Analgesia in Research Animals

Policy

In a continuing attempt to balance the research objectives and the legal and moral obligation to alleviate pain in laboratory animals, the University of Washington has adopted the following position:

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

Procedures for administering analgesics are better developed for some species (e.g., dogs) than others (rodents), and each type of analgesic may have 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. Therefore, investigators should consult with DCM or WaNPRC Veterinary Services teams when designing a plan to alleviate pain and distress for their IACUC protocol.

Indications for Use:

Surgical or other procedures that cause pain in humans should be expected to cause pain in animals. In determining which procedures require post-operative analgesia, several factors should be considered, including:

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?

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, even a minor procedure, is performed. Some form of analgesia must be “on board” when the animal recovers from anesthesia, which means that the pharmacokinetic onset of action of the analgesic(s) used must be considered (the interval between administration and establishment of blood concentration correlated with analgesic efficacy). For buprenorphine, this interval is at least 30 minutes. In many cases, this is simply achieved by administering the analgesic prior to or at the very beginning of the painful procedure. In some cases, administering the primary analgesic prior to anesthetic recovery can complicate the anesthesia recovery by potentiating the respiratory depression of the primary anesthetic (e.g., a mouse surgery in which ketamine/xylazine is the anesthetic and buprenorphine is the analgesic). In this situation, immediate, short-term post-operative analgesia can be provided by injection of a local anesthetic at the incision site, and/or administration of one pre- or peri-operative dose of a nonsteroidal anti-inflammatory drug (NSAID), neither of which pose a risk of causing excessive respiratory depression in conjunction with certain anesthetics.

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. In all cases, however, 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 of rodents less than 28 days (less than 3 mm of tail)
• ear punch biopsy or 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 should 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 in mice greater than 28 days (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 should be continued 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)