to ascertain how frequently novel psychoactive substances (NPS) were detected. Novel Psychoactive Substances (NPS) are a diverse group of synthetic substances created to mimic the effects of scheduled or illicit drugs; however, they may vary widely in both toxicity and potency from the drugs they are intended to mimic. Buprenorphine is commonly prescribed to individuals with opioid use disorder to initiate medically supervised opioid withdrawal. It is also prescribed to those with chronic pain in some instances. 

In 2023, Aegis detected buprenorphine in 252,835 samples where buprenorphine was indicated as prescribed to the donor for treatment of opioid use disorder or chronic pain. Of these samples, 803 were highly suspicious of being adulterated samples based on the ratio of buprenorphine to its metabolite, norbuprenorphine therefore, these samples were excluded from further analysis. Of the remaining 252,032 samples, 4,818 (1.9%) contained at least one NPS. Aegis offers clinicians the ability to order NPS testing for opioids, benzodiazepines, cannabinoids, stimulants, hallucinogens, dissociatives, and other substances based on their medical judgement. As such, the 252,032 samples were not uniformly tested for all NPS classes. This likely results in an underrepresentation of actual NPS use by the patients in this study.

Bup Prescribed and included in NPS analysis

252,032

%

Any NPS*

4,818

1.912

Designer Opioid

1,604

0.636

Designer Benzodiazepine

1,599

0.634

Synthetic Stimulant

284

0.113

Synthetic Cannabinoid

238

0.094

Hallucinogen/Dissociative

9

0.004

Misc. NPS

     Xylazine

1,653

0.656

     Phenibut

302

0.120

     Tianeptine

175

0.069

     Medetomidine

11

0.004

*All samples were not tested for every NPS class. Some samples contained more than one NPS class.

 

Designer Opioids

Designer opioids are sometimes referred to as fentanyl analogs (fentalogs) however, other non-fentalogs are increasingly detected in Aegis’ testing. In this study, a designer opioid was detected in 1,604 samples and 8 of the 20 designer opioid analytes detected were markers of nitazene analogs, highlighting the increasing prevalence of these compounds. Table 2 contains the list of designer opioids analytes detected from most to least prevalent. Figure 1 illustrates the top 10 designer opioid analytes detected as part of this study. It is important to note that plain, illicitly manufactured fentanyl (IMF) is not included in Aegis’ NPS testing.

Table 2. Designer Opioids Detected in Expected Buprenorphine-positive Samples, 2023

Fluoro Fentanyl

Despropionyl Fluorofentanyl

4-Hydroxy Nitazene

Metonitazene

Despropionyl Bromofentanyl

N-desethyl Isotonitazene

Norcarfentanil

Benzyl Fentanyl

Acryl Fentanyl

Valeryl Fentanyl Carboxy Mtb

Despropionyl Chlorofentanyl

N-Pyrrolidino 4-OH Nitazene

Protonitazene

N-desethyl Etonitazene

N-pyrrolidino Etonitazene

N-Pyrrolidino Metonitazene

Fluoroisobutyryl Fentanyl

Valeryl Fentanyl

Bromofentanyl

Dipyanone

 

 

Designer Benzodiazepines

Designer benzodiazepines are often found as counterfeit versions of commonly recognized prescription benzodiazepines, such as alprazolam 2mg “bars” and, in many cases, more than one designer benzodiazepine is present in counterfeit tablets. A designer benzodiazepine was detected in 1,599 samples, with markers of bromazolam, clonazolam, etizolam, flualprazolam and flubromazepam being the top five benzodiazepines detected in this study. Bromazolam has emerged as the most detected designer benzodiazepine over the last 12 months. Table 3 lists the designer benzodiazepines detected in study samples from most to least prevalent, while Figure 2 shows the top 10 analytes.

Table 3. Designer Benzodiazepines Detected in Expected Buprenorphine-positive Samples, 2023

Bromazolam

alpha-Hydroxybromazolam

8-Aminoclonazolam

alpha-Hydroxyetizolam

Etizolam

alpha-Hydroxyflualprazolam

Clonazolam

Flualprazolam

3-OH-Flubromazepam

Deschloroetizolam

Flubromazepam

alpha-Hydroxyflubromazolam

Flubromazolam

Metizolam

Delorazepam

N-desmethyl Adinazolam

4Cl-Deschloroalprazolam

Fluclotizolam

 

 

Synthetic Stimulants

A synthetic stimulant was detected in 284 samples. Synthetic stimulants are distributed in a variety of forms, including powders, crystalline formulations, and in pressed tablet forms. They are intended to mimic substances such as methamphetamine, cocaine, or ecstasy. The most widely known substances found in this class are synthetic cathinones, which are sometimes referred to as bath salts. Cathinones represented 12 of 18 stimulant analytes detected in this study, with markers of N,N-dimethyl Pentylone being the dominant analytes. Analogs of methylphenidate, methamphetamine, and piperazine were detected in smaller quantities (Table 4). Figure 3 represents the top 10 stimulant analytes detected.

Table 4. Synthetic Stimulants Detected in Expected Buprenorphine-positive Samples, 2023

N,N-dimethyl Pentylone

Pentylone

N-cyclohexyl Methylone

Eutylone

4-Fluoromethylphenidate

Alpha-PiHP

Alpha-D2PV

Butylone

Alpha-PHP

Methylenedioxy-PV8

N-cyclohexyl Butylone

Alpha-PVP

Chloro-N,N-Dimethylcathinone

MDPHP

TFMPP

2-Fluoromethamphetamine

2-Fluoroamphetamine

3/4-Fluoromethamphetamine

 

 

Synthetic Cannabinoids

Synthetic cannabinoids are among the oldest designer drugs in circulation, originally developed during research searching for compounds with medical properties similar to marijuana. Today, they are often used recreationally as alternatives to marijuana. They have been referred to as K2 or spice and are sprayed onto plant material and smoked or used in vaping devices. A synthetic cannabinoid was detected in 238 samples. Table 5 shows the breadth of synthetic cannabinoids detected in this study, with markers of MDMB-4en-PINACA and ADB-BUTINACA accounting for the majority of detections. Figure 4 further illustrates the top 10 analytes detected.  

Table 5. Synthetic Cannabinoids Detected in Expected Buprenorphine-positive Samples, 2023

MDMB-4en-PINACA BA

ADB-BUTINACA NBA

4F-MDMB-BUTINACA N-BA

ADB-PINACA PA

MDMB-4en-PINACA

4F-MDMB-BUTINACA BA

ADB-BUTINACA

ADB-FUBIATA Metabolite

ADB-4en-PINACA

FUB-PB-22 3CI

ADB-FUBIATA BA

MDMB-5Br-INACA

5F-MDMB-PICA M7

CH-PIATA

MMB-FUBICA M3

4F-MDMB-BUTICA BA

5F-MDMB-PICA/5F-EMB-PICA

 

 

Hallucinogens/Dissociatives

Designer hallucinogens and dissociatives were developed to mimic the effects of PCP, LSD, or ketamine, while remaining legal. While testing orders for these substances is not as frequent as other classes, some of these substances were detected in nine samples. Analogs of PCP and ketamine were detected, as illustrated in Table 6 and Figure 5.

Table 6. Hallucinogens/Dissociatives Detected in Expected Buprenorphine-positive Samples, 2023

2F-2-oxo-PCE

2F-Deschloroketamine

3F-PCP

3-OH-PCE

 

 

Miscellaneous NPS

Some NPS do not fit neatly into one of the previous classes for various reasons, so they are not included in previously discussed drug classes. These are found in Table 7. Xylazine has been the most notable substance detected in this grouping for the last three years and was detected in 1,653 samples. It is known to cause central nervous system (CNS) depression and many individuals exposed to it also develop skin and soft tissue infections which can result in amputations or systemic infections if left untreated. Tianeptine is sometimes referred to as “gas station heroin” because it is sold over the counter (OTC) in the US. In other countries, it is a prescription drug used as an antidepressant. Management of individuals exposed to tianeptine can be complex because of mixed actions at various receptors, including opioid receptors. In many cases, individuals use tianeptine for this effect at opioid receptors, either to replace an opioid, or to attempt to taper off an opioid. It was detected in 175 samples in this study. Phenibut is sold in many countries as a prescription anti-anxiety agent and was detected in 302 samples. Similarly to tianeptine, it is available as an OTC supplement in the US. Medetomidine has recently been detected in the illicit drug supply. Like xylazine, it contributes to CNS depression without activity at opioid receptors. Testing for medetomidine was introduced for clinicians in October, which is one reason it was only detected in 11 samples; however, it is not as prevalent in the illicit supply as xylazine (Figure 6). 

Table 7. Miscellaneous NPS Detected in Expected Buprenorphine-positive Samples, 2023

Xylazine

Phenibut

Tianeptine

Medetomidine

 

 

Conclusion

This analysis demonstrated the potential for patients undergoing medication-assisted treatment with buprenorphine to continue substance use that could otherwise go undetected without specialized testing for NPS. Having definitive results regarding recent substance use allows for more transparency in clinical decision making that helps improve outcomes. A laboratory’s decision to offer NPS testing must be accompanied by a commitment to relevant and up-to-date testing, guided by established research organizations such as the Center for Forensic Science Research & Education, among others. This increases the likelihood of the test providing meaningful results that help with achieving treatment goals.

NOTICE: The information above is intended as a resource for health care providers. Providers should use their independent medical judgment based on the clinical needs of the patient when making determinations of who to test, what medications to test, testing frequency, and the type of testing to conduct.

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