Hair Analysis of Fentalogs by Liquid Chromatography-tandem Mass-spectrometry (LC-MS/MS)

Evaluation of Fentalogs and Their Metabolites in Hair of Patients in a Monitored Clinical Context by Means of Hair Analysis

The goal of this fundamental research study is to learn how opioids are incorporated into hair after application of opioids to newborns, infants and children in a controlled medical setting. The main questions aimed to answer are: Are opioids (specifically fentalogs) incorporated into hair? Are opioids detectable in sweat and does sweat influence the incorporation into hair? Can normative opioid value ranges be established in hair? Can these values help to for interpretation of opioid positive hair results and ultimately help distinguish between medical opioid intake and intake of illegal designer opioids? Hair samples from 150 patients will be taken as well as 75 sweat sample and analyzed for their opioid concentrations. Investigators hypothesize that opioids will be detectable in hair and sweat and that the cohort size will allow to establish normative value ranges that will help for interpretation of hair results in forensic toxicology.

Study Overview

• Status: Recruiting
• Conditions: Opioid Use, Unspecified
• Intervention / Treatment: Drug: Fentanyl

Detailed Description

In recent years, new synthetic opioids (NSOs) have emerged in the illicit drug supply in an increasing rate. Many of these new registered opioids can structurally be assigned to the so called fentalogs, which are pharmacologically active derivatives of the approved pain management drug fentanyl. Many of these compounds are highly potent, relatively cheap and thereby especially fueling the current opioid crisis in the USA and posing a significant challenge for authorities, the healthcare system and forensic toxicology globally. Most of the time opioids are consumed without the user's knowledge as they are sold as heroin or counterfeit prescription pills like oxycodone or Xanax® which further increases the dangers posed by this problematic substance class. Recent cases of designer fentanyl intoxication show that this problem is also encountering Switzerland. Due to their potency, overdoses of the above-mentioned substances quickly occur, which in absence of intensive medical support can be fatal even when the antagonist naloxone is used. In order to better address the NSOs related socio-economic and health care problems, a fundamental understanding of these substance classes is essential.

As a consequence of the increasing prevalence of designer opioids, forensic and clinical laboratories worldwide are continuously challenged with updating their analytical methods for the identification and quantification of these new drugs in various biological matrices. The classical matrices used in forensic toxicology are blood and urine which represent time windows of hours to days. Keratinized matrices like hair and nail are considered complementary matrices as they provide additional information to the more traditional matrices covering time windows up to several months. The analysis of hair (a keratinized matrix) can provide significant information about the intake of opioids over extended time periods and therefore can provide access to a much wider diagnostic window than blood or urine. It allows getting information about a past exposure to the substance, repeated intake or even a single intake.

According to the Swiss Society of Legal Medicine, Swiss laboratories that offer forensic hair analysis must be able to quantify opioids in hair. The analysis of classical opioids like morphine and respective metabolites is well established in hair. However, knowledge about the incorporation of medically used fentalogs (e.g. fentanyl, remifentanil and sufentanil) and illegal designer fentalogs in hair is still limited.

The goal of this study is to gain knowledge about the incorporation and concentration of fentalogs in hair to help establish a high forensic standard for the detection these new substances. The specific aim of this study is to analyze hair samples from patients (children) of a study cohort described below which received medically approved fentalogs (either fentanyl, remifentanil or sufentanil) and to gain insights into the deposition of these substances into hair. The investigators will focus on a study cohort (150 patients) that has received medical fentanyl for pain management therapy in a clinical and therefore controlled setting. Furthermore, the study cohort consists of children which have some benefits to address the above raised research question. The hair of children is thinner and more porous than adult's hair, so that substances can incorporate into hair more easily. This makes children's hair an ideal target for our research study to see if fentalogs will be incorporated into hair. Furthermore, it is known that cosmetic treatment like e.g. bleaching etc. destroys substance that are incorporated in hair, therefore cosmetically treated hair is not suitable for the study. The probability that young children have cosmetically treated hair is considered very low.

As substances are incorporated into hair via sweat and blood, the analysis of these matrices can help to understand the general incorporation mechanisms of substances into hair. Therefore, the investigators intend to additionally analyze sweat samples from children to gain knowledge about fentalog concentrations and metabolites in sweat which can be helpful to understand their incorporation into hair.

The knowledge of this study can be used in forensic toxicology to distinguish between the intake of medically prescribed opioids and illegal new synthetic opioids.

• Study Type: Observational
• Enrollment (Anticipated): 225

Contacts and Locations

• Study Contact: Name: Tina M. Binz, Dr.; Phone Number: +41 44 635 7614; Email: TinaMaria.Binz@irm.uzh.ch
• Study Contact Backup: Name: Max Polke; Phone Number: +41 44 635 76 43; Email: max.polke@irm.uzh.ch

Study Locations

• Switzerland
  • Zurich, Switzerland, 8032
    • Recruiting
    • University's Children Hospital
    • Contact: Florian Zapf, Dr.; Phone Number: +41442667053; Email: Florian.Zapf@kispi.uzh.ch
    • Principal Investigator: Florian Zapf, Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 13 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

The study is conducted as an open study until the maximum of 50 hair respectively 25 sweat samples is reached for the three-substance groups fentanyl, remifentanil and sufentanil (in total 150 hair sample and 75 sweat samples). The biological sample material used in the present study will be hair and sweat from patients of the Children's Hospital Zurich treated with the above described opioids. The Study cohort will consist of premature infants, newborns, infants, children and adolescents. Patients will be exposed to fentalogs (fentanyl, remifentanil and sufentanil) or other opioids) morphine, hydromorphone, methadone) either during surgery or in course of post-surgical pain management on the intensive care unit.

Description

Inclusion Criteria:

• Obtained written informed consent from parents or legal caretaker and oral consent from the patient concerned.
• Patients age: from date of birth irrespective of gestational age to completed 13th year of life
• Patients that received single or multiple treatment (either with single doses or continuous drip) of fentanyl, remifentanil or sufentanil either during operation or on the intensive care unit

Exclusion Criteria:

• Patients age older than 14 years
• Inability to understand the study procedure due to language or cognitive reasons (applies to parents and children)
• denied or missing informed consent
• Insufficient amount of head hair to obtain hair sample
• Cosmetic hair treatment, like coloring, bleaching and dying

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
KISPI 000; Patients of the group received one or multiple clinically approved opioids, namely; Fentanyl, Remifentanil, Sufentanil, Hydrocodone, Oxycodone and Morphine	Drug: Fentanyl; Drug application during hospital stay; Other Names: Sufentanil; Morphine; Oxycodone; Hydromorphone; Remifentanil; Alfentanil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Detection of opioid concentration and opioid metabolite concentration in hair quantified by liquid chromatography-tandem mass spectrometry	Investigators will collect hair samples from participants for quantification of opioids. Investigators will analyse which opioid concentration will be detectable in hair following opioid intake/application in a medical setting (unit pg opioid per mg hair).	through study completion, an average of one year
Detection of opioid concentration and opioid metabolite concentration in sweat quantified by liquid chromatography-tandem mass spectrometry	Investigators will collect sweat samples from participants for quantification of opioids. Investigators will analyse which opioid concentration will be detectable in sweat following opioid intake/application in a medical setting (unit ng opioid per mL sweat).	through study completion, an average of one year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Normative values in hair	Investigators will establish normative value ranges for opioid concentrations in hair based on the cohort of 150 hair samples. The analysis will be done by using descriptive statistics (box plots) including the median, mean, the 10 % and 90 % percentile values ( unit ng opioid per mg hair).	after data evaluation, 3 months after end of study (one year)
Normative values in sweat	Investigators will establish normative value ranges for opioid concentrations in sweat based on the cohort of 75 sweat samples. The analysis will be done by using descriptive statistics (box plots) including the median, mean, the 10 % and 90 % percentile values (unit ng opioid per mL sweat).	after data evaluation, 3 months after end of study (one year)

Collaborators and Investigators

• Sponsor: University of Zurich
• Collaborators: University Children's Hospital, Zurich
• Investigators: Principal Investigator: Tina Binz, University Zurich; Principal Investigator: Florian Zapf, Dr., University's Children Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2022
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: January 31, 2023
• First Submitted That Met QC Criteria: February 13, 2023
• First Posted (Estimate): February 23, 2023

Study Record Updates

• Last Update Posted (Estimate): February 23, 2023
• Last Update Submitted That Met QC Criteria: February 13, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: fentanyl; opioids; hair analysis; fentalogs; new synthetic opioids
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Remifentanil; Fentanyl; Morphine; Oxycodone; Sufentanil; Hydromorphone; Alfentanil
• Other Study ID Numbers: 2022-01693

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The outcomes of the research will be published in peer-reviewed journals. Data will be strictly anonymized.
• IPD Sharing Time Frame: starting after publication
• IPD Sharing Access Criteria: upon request via e-mail
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No