Benzodiazepines — Educational Blog — Maimonides Emergency Medicine Residency

For this EMS protocol review, I wanted to focus on prehospital seizure treatment. Both the adult and pediatric algorithms are the same and utilize the same medications and weight based dosing. Paramedics are authorized to utilize 3 different benzodiazepines to treat active seizures:

Midazolam (Versed) 0.2mg/kg IV/IN/IM. If effect is not achieved, may be repeated after 5 minutes. Max single dose is 5mg and max cumulative dose is 10mg.

Lorazepam (Ativan) 0.1mg/kg IV/IN/IM. If effect is not achieved, may be repeated after 5 minutes. Max single dose is 2mg and max cumulative dose is 4mg.

Diazepam (Valium) 0.2mg/kg IV, infused over 1 minute. If effect is not achieved, may be repeated after 5 minutes. Max single dose is 5mg and max cumulative dose is 10mg.

The Medical Control Option for refractory seizures is to administer additional doses of any of these standing order medications. Some considerations for medication choice include availability, as Lorazepam requires refrigeration is not always carried, nor is IV Diazepam due to supply issues. Of these 3 medications, Midazolam is the fastest acting. With mounting doses of benzodiazepines, loss of spontaneous breathing should be a consideration, but typically can be outweighed by ceasing the seizure activity.

Finally, some patients with known seizure disorders, usually pediatrics, will have home prescriptions for PR diazepam, also known as Diastat. Occasionally, you will receive calls from EMS asking if they can administer this home medication. This formulation is not in the algorithm and has a much more erratic absorption than other routes of benzodiazepine administration. Because EMS is already present and has access to faster acting and more reliable medications like Midazolam, this should be administered instead.

Check out the RAMPART trial for a more in depth study on IM vs IV benzodiazepines and their efficacy!

Opioids and benzodiazepines are increasingly used alone or in combination. However, the combined use of these agents increases the risk for potentially lethal respiratory depression.

Gabapentin is a drug often used together with opioids to treat chronic pain, and both have been shown to suppress breathing with worsening complications rates in combination.

General

· In 2019, 16% of overdose deaths involving opioids also involved benzodiazepines

· Every day, more than 136 Americans die after overdosing on opioids

· From 1996 and 2013, benzodiazepine prescription increased by 67%, from 8.1 million to 13.5 million

· Many people are prescribed both drugs simultaneously

· In 2016, the Centers for Disease Control and Prevention (CDC) issued new guidelines for the prescribing of opioids. They recommend that clinicians avoid prescribing benzodiazepines concurrently with opioids whenever possible

· Both prescription opioids and benzodiazepines now carry FDA "black box" warnings on the label highlighting the dangers of using these drugs together

Pathophysiology:

· Opioids act on the opioid receptor, most prominently the µ-opioid receptor, is associated with the analgesic, respiratory depressant and rewarding effects of opioids

· Opioids’ main effect is a reduction in respiratory rate which is caused by its direct inhibitory effects on mu receptors in the brainstem

· Benzodiazepines are agonists of the GABAa receptor and predominantly bind the a1 and a2 subunits of this receptor, inhibiting neuronal signal transmission

· Benzodiazepine respiratory depression is primarily characterized by a reduction in tidal volume

· The affinity of the various types of benzodiazepines to the alpha units on the GABAa receptor determines their predominant clinical effect (i.e., sedation or anxiolysis).

· Both benzodiazepines and opioids reduce upper airway patency and cause obstructive apneas and hypopneas

Interesting Article

This article focused on 29 manuscripts written regarding opioid and benzo interactions and separated manuscripts reviewed based on the clinical context: abuse and addiction, palliative healthcare, inpatient healthcare, and ambulatory healthcare

Abuse and Addiction

· 13 manuscripts identified.

· The use of opioids with benzodiazepines or other centrally acting drugs has increased over the years

· This drug combination increases the risk for mortality significantly.

· Interestingly, patients on methadone replacement therapy may be at higher risk for mortality and severe adverse respiratory events when concomitantly using benzodiazepines, than patients on buprenorphine replacement therapy

Palliative Healthcare

· 1 manuscript identified

· This study found that survival in terminally ill patients was not reduced by concomitant use of an opioid with a benzodiazepine or antipsychotic

· In fact, the chance of surviving longer in this setting was higher

· May be safe in this context, however additional research is needed to corroborate these results

Inpatient Healthcare

· 3 manuscripts identified

· They concluded that combined use of opioids and sedatives are likely to increase the risk for in hospital cardiopulmonary and respiratory adverse events and postoperative mortality

Ambulatory Healthcare

· 12 manuscripts identified

· Looked at a variety of subpopulations including those who are receiving opioids and benzos for chronic non cancer related pain, cancer pain, psychiatric disorders, end stage COPD, and HIV

· Data suggests that the combined use of opioids and benzodiazepines increases the risk for mortality among a variety of subpopulations

Opioids + Gabapentin

· Gabapentin is a drug often used together with opioids to treat chronic pain, and both drugs have been shown to suppress breathing, which can be fatal

· Concomitant opioid use can also increase the amount of gabapentin absorbed by the body, potentially leading to higher risks when these drugs are used together

· When used together there was an association of 49% increased risk of dying from an opioid overdose

Tips:

· Be mindful of the medications you are prescribing to your patients

· Please look on DrFirst and or obtain a list of current medications that patient is taking.

· Opioids + Benzos can lead to a potentially lethal respiratory depression

· Be aware that Opioids and Gabapentin have a similar dangerous interaction causing respiratory suppression and death.

· Make sure the patient has adequate follow up and consider alternative types of analgesia for patients with chronic pain.

References:

https://apm.amegroups.com/article/view/35734/29319

https://nida.nih.gov/drug-topics/opioids/benzodiazepines-opioids

https://www.bmj.com/content/356/bmj.j1224

https://www.cms.gov/Outreach-and-Education/Medicare-Learning-Network-MLN/MLNMattersArticles/downloads/SE19011.pdf