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Observational Study
. 2025 Aug;45(8):575-582.
doi: 10.1007/s40261-025-01460-9. Epub 2025 Jun 28.

Pregabalin and Methadone Plasma Levels in Patients Receiving Methadone Maintenance Treatment: An Observational Study

Anat Sason  1 , Miriam Adelson  1 , Shaul Schreiber  1   2   3 , Einat Peles  4   5   6
Affiliations
Observational Study

Pregabalin and Methadone Plasma Levels in Patients Receiving Methadone Maintenance Treatment: An Observational Study

Anat Sason et al. Clin Drug Investig. 2025 Aug.

Abstract

Background and objectives: The combination of pregabalin and opioid usage is a known risk for fatalities. The pregabalin misuse rate among patients in methadone maintenance treatment (MMT) is reported to be high. However, pregabalin's risk among MMT patients, specifically concerning methadone dose and plasma level, is not yet determined. We aimed to study retention, survival, and whether pregabalin misuse is related to methadone dose and plasma level in MMT patients.

Methods: An observational study was conducted on 273 patients at the MMT clinic in Tel Aviv, Israel. Inclusion criteria required having urine drug-screening results for pregabalin when evaluated for methadone plasma levels. Methadone dose and plasma level, drug in urine, sociodemographic, and addiction variables were taken from patients' records.

Results: Patients with positive urine for pregabalin (n = 50) were comparable to 223 negative patients tested in methadone dose (124.3 ± 30.7 vs. 117.1 ± 42.5, p = 0.3) but had higher methadone plasma levels (693.8 ± 327.6 vs. 572.3 ± 286.5 ng/ml, p = 0.009) and QTc intervals on ECG (422.8 ± 31.8 vs. 412.1 ± 29.8 ms, p = 0.03). Logistic regression model found pregabalin tested positive as more likely to test positive for benzodiazepine (OR = 9.1), methylphenidate (OR = 5.5), and fentanyl (OR = 5.9), and to have higher methadone plasma levels (OR = 1.002). Cumulative retention (p < 0.001) and survival (p = 0.007) since admission to MMT were both shorter in the pregabalin group.

Conclusions: Patients who tested positive for pregabalin presented high methadone plasma levels, even though they were treated with normal or low methadone doses. This phenomenon highlights the importance of monitoring methadone levels, which is not a routine procedure, to reduce patients' risk.

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Conflict of interest statement

Declarations. Funding: The study was funded by the Adelson Family Foundation. The study’s design, data collection, analysis, interpretation, and manuscript writing were independent of the funding. Conflict of interest: The authors have no competing interests to declare that are relevant to the content of this article. Ethics approval: The study analyses were approved by the Helsinki Committee (IRB) 07-111 of the Tel Aviv Sourasky Medical Center. The study was performed under the standards of ethics outlined in the Declaration of Helsinki. Consent to participate: All participants provided signed informed consent. Consent for publication: Not applicable. Code availability: Not applicable. Availability of data: Data can be provided on reasonable request to the corresponding author. Author contributions: Einat Peles did the statistical analyses and wrote the manuscript together with Shaul Schreiber. Miriam Adelson participated in writing. Anat Sason collected the data for the analyses. All authors read and approved the final version, and agree to be accountable for the work

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