Analgesia in Research Animals

Policy

Unless there is a scientific reason to the contrary and approved by the IACUC, investigators must administer analgesics for procedures associated with more than momentary or slight pain in animals.

The IACUC acknowledges that procedures for administering analgesics may be better developed for some species (e.g., dogs) than others (e.g., rodents), and each type of analgesic may have a different efficacy in the alleviation of different kinds of pain. One should also consider that the alleviation of pain and distress is often a diverse task that may require drugs, adjustments to environmental enrichment, modifications in research protocols, and other appropriate and humane strategies.

Investigators should consult with DCM or WaNPRC Veterinary Services teams when designing a plan to alleviate pain and distress for their IACUC protocol. When establishing analgesic plans, pre-emptive analgesics should be used and multi-modal analgesia should be utilized whenever possible (e.g., combinations of local anesthetics and systemic medications that utilize different pathways).

Indications for Use:

Surgical or other procedures that cause pain in humans should be expected to cause pain in animals. Consider the following when developing appropriate pre-, intra-, and post-operative analgesic plans.

1. Invasiveness of the procedure:

• Are body cavities invaded?
• Are especially sensitive tissues involved, e.g., weight-bearing bones, joints or teeth?
• Is there significant tissue manipulation or inflammation?
• Is there substantial impairment of physical or physiologic functions?

2. The degree of severity of pain expected:

• How painful is a similar procedure in humans?
• How is the behavior of the animal during post-operative period? (e.g., level of activity, attitude, appetite, hydration status, weight loss, roughness of hair coat compared to sham anesthetized controls.)

Superior pain control is usually provided when analgesics are provided preemptively. Some anesthetic regimens contain anesthetics that have analgesic properties, such as ketamine and xylazine in the ketamine/xylazine mix commonly used in rodents. Other anesthetics (i.e., propofol, pentobarbital, most inhalation anesthetics such as isoflurane) have no analgesic properties and must be used with an analgesic when a painful procedure is performed.

Some form of analgesia must be “on board” prior to recovery from anesthesia, which means that the pharmacokinetic onset of action (the interval between administration and establishment of blood concentration correlated with analgesic efficacy) of the analgesic(s) must be considered.

For example, in most species, buprenorphine takes about 30 minutes from the time of injection to reach therapeutic levels in the blood. Thus, an injection of Buprenorphine should be given at least 30 minutes before recovery from anesthesia. In many cases, this is achieved by administering the analgesic prior to or at the very beginning of the painful procedure. In some cases, administering certain analgesics prior to anesthetic recovery can complicate the anesthesia recovery by potentiating the respiratory depression of the primary anesthetic. In these situations, immediate, short-termanalgesia could be provided by injection of a local anesthetic at the incision site, and/or administration of a nonsteroidal anti-inflammatory drug (NSAID) prior to surgery.

Administration of analgesics should be a multi-modal approach whenever possible. Local anesthetics (lidocaine and bupivacaine) are commonly used and have few side effects. In addition to local anesthetics, opioids and NSAIDs can be used in combination for potentially severe pain or individually for less painful procedures. Consult with Veterinary Services regarding side effects, drug interactions, and species-specific variation. See Appendix 1 for DCM recommended drug doses. See Appendix 2 for species-specific signs of pain.

The following lists provide general analgesic recommendations for categories of procedures, based on invasiveness and expected post-operative pain. Depending on the species, the expected pain from some procedures may require a longer duration of analgesic use than what is indicated in the lists. All potentially painful procedures must include post-procedural monitoring within the approved protocol to allow for evidence of pain that is not controlled as predicted with the analgesic regimen. In all cases, analgesics should be given if signs of pain are observed.

Category 0 – Procedures which cause only momentary pain, and post-operative pain is not expected. No analgesics are recommended for these procedures.

Procedures likely to cause little to no post-operative pain or discomfort:

• placement of transponder with a needle
• injections of substances with low irritation potential
• tail biopsy (less than 3 mm of tail) in mice less than 21 days old
• ear punch biopsy notching
• ear tagging
• blood collection by percutaneous venipuncture
• endoscopy without biopsy

Category 1 – Minimally invasive; mild post-operative pain expected. At least 6 to 12 hours of preemptive peri- and post-operative analgesia is recommended. Analgesic administration must be continued if signs of pain are noted beyond this period.

Inhaled anesthetics and pentobarbital have little to no peri-operative or post-anesthesia analgesic properties, and analgesics must be used in conjunction with these agents. In some cases, some short-term peri- and post-operative analgesia may be provided by the choice of agents used for anesthesia. Please consult with DCM or WaNPRC Veterinary Services teams for clarification as needed.

Procedures likely to cause minimal or mild post-operative pain or discomfort:

• relatively non-invasive catheter or electrode placement
• skin incisions, suture or wound clip placement, such as skin biopsies
• dental cleaning
• subcutaneous implant of mini-osmotic pump in rodents
• bone marrow aspirates
• cranial implants (cannulas) or intracranial injections
• intrathecal catheter
• vasectomy in mice
• tail biopsy (less than 3mm of tail) in mice greater than 21 days old (anesthetized)
• tail biopsy (greater than 3mm of tail) in mice at any age (anesthetized)
• rectal or vaginal biopsy (some could be Category 2)
• usage of stereotaxic instrument with ear bars for head restraint
• endoscopy with biopsy

Category 2 – Moderately invasive; moderate pain of longer duration expected. Peri-operative analgesia plus 48 hours of post-operative analgesics are required. Analgesic administration must continue if signs of pain are noted beyond this period.

Procedures likely to cause moderate pain or discomfort of a longer duration (48 hours):

• castration, ovariectomy, neuter, or spaying
• c-section (depending on the species)
• embryo transfer surgery
• thymectomy
• laparotomies including splenectomies, kidney capsule transplant, nephrectomy in rodents
• invasive electrode or catheter placement (peritoneum or thorax)
• cutaneous mass removal (could be Category 1 depending on the situation)
• extraocular surgery
• laparoscopic procedure
• partial thickness skin wounds

Category 3 – Invasive; moderate to severe pain, longer duration expected. Peri-operative analgesia plus 3-7 days of post-operative analgesics are required. Analgesic administration must be continued if signs of pain are noted beyond this period.

Procedures likely to result in moderate, severe or prolonged pain or discomfort:

• extensive dissection of soft tissues
• entry to the pleural or peritoneal cavity with significant tissue trauma
• intraocular surgery
• orthopedic or dental surgery
• dissection into joints
• reperfusion/ischemia
• gastro-intestinal surgery, e.g. enterotomy
• burns
• peripheral nerve injury
• c-section (depending on the species)