Methadone with Estazolam Interaction Details

Brand Names Associated with Methadone

Brand Names Associated with Estazolam

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Jan 02, 2024

Interaction Effect

Increased risk of respiratory and CNS depression

Interaction Summary

When concomitant use of methadone and CNS depressants are necessary, use lowest dose and shortest duration; monitor for sedation and respiratory depression. Cardiac monitoring may also be necessary. Withholding access to medication-assisted treatment (MAT) may lead to greater risk of morbidity and mortality related to opioid use disorder, despite serious side effects that may occur. Discontinuation of the CNS depressant is preferred; if concomitant use is necessary, monitor and manage cautiously. The CNS depressant should be tapered to the lowest effective dose or alternative options for the treatment of anxiety or insomnia should be used. An epidemiological study from Sweden reported that patients receiving methadone- or buprenorphine-based MAT along with benzodiazepines or other CNS depressants (eg, drugs that treat insomnia), increase the risk of death. According to a study of aggregate nationwide death certificate data from 2010 to 2014, the majority of buprenorphine- and methadone-involved overdose deaths involved concomitant CNS depressant use. It is unknown whether the risk of overdose death with concomitant CNS depressant drugs differed between buprenorphine and methadone .

Severity

Major

Onset

Unspecified

Evidence

Theoretical

How To Manage Interaction

Reserve the concomitant use of methadone and CNS depressants to patients for whom alternatives are inadequate. If concomitant use is necessary, use the lowest dose and shortest duration necessary to achieve treatment goals. Consider using a lower dose of methadone or the CNS depressant and closely monitor for sedation and respiratory depression. Patients receiving therapy with benzodiazepines or other CNS depressants should not be denied access to medication-assisted treatment (MAT) drugs (eg, methadone and buprenorphine). Although the risk of serious side effects, overdose, and death is increased with concomitant use, withholding access to MAT may lead to greater risk of morbidity and mortality related to opioid use disorder. Discontinuation of the benzodiazepine or CNS depressant is preferred in most cases. If concomitant use is necessary, monitor and manage cautiously; consider tapering the benzodiazepine or CNS depressant to the lowest effective dose or using alternative options for the treatment of anxiety or insomnia .

Mechanism Of Interaction

Additive CNS depression effects

Literature Reports

A) An epidemiological study from Sweden reported that patients receiving methadone- or buprenorphine-based medication-assisted treatment (MAT) along with benzodiazepines or other CNS depressants (eg, drugs that treat insomnia), increase the risk of death. Between July 1, 2005 and December 31, 2012, the risk of fatal overdose, non-overdose related mortality, and all-cause mortality during periods of prescribed CNS depressants to periods of time without CNS depressant therapy were analyzed in MAT prescribed patients (aged 18 to 50). The results found an elevated risk of all-cause mortality (adjusted hazard ratio (HR) 1.44; 95% CI, 0.93 to 2.23) and non-overdose related mortality (HR 1.74; 95% CI 1.00 to 3.01) with MAT and benzodiazepine treatment; however, the data was not considered statistically significant. While results demonstrated an elevated risk of fatal overdose, non-overdose morality, and all-cause mortality during periods of coadministration of MAT and non-benzodiazepines, only the data for fatal overdose and all-cause mortality was considered statistically significant; HR 2.34 (95% CI, 1.37 to 3.99) and HR 1.33 (95% CI, 1.12 to 2.45), respectively. A comparison between the benzodiazepine cohort and non-benzodiazepine cohort was not conducted due to the authors not adjusting for the indication of use for the drugs .

B) According to a study of aggregate nationwide death certificate data from 2010 to 2014, there were 3495 drug overdose deaths reported in 2014. Methadone and other CNS depressants were frequently reported as culprits in those deaths. Concurrent alprazolam use was reported in 18.1% of cases followed by oxycodone (10.1%), cocaine (9.6%), heroin (9%), and diazepam (6.6%). The FDA reported 322 drug overdose deaths in 2014 involving buprenorphine. Of these 322 deaths, 32.9% involved alprazolam, 17.4% involved clonazepam, 11.2% involved diazepam, 11.2% involved heroin, and 9.9% involved fentanyl. The absolute number of methadone-involved deaths was 10 times the number of buprenorphine-involved deaths, although confounding factors and differences in drug utilization were not accounted for. It is unknown whether the risk of overdose death with concomitant CNS depressant drugs differed between buprenorphine and methadone .

C) In a study, the rate of nonmedical use-related emergency department visits occurring between 2004 and 2011 and involving opioid analgesics and benzodiazepines significantly increased from 11 to 34.2 per 100,000. Drug overdose deaths due to prescribed and greater than prescribed doses of both drug classes also significantly increased from 0.6 to 1.7 per 100,000, and overdoses deaths due to benzodiazepines significantly increased from 18% to 31% .

D) In a prospective cohort study, the rate of overdose deaths involving the dispensing of both opioid analgesics and benzodiazepines was 10 times higher compared with dispensing of opioid analgesics alone (7 vs 0.7 per 10,000 person years) .

E) In a cohort study of data from 2004 to 2009, the risk of fatal overdose significantly increased by 2.33 fold in patients taking opioid analgesics with a history of a benzodiazepine prescription and increased by 3.86 fold in those with a current benzodiazepine prescription compared with those taking opioid analgesics without a history of a benzodiazepine prescription. The risk of drug overdose deaths increased with increasing daily doses of benzodiazepines .

Methadone Overview

• Methadone is used to relieve severe pain in people who are expected to need pain medication around the clock for a long time and who cannot be treated with other medications. It also is used to prevent withdrawal symptoms in patients who were addicted to opiate drugs and are enrolled in treatment programs in order to stop taking or continue not taking the drugs. Methadone is in a class of medications called opiate (narcotic) analgesics. Methadone works to treat pain by changing the way the brain and nervous system respond to pain. It works to treat people who were addicted to opiate drugs by producing similar effects and preventing withdrawal symptoms in people who have stopped using these drugs.

Estazolam Overview

• Estazolam is used for the short-term treatment of insomnia (difficulty falling asleep or staying asleep). Estazolam is in a class of medications called benzodiazepines. It works by slowing activity in the brain to allow sleep.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.