Report Animal Concerns

Changes to Buprenorphine Dosing in Mice and Rats

Drugs Guidelines

Fidelis Pharmaceuticals, the company that produces Ethiqa XR®, the first FDA-indexed extended-release buprenorphine formulation specifically for mice and rats, recently announced a change to the drug’s storage requirements.

Previously, once broached, each vial had to be discarded at 56 days. The company has now collected sufficient data to extend the drug’s storage and use to 90 days post vial broach. This change should be reflected on newly purchased Ethiqa XR® within the next few months. Effective immediately, the manufacturer has also advised that bottles already in distribution and labeled with the 56-day expiration date may be used up to the extended 90-day limit.

If you have additional questions about this change, or about using Ethiqa XR® in your mouse or rat studies, please contact your ULAM Faculty Veterinarian.

Original Announcement from March 8, 2022

Icons of Buprenorphine vials with dosing interval changes and rodent silhouettesAs advancements occur in lab animal medicine, the Animal Care & Use Program is committed to re-assessing our institutional guidelines to ensure that all animals housed on the University of Michigan campus continue to receive the highest standards of care.

To that end, buprenorphine dosing intervals, specifically the injectable formulation(s) of buprenorphine hydrochloride for mice and rats, will soon be changing. These changes, which are outlined in greater detail in the analgesia guidelines for both species (Guidelines on Anesthesia & Analgesia in Mice, Guidelines on Anesthesia & Analgesia in Rats), are the result of a careful review of scientific literature (Foley P, et al. 2019) regarding the effectiveness of twice-a-day buprenorphine dosing in mice and rats.

This study examined all recent data related to buprenorphine dosing in rodents (specifically mice and rats) and concluded that, based on pharmacokinetic (PK) and behavioral data** from multiple publications, twice-a-day dosing (e.g., dosing at 12-hour intervals) was no longer considered adequate for mice and rats.

With the understanding that all Principal Investigators (PIs) and labs impacted by this change need sufficient time to explore available alternatives, consult with their ULAM Faculty Veterinarian, and make the necessary amendments to their protocol(s), updates are being announced now with the expectation that all protocols will be updated no later than July 1, 2022, to align with the new guidance.

**PK data showed therapeutic levels (above 1 ng/mL) for only 4-6 hours in most publications. Behavioral data showed clinical efficacy of up to 8 hours, at most.

About The Changes

This specific dosing change is for the injectable formulation of buprenorphine hydrochloride.

An updated dosing table for both mice and rats is outlined below:

Species

Dose

Mice

0.05 – 0.1 mg/kg

Every 4 – 8 hours

Subcutaneous (SC) or Intraperitoneal (IP)

Rats

0.01 – 0.05 mg/kg

Every 6 – 8 hours

Subcutaneous (SC) or Intraperitoneal (IP)

PIs and labs using buprenorphine in mice and rats will need to ensure that their animals are receiving adequate analgesia to reflect the change in dosing intervals (e.g., transitioning from 12-hour/twice-daily dosing to 8-hour/thrice-daily dosing).

Therefore:

If surgeries are at 6:00 AM, 8-hour dosing would be at:

6:00 AM

2:00 PM

10:00 PM

Depending on the timing of surgeries and staffing in the lab, adjusting to the new intervals (especially if dosing is to occur overnight) may be challenging.

What Should Happen BEFORE July 1?
  • PIs and/or their designees are strongly encouraged to review all available alternatives (e.g., multi-modal analgesia, extended-release buprenorphine – also known as Ethiqa XR®, other classes of analgesics) with their ULAM Faculty Veterinarian to determine the most appropriate option(s) for their animals/studies.
    • If your lab is interested in using Ethiqa XR® for rat studies, please consult with your ULAM Faculty Veterinarian and ULAM Husbandry Supervisor prior to any animal dosing. Due to a high incidence of pica, which could cause serious animal health issues, rats given Ethiqa XR® MUST be housed on paper bedding for 72 hours post-injection.
  • After determining the appropriate drug regimen, PIs and/or the PI Proxy (as assigned in eRAM) should work with the Quality Assurance Team in the Animal Care & Use Office to amend their protocol(s).
  • To avoid any potential delays in drug acquisition or amendment processing, labs are advised to reach out now with any questions or concerns they may have. Please also consider proceeding with protocol amendment(s) as soon as a suitable alternative has been identified.
What Should Happen AFTER July 1?
  • Individuals who are found to be conducting procedures inconsistent with what is outlined in their IACUC approved protocol may be reported for non-compliance, pursuant to standard practices.
  • IACUC inspectors may also ask about these changes during the Fall 2022 round of semi-annual facility inspections.

What are the Alternatives?

There are a variety of available alternatives for labs to consider based on the unique needs of their research projects. These alternatives are outlined in detail below.

Regardless of the option you select, please remember that you should ONLY be dosing based on the details outlined in the IACUC approved protocol for the SPECIFIC study you are conducting.

If your study allows for the use of multi-modal analgesia (using more than one type of analgesic to alleviate pain), alternate buprenorphine dosing schedules may be possible.

Example: Dr. Smith’s lab performs laparotomies in mice. Prior to beginning the surgery, the lab member administers a dose of buprenorphine AND carprofen. Carprofen covers 24 hours’ worth of analgesia. Because the carprofen is also on board, Dr. Smith spoke to his veterinarian and amended his protocol to give buprenorphine twice a day, 8 hours apart, for 48 hours, while also giving carprofen every 24 hours. This is appropriate analgesic coverage for this procedure.

If you are interested in using multi-modal analgesia for your surgeries, schedule a meeting with your ULAM Faculty Veterinarian to discuss appropriate plans.

In 2020, Fidelis Pharmaceuticals made available the first FDA-indexed extended-release buprenorphine formulation (Ethiqa XR®) specifically for mice and rats.

About Ethiqa XR® Dosing & Administration

Mice

Rats

Dose

3.25 mg/kg (0.05 mL in a 20g mouse)

0.65 mg/kg (0.1 mL in a 200g rat)

Dosing Interval

A single subcutaneous dose maintains efficacy for 48 hours in mice**

A single subcutaneous dose maintains efficacy for 72 hours in rats

Administration

Use a 0.5-1.0 mL syringe with a 20- to 23-gauge needle

Use a 0.5-1.0 mL syringe with a 20- to 23-gauge needle

# of Doses per Vial / Cost Per Dose

60 / $6.25 for 20g mouse 

30 / $12.50 for 200g rat 

Precautions

May be obtunded up to 4 hours
post-injection

Not tested in pregnant, lactating, neonatal, or immune-compromised animals 

Nausea with pica seen up to 3 days after injection; rats should only be maintained on paper or soft bedding, NOT wood chip

Not tested in pregnant, lactating, neonatal, or immune-compromised animals 

Adverse Reactions

Weight loss seen in treated mice 

Signs of nausea observed at all dose levels within 24 hours (self-licking, self-gnawing, eating bedding) 

Contraindications

Do not use on mice with pre-existing respiratory deficiencies

Only administer subcutaneously

Do not use on rats with pre-existing respiratory deficiencies

Only administer subcutaneously

Pricing subject to change.

**Several internal studies have shown that a single subcutaneous dose of extended-release buprenorphine provides only 48 hours of pain control in mice; therefore, institutional guidelines differ from the manufacturer’s dosing recommendations for mice.

Important Information About Ethiqa XR®
  • 3mL multi-use vial
  • Once opened, expires in 90 days (please see October 2023 Update below for additional information)
  • Cannot be frozen or aliquoted
  • Institutional guidelines require a 48-hour dosing interval for mice, which differs from manufacturer recommendations
  • If used in rats, the animals MUST be housed on paper bedding for 72 hours post-injection due to pica

Ethiqa XR® is available for purchase through MWI. Contact the ULAM Business Office at ulam-questions@umich.edu( or (734) 764-0277 if you need ordering assistance.

October 2023 Update – Ethiqa XR® Storage & Use:

Fidelis Pharmaceuticals recently announced a change to the drug’s storage requirements.
Previously, once broached, each vial had to be discarded at 56 days.

The company has now collected sufficient data to extend the drug’s storage and use to 90 days post vial broach. This change should be reflected on newly purchased Ethiqa XR® within the next few months.

Effective immediately, the manufacturer has also advised that bottles already in distribution and labeled with the 56-day expiration date may be used up to the extended 90-day limit.

Depending on the EXACT surgical procedures being performed, you may be able to use other classes of analgesics, such as non-steroidal anti-inflammatory drugs (also known as NSAIDs), alone or in combination with local anesthetics.

To determine whether the use of other analgesics will provide appropriate analgesic coverage for the specific procedures your lab performs, contact your ULAM Faculty Veterinarian.

Questions?

Members of both the veterinary care and compliance teams are here to provide the guidance and assistance necessary for ensuring a smooth transition in your analgesic plans and can address any questions or concerns you may have about buprenorphine dosing changes.

  • For questions about drug dosing, proper analgesia, or surgical techniques, contact your ULAM Faculty Veterinarian. If you don’t know your veterinarian, send an email to ulam-questions@umich.edu and your question will be routed appropriately.
  • Questions about protocol amendments or programmatic compliance should be directed to the Quality Assurance Team in the Animal Care & Use Office at ACUO-RCAs@umich.edu.

Additional Resources & More Information

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