Analgesia in Research Animals
Approved: December 18, 2003 Revised: October 25, 2012, July 18, 2013
Pain usually results from stimuli that damage tissue or have the potential to damage tissue. Unrelieved pain can lead to unacceptable levels of stress and distress in animals, resulting in spurious or inconsistent experimental results. Numerous studies indicate that both laboratory animals and humans receive and process painful stimuli using similar mechanisms and thresholds of awareness. The maximum tolerance for pain varies between species and between individuals of the same species, including humans. Since it is disadvantageous for non-human animal species to display signs of pain (due natural selection by predators), animals often do not show signs of pain (or show minimal atypical signs of pain). In accordance with these notions, Federal regulations in the U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training, state that “…minimization of discomfort, distress, and pain when consistent with good scientific practices, is imperative. Unless the contrary is established, investigators should consider that procedures that cause pain or distress in human beings may cause pain or distress in other animals. Furthermore, the National Institutes of Health (N.I.H.) state that “Procedures that may cause more than momentary or slight pain or distress to the animals will be performed with appropriate sedation, analgesia, or anesthesia, unless justified for scientific reasons in writing by the investigator.”
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 or other justified reason to the contrary, investigators
must administer analgesics for procedures associated with more than momentary
or slight pain in animals.
Protocols for administering analgesics are better developed for some species (e.g., dogs) than others
(e.g., rodents), and each type of analgesic may have different efficacy in the alleviation of different kinds of pain. Therefore investigators should consult with DCM or WaNPRC veterinary services teams when designing an analgesia regimen for their animal care and use protocol.
Issues to Consider
- The evaluation of potential pain is complex because thresholds and manifestations of pain and distress vary among species and among individuals within a species.
- The determination of what constitutes pain in animals is further complicated by the fact that there are no universal criteria for assessing or determining what is, or is not, painful to an animal.
- Many animals, especially prey species such as rodents and birds, have evolved to hide signs of pain, especially when humans are present. Thus, it can appear to the observer that these species are not exhibiting behaviors indicative of pain, when in fact, there are subtle signs that can be seen with the use of cameras and trained observers.
- 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.
Indications for Use
Operative procedures which cause pain in humans should be expected to cause pain in animals. In determining which procedures require postoperative analgesia, several factors should be considered, including:
- 1. The 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?
- What is the behavior of the animal during postoperative period? (e.g., level of activity attitude, appetite, hydration status, weight loss, roughness of hair coat compared to sham anesthetized controls.)
Peri-operative analgesia: Peri-operative (during the period of time a procedure or surgery is taking place) analgesia is generally recommended. Superior pain control is usually provided when analgesics are provided preemptively. Some anesthetic regimens contain anesthetics that have analgesic activities such as both ketamine and xylazine in the ketamine/xylazine mix commonly used in rodents. Other anesthetics (i.e., Avertin, 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. In addition, there are certain drugs that should not be combined. For example, rodents should not receive pre-operative buprenorphine when xylazine is used! This can result in severe respiratory depression. Consult with the veterinary staff when designing new protocols that may require analgesic administration.
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 nonsteroidal anti-inflammatory drugs can be used in combination for severe pain or individually for less severe pain. Please consult with veterinary services regarding side effects, drug interactions, and species-specific variation. See Appendix 1 for recommended drug doses. See Appendix 2 for species-specific signs of pain.
Preemptive administration of post-operative analgesics is required when a painful procedure is performed. Signs of pain are difficult to detect in many animal species and thus a plan must be developed to administer analgesics based on what is known about the invasiveness of the procedure and the likely amount of post-operative pain it will produce. The following lists provide a guide.
In all cases, however, analgesics should be given if signs of pain are observed.
Category 0: Procedure causes only momentary pain and post-operative pain is not expected.
No analgesics are recommended for these procedures.
Procedures likely to cause little to no postoperative pain or discomfort, e.g.:
- 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 notching
- ear tagging
- blood collection by percutaneous venipuncture
Category 1 -Mild pain expected. At least 6 to 12 hours of pre-emptive peri- and post-operative analgesia is recommended. Analgesic administration should be continued if signs of pain are noted beyond this period.
Inhalation anesthetics, pentobarbital and Avertin 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 Veterinary Services (firstname.lastname@example.org) or the WaNPRC veterinary services for clarification as needed.
Procedures likely to cause minimal or mild postoperative pain or discomfort, e.g.:
- relatively non-invasive catheter or electrode placement
- skin incisions, suture or wound clip placement such as skin biopsies
- dental cleaning
- SC 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 4 weeks of age (anesthetized)
- rectal or vaginal biopsy (some could be category 2)
Note: As more research is done, these recommendations may change!
Category 2 – Moderate pain of longer duration expected. Peri-operative analgesia plus 48 hrs 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), e.g.:
- castrations (ovariectomies, neuters, spay)
- c-section (depending on the species)
- embryo transfer surgery
- 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
- most endoscopic surgeries with minimal tissue manipulation (some could be category 1)
- partial thickness skin wounds
Category 3 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, e.g.:
- 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
- gastro-intestinal surgery, e.g. enterotomy
- peripheral nerve injury
- c-section (depending on the species)