Benzodiazepine Use With Methadone Prolonged Heart Rhythm Intervals More Than Methadone Alone | Research

The takeaway

Among 421 methadone maintenance patients, QTc prolongation occurred during early treatment but was clinically insignificant, except when patients also used benzodiazepines, which significantly increased QTc prolongation beyond methadone alone.

Read this if you are on methadone maintenance and also use benzodiazepines or cannabis.

Benzodiazepine use significantly increased QTc prolongation beyond methadone alone (p=0.003)

What the researchers found

Four hundred twenty-one opiate addicts newly admitted to methadone maintenance were followed prospectively for 4.5 years. QTc intervals were measured at baseline and again at a steady methadone dose. QTc prolonged significantly from 424.5 ms at baseline to 438.6 ms at steady dose, but this prolongation was not affected by methadone dose level or treatment duration beyond 2 years.

The critical finding was that patients whose urine tested positive for benzodiazepine during steady-dose treatment had significantly greater QTc prolongation (p=0.003). Two patients who were benzodiazepine abusers died from undefined causes. Cannabis use was included as a variable but was not associated with additional QTc risk.

Why it matters

QTc prolongation can lead to fatal cardiac arrhythmias. This study identifies benzodiazepine co-use as a specific risk factor that clinicians should monitor in methadone patients. The finding that cannabis did not add QTc risk provides reassurance for methadone patients who also use cannabis.

The numbers in context

421 patients. QTc: 424.5 ms baseline to 438.6 ms at steady dose (significant). Benzodiazepine positive: significantly greater QTc prolongation (p=0.003). Cannabis positive: no additional QTc effect. 2 benzodiazepine-abusing patients died (undefined causes).

How the study worked

Prospective cohort study of 421 newly admitted methadone patients at 2 clinics. 4.5-year follow-up. Baseline ECG within 28 days of admission. Follow-up ECG at steady methadone dose with negative or positive urine toxicology. QTc intervals compared across conditions.

What this study cannot tell us

Urine testing provides only a snapshot of substance use. Cannabis and benzodiazepine categories were combined in some analyses. The "undefined" deaths in benzodiazepine users cannot be definitively attributed to QTc prolongation. Not all patients had follow-up ECGs. Methadone dose was not randomized.

How to read the evidence

Prospective cohort with objective ECG measurements; moderate evidence for benzodiazepine-methadone cardiac interaction.

When this study was published

Published in 2013. Guidelines for cardiac monitoring during methadone treatment have been updated based on this and similar findings.

The bigger picture

Methadone's QTc-prolonging effect is well recognized, but this study identified benzodiazepine co-use as an additive risk factor. Given that benzodiazepine use is common among methadone patients, this interaction has important clinical safety implications.

Questions still open

Should all methadone patients be screened for benzodiazepine use with regular ECGs? Does the QTc prolongation from benzodiazepine + methadone translate to increased cardiac events? Should cannabis be viewed as relatively safe regarding cardiac rhythm in methadone patients?

Common questions

Is it dangerous to mix methadone with benzodiazepines?

This study adds cardiac risk to the already-known respiratory risk of combining these drugs. Patients using benzodiazepines with methadone showed significantly greater prolongation of QTc intervals (a heart rhythm measure), which can predispose to dangerous arrhythmias. Two patients in this study who abused benzodiazepines died from undefined causes. This combination requires careful medical monitoring.

Does cannabis affect heart rhythm in methadone patients?

In this study, cannabis use did not add additional QTc prolongation risk beyond methadone alone, in contrast to benzodiazepines which significantly increased the risk. This suggests that regarding heart rhythm specifically, cannabis is a lower-risk co-substance for methadone patients than benzodiazepines.

Read the original research

Prospective study of QTc changes among former opiate addicts since admission to methadone maintenance treatment: benzodiazepine risk.

Journal of addiction medicine, 7(6), 428-34

View on PubMed ↗Publisher’s paper ↗

Citation

Peles, Einat; Linzy, Shirley; Kreek, Mary Jeanne; Adelson, Miriam. (2013). Prospective study of QTc changes among former opiate addicts since admission to methadone maintenance treatment: benzodiazepine risk.. Journal of addiction medicine, 7(6), 428-34. https://doi.org/10.1097/ADM.0b013e3182a8a4f2