Enhancing addiction care: Benefits of urinary screening with LC-HRMS (liquid chromatography-high resolution mass spectrometry) for psychoactive substances and drugs

This study compared LC-HRMS with immunoassay (IA) for urine drug screening in an inpatient addiction unit. LC-HRMS demonstrated superior detection for two-thirds of all molecules, including many substances missed by IA despite being part of its target panel. Among 154 patients, physicians reported that LC-HRMS findings would have changed clinical management for one in four cases.

A history of opioid use was the strongest predictor of clinical benefit. These results highlight the added diagnostic value of LC-HRMS for patients with complex or multiple substance use, supporting its implementation in addiction-care settings.

The original article

Enhancing addiction care: Benefits of urinary screening with LC-HRMS (liquid chromatography-high resolution mass spectrometry) for psychoactive substances and drugs

Edouard Le Carpentier, Morgane Helesbeux, Vanessa Biering, Aurélie Aquizerate, Morgane Rousselet, Malcolm Barrangou-Poueys-Darlas, Audrey Verholleman, Eric Dailly, Matthieu Grégoire, Caroline Victorri-Vigneau, Mélanie Duval

Progress in Neuro-Psychopharmacology and Biological Psychiatry
Volume 141, 2025, 111465

https://doi.org/10.1016/j.pnpbp.2025.111465

licensed under CC-BY 4.0

Selected sections from the article follow. Formats and hyperlinks were adapted from the original.

The Nantes University Hospital has a full-time inpatient addiction unit dedicated to the management of patients with substance use disorders. This type of hospitalisation offers patients a temporary break from the substance(s) of abuse and environmental factors, enabling them to refocus on their own personal functioning and helping to restore their physical health. These patients receive comprehensive care, combining a psychological, biological and social approach. The objectives of the hospitalisation are set out in advance in an individualized care contract. As part of this care contract, a targeted urinary drug screening is carried out systematically at the start of hospitalisation. The results of this screening can be used as a support for discussions between patients and caregivers, and may lead caregivers to redefine the objectives of care. It is therefore important that the method used for urinary drug screening is reliable, as an error in detection can have significant consequences for care and the patient-caregiver relationship.

Immunoassay (Roche diagnostic®) is used at Nantes University Hospital to perform urine drug screening for the inpatient addiction unit. Although this method has a number of strengths, such as ease of sample handling and automation for rapid results, it has a number of limitations (Schütz et al., 2006). This method is used to detect 7 pharmacological categories of psychoactive substances (some opiates, benzodiazepines, amphetamines, cocaine, buprenorphine, methadone and cannabis) without giving details of the molecule that made the test positive. Moreover, some molecules such as tramadol, zolpidem, zopiclone and cannabidiol (CBD) do not make the test positive for opiates, benzodiazepines and cannabis respectively and are therefore not detectable by the immunoassay drug screen test. The scope of substances detectable by the immunoassay is therefore limited in comparison with all the psychoactive substances consumed by the patients. In addition, this method has a significant rate of false-negative and false-positive results, particularly for amphetamines (Pope et al., 2023; Saitman et al., 2014; Mina, 2020; Możdżeń, 2023; Battini et al., 2023), with potentially harmful consequences for patient management and the therapeutic alliance between carers and patients. It therefore seems necessary to consider the use of another method for urinary drug screening that is both more effective and offers a wider range of detectable substances. This would also make it possible to identify new substances in circulation and to detect the misuse of drugs, whether prescribed or not.

The method evaluated in this study, is a drug screening technique performed by Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS) (ThermoFisher Scientific®), already in use at the Nantes University Hospital and other establishments in fields such as emergency medicine and forensic medicine (Helfer et al., 2015). This method, which is more sensitive and specific than the immunoassay, has a number of valuable assets for the management of addiction patients. Its value in psychiatry and addiction medicine has been demonstrated in several studies, particularly in the management of patients with opiate use disorders (Marchei et al., 2021; Sundström et al., 2016; Heikman et al., 2016; La Maida et al., 2024; Virmani et al., 2023; Alías-Ferri et al., 2022). Unlike immunoassay, it can be used to precisely identify the substances found in urine samples. It also has the major advantage of being able to detect all substances, including new psychoactive substances (NPS), as long as their mass spectra have been previously recorded in the LC-HRMS library. To date, around 1540 molecules can be detected by LC-HRMS at the Nantes University Hospital. However, the need to prepare samples beforehand and to analyze them in subgroups increases the time taken to deliver results compared with urine drug screening immunoassay.

Before considering the implementation of urine drug screening by LC-HRMS in an inpatient addiction unit, it is necessary to ensure that the benefit of this method over immunoassay is real and significant. Several studies have compared the analytical results of immunoassays and liquid chromatography-mass spectrometry methods for the detection of substances in patients with substance use disorders (Mina, 2020; Sundström et al., 2015; Gerona and French, 2022; Rossi et al., 2021; Tolan et al., 2024), but none have looked at the impact of these results on the management of these patients. Knowing that a substance detection error has occurred could change the overall management of these patients, from both an addictive and a physical point of view.

The primary objective of this study was therefore to evaluate the overall benefit (analytical and clinical) of the LC-HRMS urinary screening method compared with the immunoassay targeted urinary screening method in the management of patients hospitalised on an addiction unit. The secondary objective was to identify the profiles of patients for whom the use of the LC-HRMS method had a clinical benefit on their overall management.

2. Method

2.2.2. LC-HRMS toxicological screening

LC analyses were performed using a Transcend II TLX-1 and Vanquish systems in patients'urine. Data were acquired on an Exploris 120 Orbitrap Mass spectrometer and processed with TraceFinder 5.1 software (ThermoFisher Scientific®, San Jose, USA). The gradient elution was performed on a Thermo scientific Accucore™ Phenyl Hexyl (100 mm × 2.1 mm; 2.6 μm). Column temperature was sat at 40 °C. The mobile phases consisted of 2 mM aqueous ammonium formate plus 0.1 % formic acid (eluent A) and 2 mM aqueous ammonium formate with acetonitrile:methanol (50:50, v/v; 1 % water) plus 0.1 % formic acid (eluent B). The flow rate was set to 0.5 mL/min. The gradient was programmed as follows: 0 to1.42 min at 99 % A, 1.42 to 10.42 min to 1 % A, 10.42 to 11.92 min to 0 % A, 11.92 to 12.75 to 99 % A, 12.72e15 min at 99 % A.

The Exploris 120 system was equipped with a heated electrospray ionization (HESI) source. The instrument was used in positive/negative switching ionization mode with full scan (FS) and a subsequent data dependent acquisition (DDA) mode. Mass calibration was done according to the manufacturer's recommendations using external mass calibration in the mass range of m/z 150–2000. The scan rate was up to 7.5 Hz at a resolution of 30,000. The settings for FS were as follows: resolution, 30,000; automatic gain control (AGC) target, standard; maximum injection time (IT), automatic; and scan range, m/z 70–1000. For general screening (GS), high energy collisional dissociation (HCD) experiments were performed on the three most intense precursor ions selected from FS using DDA with an inclusion list of the ions to select for fragmentation. The three most intense precursor ions were transferred to an exclusion list for 3 s (dynamic exclusion). The remaining settings for DDA mode were as follows: resolution, 15,500; AGC target, standard; maximum IT, automatic; isolation window, m/z 2.0, HCD 18.7, 37.5, and 56.3 %; spectrum data type, profile.

3. Results

3.4. Evaluation of the potential clinical benefit of the LC-HRMS screening method on the overall management of patients hospitalised in an addiction unit

For a quarter of the patients (n = 42, 27 %), the addiction physicians considered that the new results provided by the LC-HRMS screening method would have had an impact on the overall management of their patients. For almost all of these 42 patients, it was the better performance of LC-HRMS in detecting a non-prescribed molecule that prompted the addiction physicians' decision. In general, the potential clinical benefit of the new data provided by LC-HRMS was influenced by whether or not the patient reported recent use of the substance under consideration. Thus, if a non-prescribed molecule was not detected by the immunoassay whereas it was detected by the LC-HRMS, but its use had been reported by the patient, the results provided by the LC-HRMS were not considered to have any impact on patient management.

In addition, for only one patient, the better performance of the LC-HRMS over the immunoassay in detecting a prescribed drug justified the choice made by the addiction physicians. This was a patient dependent on oxycodone hospitalised in the addiction unit for withdrawal from this substance. Oxycodone is a synthetic molecule that cannot be detected by the immunoassay method; monitoring the patient's use of this drug during hospitalisation using the LC-HRMS screening method was considered to be decisive for the management of the patient by the addiction physicians.

3.5. Identification of the profiles of patients for whom urine screening by LC-HRMS would have had a clinical benefit

The comparison of the characteristics of patients for whom the LC-HRMS screening method would have had an impact on their overall management with those for whom LC-HRMS would not have had an impact (bivariate analysis) is detailed in Appendix (Table S5). Patients for whom the new results provided by LC-HRMS would have had an impact on their management were significantly more likely to have a history of opiate abuse/dependence (52 % vs. 31 %, p = .013) and reported recent opiate use significantly more often (24 % vs. 10 %, p = .026).

4. Discussion

4.1. Main results

In this study, toxicological screening by LC- HRMS had higher analytical performance than drug screen test by immunoassay for the detection and identification of around 2/3 of the drugs and substances analyzed. Its implementation in the follow-up of patients hospitalised in addiction units has been assessed by addiction physicians as having a potential impact on their management for 1/4 of the patients included in this study. Moreover, statistical analysis showed that LC-HRMS toxicological screening was of preferential benefit to patients with a history of opiate abuse/dependence.

4.2. Analytical benefit of the LC-HRMS screening method

In our study, we observed that the LC-HRMS and immunoassay methods produced different results. Most often, the molecule was identified by LC-HRMS but not by the immunoassay. The known deficiencies of the immunoassay led previous laboratory to investigate the feasibility of using LC-HRMS in post-mortem urine samples (Sundström et al., 2015). It showed a clear superiority in compound-identification over immunoassays (Sundström et al., 2015). So in this context we expected same results concerning analytical benefit of our LC-HRMS method.

The differences between the LC-HRMS LOI and the immunoassay cut-off values can explain these variations. Immunoassay cut-off values are high to avoid the risk of false positive results. For instance, for cocaine, the cut-off value is 300 ng/mL of benzoylecgonine (BEG), a cocaine metabolite, whereas LC-HRMS can identify BEG from a concentration of 0.5 ng/mL. Another example, the immunoassay requires diazepam and its metabolites to trigger a reaction greater than or equal to 300 ng/mL of nordazepam to yield a positive result. Among those metabolites oxazepam, temazepam and their conjugates oxazepam and temazepam glucuronide (OG and TG) had a bad cross-reactivity. On other hand, LC-HRMS can identify diazepam and its metabolites at much lower thresholds, from 1 to 10 ng/mL. Diazepam and metabolites concentrations in urine after a single dose are often low (Wang et al., 2022). As their time to maximum concentration is different, in the case of a patient beginning a treatment by diazepam, the initial low concentrations in urine and the weak cross-reactivity of some metabolite could lead to an insufficient reaction and a false-negative results. This could explain the difference between the two methods, in the case of patients with a long-standing use or who have recently started treatment.

5. Conclusion

Urine toxicology screening using LC-HRMS is a high-performance tool, whose sensitivity and wide compound identification range may be of interest to addiction physicians in the management of their patients. The use of this urine screening method seems particularly useful in patients with multiple substance use, especially those with a history of opioid use.